William C. Zamboni
Topoisomerase I–targeting agents, such as the camptothecin analogs, belong to a class of anticancer drugs that target the DNA-relaxing enzyme topoisomerase I. The first identified compound in this class, camptothecin, is a naturally occurring alkaloid found in the bark and wood of the Chinese tree Camptotheca acuminata. The camptothecins have generated broad interest, both as a research tool for studying the molecular function and activity of DNA topoisomerase I and as therapeutic agents with proven activity in the treatment of various human malignancies.
As early as the 1950s, a National Cancer Institute screening program discovered that extracts derived from the Camptotheca tree were cytotoxic to cancer cells. Not until 1966, however, did Wall and colleagues identify camptothecin as the active agent.1 Biochemical studies performed in the early 1970s of the pharmacology of camptothecin showed that it could damage DNA,2 ultimately inhibiting both DNA and RNA synthesis3, 4, 5, 6, 7, 8, 9, 10; the mechanisms underlying these drug actions remained obscure. Because of promising preclinical activity, the drug entered clinical trials in the early 1970s under National Cancer Institute sponsorship. Because of its insolubility in aqueous solutions, camptothecin was formulated as its sodium salt (NSC-1000880). In early clinical studies, a few responses were observed in patients with colorectal, stomach, small-bowel, and non–small cell lung cancers (NSCLC) and melanoma. Unfortunately, severe toxicities, including hemorrhagic cystitis, nausea, vomiting, diarrhea, and dose-limiting myelosuppression, were also observed.11, 12, 13When limited phase II testing failed to demonstrate meaningful antitumor activity in gastrointestinal cancers14 and malignant melanoma,15 further clinical development was halted.
Important advances in the 1980s led to a resurgence of interest in the camptothecins. First was the discovery that camptothecin had a unique molecular target, DNA topoisomerase I, a key nuclear enzyme responsible for relaxing torsionally strained DNA.16, 17 Currently, the camptothecins remain the best-characterized inhibitors of topoisomerase I. Corporate interest in this field led to the synthesis of more soluble and less toxic camptothecin analogs with even greater preclinical anticancer activity, such as irinotecan (CPT-11) and topotecan.18, 19 In 1996, topotecan hydrochloride (Hycamtin) was approved in the United States for use as second-line chemotherapy for patients with advanced ovarian cancer, and in that same year, irinotecan hydrochloride (Camptosar) was approved for use in patients with 5-fluorouracil (5-FU)–refractory advanced colorectal cancer. Additional camptothecin analogs currently in clinical testing include 9-nitrocamptothecin (9-NC), lurtotecan (GG211, GI47211), exatecan mesylate (DX8951f), diflomotecan (BN80915), karenitecin (BNP1350), and gimatecan (ST1481). Several noncamptothecin agents that also interact with topoisomerase I have entered clinical trials, including NB-506, intoplicine (RP60475), TAS 101, and (N-[2-(dimethylamino) ethyl] acridine-4-carboxamide. The development of these new agents may further increase the importance of topoisomerase I as a target for cancer chemotherapy.20
MECHANISM OF ACTION
DNA topoisomerases are essential enzymes found in all nucleated cells. These enzymes are involved in the regulation of DNA topology and are necessary for the preservation of the integrity of the genetic material during DNA metabolism, including RNA transcription, DNA replication, recombination, chromatin remodeling, chromatin condensation, and repair during cell division.21, 22 Based on their different reaction mechanism and cellular function, there are two types of DNA topoisomerases (type I and type II). Their characteristics are summarized in Table 17.1.
Human topoisomerase I is a monomeric ~91 kd polypeptide of 765 amino acids encoded by an active copy gene located on chromosome 20q12-13.2 and two pseudogenes on chromosomes 1q23-24 and 22q11.2-13.1.23, 24, 25 The coding sequence of the gene is split into 21 exons spread over at least 85 kilobase pairs of human genomic DNA. The human topoisomerase I gene promotor is influenced by positively and negatively acting transcription factors, as described elsewhere.26
This protein is comprised of four major domains: a highly charged NH2-terminal domain, a conserved core domain, a positively charged linker domain, and a highly conserved COOH-terminal domain containing the active site tyrosine, that is, the nucleophilic Tyr723 amino acid residue.25, 27 The relaxation of torsionally strained (supercoiled) duplex DNA by human topoisomerase I, with subsequent transcription and replication, is independent of charge (positively or negatively).25 A transesterification reaction takes place by which topoisomerase I cleaves one strand of the double-helix structure of DNA, attacking the C4-oxygen atom of the active site tyrosine (Tyr723) residue. The enzyme forms a transient, covalent phosphotyrosyl intermediate with the 3′-end of the nicked DNA strand, the so-called cleavable complex.28 Afterwards, the energy of this covalent attachment is recycled for the reverse transesterification reaction that reseals the DNA strands (religation) and liberates the enzyme. Consequently, for these intertwining processes neither energy cofactors nor metal cations are required by human topoisomerase I.29 Recent studies have provided more detailed insights into the three-dimensional structure of human topoisomerase I and its interactive function with the DNA molecule.30, 31 In Table 17.2, the principal structural characteristics of human topoisomerase I are summarized.
TABLE 17.1 DIFFERENTIATION OF HUMAN DNA TOPOISOMERASES TYPE I AND II
The mechanism of DNA relaxation after formation of the covalent complex and before religation is still not completely elucidated.30 So far, two mechanisms are supposed, viz. the strand passage model and the free rotation model. Both models represent the two extremes of a continuum in the conceptual framework for how topoisomerase I might effect changes in linking number.30, 31 In the strand passage (or enzyme-bridging) model, it is hypothesized that the intact DNA strand is passed through an enzyme-bridged gate, which is made by the covalent linkage of the 3′ end and by noncovalent binding to the 5′ end of the broken strand. On the other hand, in the free rotation model, relaxation of torsionally strained duplex DNA is possible due to the releasing of the 5′ end of the broken strand from the active site and its consequent ability to rotate freely about the complementary unbroken strand.25, 31 X-ray crystallographic studies with complexes of human topoisomerase I and DNA led to the proposal that the relaxation of supercoiled DNA proceeds by a controlled rotation mechanism.30, 31
In the controlled rotation model, the DNA structure is allowed to rotate completely free at 30S°S intervals downstream of the cleavage site round the intact DNA strand modulated by the interaction of the nose-cone helices of subdomain I and II in a positively charged cavity formed by the cap of the enzyme and the linker domain.25 In vitro studies with reconstituted human topoisomerase I have revealed the more precise function of the linker region. During the normal relaxation of supercoiled DNA, it acts to slow the relegation.27 From these studies, it is also hypothesized that the inhibition of DNA relaxation caused by camptothecin—by stabilizing the cleavable complex—depends on a direct effect of the cytotoxic agent on DNA rotation that is mediated by electrostatic interactions between the linker domain and DNA.27
When the attachment of camptothecin is modeled in the three-dimensional structure of human topoisomerase I, it is believed that the DNA duplex is extended in such a way that carbon positions 7 and 9 of the camptothecin structure are facing out into open space. These carbon positions are very accessible to chemical modifications. Consequently, this gives the opportunity to expand the potency of modified camptothecin analogs by auspicious interactions of these derivatives with distant proteins or DNA atoms at the binding site.31
TABLE 17.2 STRUCTURAL CHARACTERISTICS OF HUMAN DNA TOPOISOMERASE TYPE I
Stabilization of the cleavable complex by camptothecins is not sufficient in itself for the induction of cell death because the complex can reverse spontaneously. The lethal effects of these drugs are caused by the interaction between a moving replication fork (or transcription process) and the drug-stabilized cleavable complex, resulting in irreversible arrest of DNA replication and the formation of a double-strand break located at the fork. This so-called fork collision model leads to the arrest of the cell cycle in the S/G2 phase and finally to apoptosis.32 As cells in the S phase division are up to 1,000-fold more sensitive to topoisomerase I inhibitors than cells in the G1 or G2/M phases after exposure, the cytotoxicity of these agents is considered S-phase specific.33,34, 35
The time of persistence of the drug-stabilized cleavable complex depends on the production and/or repair of replication or transcription lesions. In general, transcription lesions require longer persistence, that is, greater stability of the cleavable complex, than do replication lesions.36 Unfortunately, the fraction of replicating cells in tumor tissues is underrepresented. This means that cell kill results predominantly from the transcription lesion mechanism. For this reason, the potency of different camptothecin analogs to stabilize the cleavable complex is of paramount importance for efficacious therapeutic use.36 Of relevance for all topoisomerase I inhibitors are the data from in vitro experiments that revealed that the cytotoxicity increases with the duration of exposure. Short-time exposures to high concentrations are less effective than long-term exposures to low concentrations.37, 38
Due to their mechanism of action, topoisomerase I inhibitors are potential mutagens, although their clinical mutagenicity and oncogenicity have not been established.39, 40, 41 Furthermore, the tendency to administer topoisomerase I inhibitors using protracted schedules or prolonged exposure regimens could hypothetically lead to an increased risk of mutagenicity.42, 43
The stabilization of the cleavable complexes by topoisomerase I inhibitors disrupts the DNA integrity and interferes with the normal processes of DNA topology, including replication, transcription, DNA repair, chromosome condensation, and chromosome separation.39 The formation of these drug-induced cleavable complexes is essential but is not sufficient in itself to cause cytotoxicity. This implies that cells need to undergo DNA synthesis to yield maximum toxicity.44,45, 46 Experimental studies showed that in the presence of topoisomerase II inhibitors chromosomal aberrations arise during replication, which seems a more important cause of cytotoxicity.47 Furthermore, it was postulated that recombination processes must be initiated to bypass the replication block created by topoisomerase II inhibitor–stabilized complexes and that some of these events cause aberrant, illegitimate, or nonhomologous recombination, which may lead to cytotoxicity and/or mutations. Nonhomologous recombination that causes deletions of an essential gene, partially or completely, resulted in the loss of gene products and finally to cell death. In contrast, aberrant recombination or rearrangement causing deletion of a suppressor gene or activation of a proto-oncogene have the potential to induce secondary cancers.39 Topoisomerase II inhibitors cause an increased risk of acute myeloid leukemia48 characterized by balanced chromosomal translocations involving either the MLL (ALL-1, HRX) gene49 at 11q23 or the AML1 gene50 at 21q22.
In principal, topoisomerase I inhibitors could produce similar molecular alterations as those caused by topoisomerase II inhibitors. Direct comparative in vitro studies have shown that, on a molar basis, the topoisomerase I inhibitors were more mutagenic than the topoisomerase II inhibitor etoposide.39 Topotecan was found to be less mutagenic than the parent compound camptothecin. So far, the clinical use of topoisomerase I inhibitors has not been linked to secondary malignancies. However, the relative survival time of patients treated with irinotecan or topotecan as compared with those treated with anthracyclines and epipodophyllotoxins (e.g., for lymphomas, testicular cancer, or hematological malignancies) possibly indicates a less clinically apparent mutagenic risk associated with topoisomerase I inhibitors.
MECHANISMS OF RESISTANCE
Based on preclinical studies, it is likely that clinical resistance to the camptothecins might be the result of three main mechanisms: (a) alterations in the target (topoisomerase I), (b) inadequate accumulation of drug in the tumor, and/or (c) alterations in the cellular response to the topoisomerase I–camptothecin interaction.51, 52
Alterations in Topoisomerase I
Various point mutations of topoisomerase I in different camptothecin-resistant cell lines have been associated with camptothecin resistance.53, 54, 55, 56, 57, 58,59, 60, 61 The different point mutations in human topoisomerase I in several camptothecin-resistant cell lines are summarized in Table 17.3. These point mutations result in decreased topoisomerase I catalytic activity or impaired binding of camptothecin to topoisomerase I.53, 62 In some models, single amino acid changes resulted in partial resistance, while double mutation induced a synergistic resistance.
TABLE 17.3 DIFFERENT POINT MUTATIONS OF HUMAN TOPOISOMERASE I
In a small clinical study involving eight NSCLC patients treated with irinotecan, two point mutations were identified that were located near a site in topoisomerase I that was previously identified62 as a position of a mutation in the camptothecin-resistant human lung cancer cell line PC7/CPT. Although this is the first prospective clinical study demonstrating that point mutations in topoisomerase I occur after chemotherapy with irinotecan, further clinical studies will be needed to verify if the incidence of topoisomerase I gene mutations relates to the occurrence of clinical resistance to topoisomerase I inhibitors.
Altered Cellular Accumulation and Transport of Camptothecins
The role of the P-glycoprotein (ABCB1)–associated multidrug resistance (MDR) phenotype in camptothecin resistance has still not been clearly defined. Irinotecan and SN-38 do not appear to interact significantly with P-glycoprotein,63 and cross-resistance to irinotecan is not seen in P388 leukemia cells expressing pleiotropic drug resistance to vincristine and doxorubicin.64 In comparative studies, MDR-expressing sublines were nine-fold more resistant to topotecan than were parental wild-type cells.65 Although other investigators have confirmed these findings for topotecan, this degree of MDR-associated resistance is much less than the 200-fold change in sensitivity typically described for classic MDR substrates, such as doxorubicin or etoposide.66, 67, 68
Several camptothecin analogs, including SN-38, topotecan, and 9-aminocamtothecin, are also substrates for other transport systems in addition to P-glycoprotein, such as the MDR-associated protein-1 (MRP1, ABCC1)69 and the breast cancer resistance protein (BCRP, ABCG2),70, 71 and preliminary evidence for the clinical relevance of this observation to in vivo resistance has been provided.72 In human colon cancer xenografts that highly express MDR, irinotecan was still quite effective, even against a cell line resistant to topotecan.73 Thus, different mechanisms of camptothecin resistance may be specific for certain camptothecin analogs. Further characterization of these specific mechanisms of resistance is urgently required.
In addition to active transport, cellular metabolism may be particularly important for irinotecan, which is converted to SN-38 by carboxylesterases.74 Indeed, increased levels of these esterases is associated with increased sensitivity to irinotecan.75, 76 In addition, there is large interindividual variation in expression of carboxylesterases in colon tumors that may contribute to variation in the therapeutic outcome of irinotecan therapy.77, 78 SN-38 is also conjugated and detoxified by UDP-glucuronosyltransferase (UGT) to yield an SN-38-glucuronide.79 Furthermore, glucuronidation of SN-38 is associated with increased efflux of the drug from colon cancer cells,80 and glucuronidation of camptothecins has been associated with altered chemosensitivity of breast cancer and lung cancer cells.81 It is of interest to note that reactivation of SN-38 in tumor specimens by β-glucuronidases might also take place and may represent an important route of tumor drug activation.82
Other potential mechanisms of decreased sensitivity to camptothecins include a reduction in the number of cells in the S phase83 and increased expression of metallothionein.84 Furthermore, double-stranded DNA break repair activity may also modulate camptothecin-induced cytotoxicity. For example, yeast mutants defective in the RAD52 double-stranded DNA break repair gene are hypersensitive to camptothecin.85, 86
The key biochemical or molecular determinants of tumor response to clinical camptothecin therapy have not yet been identified. Because of the complex, stepwise pattern of drug-induced perturbations in cellular metabolism, no single parameter may be able to identify sensitive or resistant tumors completely. Although the overall topoisomerase I activity may be important,87, 88 other factors might also be relevant, including topoisomerase I enzyme mutations, the amount of cleavable complexes formed, and the extent of ongoing DNA synthesis. Total topoisomerase I protein levels in tissues as measured by Western immunoblotting correlate poorly with sensitivity to camptothecins in experimental studies.89 Likewise, total topoisomerase I mRNA does not predict drug sensitivity when different cell lines are compared.90 This poor correlation between total topoisomerase I expression and drug effects may be due either to posttranslational regulation of the enzyme, to subcellular localization of topoisomerase I away from DNA, or to other as yet unidentified factors. Preliminary studies suggest that camptothecin sensitivity may be predicted by changes in topoisomerase I immunofluorescence patterns indicative of translocation of the protein from the nucleus to the cytoplasm. This change occurs during drug treatment.91, 92, 93 Newer methods of purifying topoisomerase I from human tumor tissues have been developed94 and may help to further define our understanding of the important determinants of clinical response to topoisomerase I poisons.
Although DNA cleavable complex formation is necessary but not sufficient for drug toxicity, measurement of these lesions as a predictor of drug effects is an attractive approach.89 The cleavable complex is the specific lesion in the DNA that accumulates within the cell during drug exposure. Clinical measurement of the amount of cleavable complexes formed has been hampered, however, by the lack of sufficiently sensitive tests that can be easily applied to patient tissues.95, 96, 97 One potentially promising approach is the use of ligase-mediated polymerase chain reaction, which does not require radioactive prelabeling of cells to monitor cleavable complex formation.98
Also important, but even less well understood, is the role of events downstream from the formation of cleavable complexes, such as DNA damage repair,99 the triggering of apoptosis,100, 101, 102 and alterations in the integrity of the G2 cell-cycle checkpoint.103, 104 For example, two different colon cancer cell lines with different sensitivity to camptothecin were found to differ in their cell-cycle response.105 In one experiment, the more resistant cells arrested in the G2phase of the cell cycle after camptothecin exposure, whereas the more sensitive cells passed through the G2 checkpoint after experiencing camptothecin-induced damage. The more sensitive cells also showed a greater capacity to arrest in the S phase, and they failed to down-regulate cyclin B–cdc kinase activity after camptothecin exposure. Thus, cell-cycle checkpoint integrity may also be an important determinant of camptothecin sensitivity. Despite the extensive ongoing research in this complex area, however, no single method or molecular marker can as yet reliably predict tumor responsiveness to camptothecins.
CAMPTOTHECIN STRUCTURE-ACTIVITY RELATIONSHIPS
Most of the currently known camptothecin analogs share a basic 5-ring structure with a chiral center located at C20 in the terminal E ring (Fig. 17.1). Structure-activity studies have also shown a close correlation between the ability to inhibit topoisomerase I and overall cytotoxic potency.106 Some important general relationships have emerged from attempts to synthesize improved analogs.107, 108 While these relationships will clearly be refined in the years to come, current knowledge is potentially adequate for the design of improved analogs of camptothecin. This current knowledge is here summarized rather than described exhaustively. For the purpose of this overview, a number of regions in the camptothecin structure are particularly relevant:
1. It has been shown that the topoisomerase I inhibitory activity of these agents is stereospecific, with the naturally occurring (S)-isomer being manyfold more potent that the (R)-isomer.16, 109
2. In general, substitutions at C7, C9, and C10 tend to increase topoisomerase I inhibition and sometimes increase water solubility, whereas substitutions at C12 decrease antitumor activity.110
3. Similarly, additional ring structures (e.g., between C7-C9 or C10-C11) may increase activity.111, 112, 113, 114
4. One of the principal chemical features of this class of agents is the presence of a lactone functionality in the E ring, which is not only essential for antitumor activity but also confers a degree of instability to these agents in aqueous solutions.115 Most camptothecins can undergo a pH-dependent reversible interconversion between this lactone form and a ring-opened carboxylate (or hydroxy acid) form (Fig. 17.1), of which only the lactone form is able to diffuse across cell membranes and exert the characteristic topoisomerase I inhibitory activity. At neutral or physiologic pH, the equilibrium between the two species favors the carboxylate form for all the camptothecins. As outlined, an understanding of this hydrolysis reaction helps to explain several observations in the early development of these agents. The equilibrium between the lactone moiety ring and the carboxylate form of the camptothecins is not solely dependent on the pH, but also on the presence of specific binding proteins in the biological matrix, most notably human serum albumin (HSA). Following establishment of equilibration at 37°C in phosphate buffered saline, equal amounts of the various camptothecin analogs are present in the pharmacologically active lactone form, with values of 17%, 19%, 15%, 13%, and 15% for camptothecin, 9-amino camptothecin (9-AC), topotecan, irinotecan, and SN-38, respectively.116 Addition of 40 mg/mL HSA shifts the equilibrium for camptothecin and 9-AC toward the carboxylate form, with approximately 1% present in the lactone form at equilibrium.117 In contrast to HSA, addition of murine serum albumin to 9-AC leads to approximately 35% existing in the lactone form at equilibrium.117 As opposed to camptothecin and 9-AC, HSA actually stabilizes the lactone moiety of irinotecan and SN-38, with 30% and 39%, respectively, present in the lactone form at equilibrium, while almost no effect was seen for topotecan.116, 118 It has been proposed that the differences in the percentages present in the lactone form at equilibrium are related to sterical considerations of the various substituents at the R1 and R2 positions (Fig. 17.1, panel A). For some of the more recently developed analogs, the substituents cause sterical hindrance and prevent binding of the carboxylate forms to HSA, thus driving the equilibrium towards the lactone species.
Figure 17.1 Structure of camptothecin analogs (modified from reference 532).
Topotecan is a water-soluble camptothecin derivative containing a stable basic side chain at position 9 of the A ring of 10-hydroxycamptothecin (Fig. 17.1). Clinical trials of topotecan were initiated in 1989. In 1996, topotecan was approved in the United States for use as second-line chemotherapy in patients with advanced ovarian cancer, and in 1998 it was approved for the treatment of small cell lung cancer (SCLC) after failure of initial or subsequent chemotherapy. Key features of topotecan are listed in Table 17.4.
TABLE 17.4 KEY FEATURES OF TOPOTECAN
Dosages and Routes of Administration
The most common dose and schedule of topotecan administration is a 30-minute intravenous (i.v.) infusion of 1.5 mg/m2 daily for 5 days every 3 weeks.119,120 This regimen has undergone the most widespread clinical testing, and it is currently the dosage of topotecan approved by the US Food and Drug Administration (FDA) for treating ovarian and lung cancer patients. Five-day continuous infusions of topotecan at 2.0 mg/m2 per day have been tested in patients with hematologic malignancies, although in these studies gastrointestinal toxicities such as mucositis and diarrhea became more problematic.121Based on a promising theoretical rationale,35 prolonged 21-day infusion schedules at 0.5 to 0.6 mg/m2 per day122 have been disappointing in phase II studies.123, 124, 125 Other schedules tested in phase I or phase II studies include a single 30-minute infusion,126 24-hour infusions,127, 128, 129 and 3-day,130, 131 5-day,130, 132 and 14-day continuous infusions.133Oral administration has also been tested clinically134, 135, 136, 137, 138, 139 and has been compared with i.v. administration in two randomized studies.140, 141Finally, intraperitoneal (i.p.),142, 143 intrathecal,144, 145 and individual adaptive, pharmacokinetically guided topotecan studies have been completed.146, 147
Most analytic assays for topotecan in biologic matrices use reversed-phase high-performance liquid chromatography (HPLC) with fluorescence detection (reviewed in reference 148). Deproteinization by rapid precipitation of samples with cold methanol (-30°C) can stabilize the topotecan lactone for later analysis.149 The lactone concentration can then be determined by direct HPLC injection to separate the lactone from the carboxylate forms. In addition, preinjection acidification of plasma samples allows for total plasma topotecan (carboxylate and lactone) to be determined by the same methodology. The plasma carboxylate concentrations are then calculated by subtracting the lactone concentrations from the total drug measurement. A newer validated method for simultaneously measuring both the lactone and carboxylate forms of topotecan in plasma as a single HPLC injection has also been developed,150 and assays for measuring topotecan in other human matrices, including saliva,151 urine, feces,152 whole blood, and erythrocytes have been reported.153
After i.v. topotecan administration, the lactone ring undergoes rapid hydrolysis to generate the carboxylate species.154 Less than 1 hour after the start of an infusion, the majority of the circulating drug in plasma is in the carboxylate form, and this species predominates for the duration of the monitoring period.154In most studies, the ratio of the lactone to total topotecan area under the concentration versus time curve (AUC) ranged from 20% to 35%.155 Interindividual variation in the AUC and the total-body clearance was quite large for both lactone and total topotecan (lactone plus carboxylate).155 In general, plasma concentrations and AUC levels tended to increase with increasing dose levels, consistent with linear pharmacokinetics, although in some studies, nonlinearity in drug clearance at higher dose levels was seen.126, 156
The kinetics of topotecan were analyzed using a linear, two-compartment, open model in most studies.155 For topotecan lactone, the terminal half-life ranged from 2.0 to 3.5 hours, which is relatively short compared with that of other camptothecin analogs. Consequently, no accumulation of drug was observed when it was administered daily for 5 consecutive days.154 The total-body clearance of topotecan lactone after a 30-minute infusion ranged from 25.7 to 155 L/h/m2, and the volume of distribution at steady state ranged from 23 to 25 L/m2. No evidence exists that topotecan kinetics changes with repeated dosing cycles.154Limited sampling models for topotecan pharmacokinetics have been developed157, 158 and applied to clinical pharmacodynamic studies of topotecan in patients in phase II studies.159 The pharmacokinetics of topotecan has also been studied in pediatric populations, and no substantial difference from kinetics in adults has been observed.128, 131, 160, 161 Finally, population pharmacokinetic studies in patients treated with i.v. or orally administered topotecan revealed that patient characteristics (i.e., gender, height, weight) and laboratory values (i.e., serum creatinine concentration) give a moderate ability to predict the clearance of topotecan in an individual patient.162, 163, 164, 165, 166, 167 Although a significant correlation between the clearance of topotecan and patient age has not been established, pharmacokinetic results of a larger number of elderly patients are warranted in order to make more definite conclusions on this specific issue.
The most common route for topotecan administration has been i.v.; however, oral formulations using prolonged administration schedules have undergone preclinical168 and clinical testing.138, 169, 170 Animal studies demonstrated an oral bioavailability of approximately 28% and antitumor efficacy equivalent to that with parenteral treatment in four of the five murine models studied.168 In humans, the reported oral bioavailability ranged from 30 to 42%.134, 136 Plasma concentrations peaked within one hour after oral ingestion, and no difference in the lactone-carboxylate ratio was observed when oral dosing was compared with i.v. administration. Coadministration of food slightly deceased the rate of absorption, but it did not affect the amount of drug absorbed.134
The oral bioavailability of topotecan is influenced by many different factors. First, the relatively high pH in the small bowel leads to conversion to the carboxylate form, which is poorly absorbed by the intestinal walls.171 Second, the bioavailability is reduced by protein-mediated, outward-directed transport of topotecan by ABCG2.172 Third, the bioavailability is partly influenced by the binding of topotecan to food, proteins, and intestinal fluids and/or by decomposition in the gastrointestinal fluid.
From a clinical point of view, as long as equivalent safety and efficacy can be ensured, the majority of patients prefer oral instead of i.v. administration of chemotherapy,173 predominantly due to the convenience of administration outside a clinical setting and avoidance of vascular complications related to i.v. access, including catheter-associated infections or potential thrombosis.170
From a pharmacological point a view, the oral route of topotecan administration has some disadvantages.
Absorption of topotecan from the gastrointestinal (GI) tract is a prerequisite for its activity, but this process can be influenced by several factors. Delays or losses of the drug during absorption may contribute to variability in drug response or may even result in failure of the treatment.170 Both anatomical and physiological factors affect the overall rate and extent of absorption from the GI tract, and they influence the precise quantitative prediction. Ideally, a cytostatic drug should have little interpatient variability in absorption and AUC and, even more important, little intrapatient variability with successive doses.174 As an inverse relationship is demonstrated between decreasing absolute bioavailability of drugs and the interindividual variation in bioavailability, it is recommended that caution be taken in prescribing oral drugs with low oral bioavailability, as the therapeutic index is narrow, and thus either toxic or subtherapeutic dosing may easily occur. For instance, given the relatively low bioavailability of orally administered topotecan and the relatively high variability in the AUC both between patients and within the same patient, this issue of a narrow therapeutic index is clearly demonstrated for the oral administration of topotecan at its maximum tolerated dose (MTD).
The variability of pharmacokinetics of orally administered topotecan can be explained in part by the affinity for drug-transporting proteins expressed in the intestinal epithelium and directed toward the gut lumen. Currently, two major classes of drug pumps, including P-glycoprotein (ABCB1) and ABCG2, have been characterized that may play a role in mediating transmembrane transport of topotecan.172 These proteins belong to the large superfamily of ATP-binding cassette transporters found in almost all prokaryotic and eukaryotic cells. The characteristic tissue distribution of these drug transporters strengthens the indication that they play an important role in detoxification and protection against xenobiotic substances. In vivo studies with genetic knockout of murine Abcb1 and Abcg2 genes revealed that the intestinal absorption of topotecan was increased in the absence of the transporters.172 These experimental studies led to the development of clinical trials of anticancer drugs modulated by coadministration of inhibitors of P-glycoprotein and ABCG2. Recently, a proof-of-concept study in 16 patients with solid tumors was reported in which topotecan was administered in the presence and absence of GF120918, a potent inhibitor of ABCG2 and P-glycoprotein.175 This study showed that the coadministration of the inhibitor of the drug transporters significantly increased the systemic exposure of oral topotecan, with the mean AUC of total topotecan increasing from 32.4 ± 9.6 µg•h/L without coadministration of GF120918 to 78.7 ± 20.6 µg•h/L with coadministration of GF120918 (P = .008). Furthermore, the apparent oral bioavailability increased significantly from 40 to 97.1% (P = .008).
Other routes of topotecan administration have been tested in preclinical or clinical models. The pharmacokinetics of intrathecally administered topotecan was studied in nonhuman primates and pediatric patients.128, 176 Intraventricularly administered topotecan showed a 450-fold relative pharmacologic advantage compared with systemic administration. No clinically significant acute or chronic neurologic toxicities were associated with intrathecal drug administration, which suggests that this may be a promising means of delivering this agent to patients with CNS tumors. I.p. topotecan administration was studied in nude mice bearing peritoneally implanted human ovarian cancer xenografts.177 Excellent antitumor efficacy and modest systemic toxicity were observed, but pharmacokinetic monitoring was not performed, so a rigorous assessment of the relative pharmacokinetic advantage for this regional drug delivery approach could not be made. A phase I study on the i.p. administration of topotecan revealed that the MTD was 20 mg/m2 once every 3 weeks delivered by the i.p. route, achieving cytotoxic plasma levels of topotecan, with acceptable toxicity and avoidance of myelotoxicity.143 I.p. total topotecan was cleared from the peritoneal cavity at 0.4 ± 0.3 L/h/m2 with a half-life of 2.7 ± 1.7 hours. The mean peritoneal to plasma AUC ratio for total topotecan was 54 ± 34%.143 These data were in good agreement with those from a phase I study using a topotecan 24-hour continuous i.p. infusion.142 The terminal half-life for peritoneal topotecan and for plasma total topotecan were similar for both studies. These data suggest that it would be possible to combine the i.p. administration of topotecan with other active chemotherapeutic agents. Further efficacy testing of regional topotecan delivery for patients with ovarian cancer was recommended.
In experiments in rhesus monkeys, cerebrospinal fluid (CSF) topotecan lactone concentrations were approximately 32% of simultaneous plasma levels, and these concentrations tended to decline in parallel over time.178, 179 A physiologic pharmacokinetic model based on these primate experiments was developed and may help guide future investigations of topotecan's activity against CNS tumors.179 The pharmacokinetic findings were confirmed in children who received topotecan by 24- or 72-hour continuous i.v. infusions.180 The median CNS penetration of topotecan lactone and total drug was 29% (range, 10 to 59%) and 50% (range, 11 to 97%), respectively. Due to its hydrophilic properties, topotecan showed a moderate steady-state apparent volume of distribution, approximately only 2 times the body weight for the lactone species and total drug. In comparison with other camptothecin analogs, the fraction of topotecan bound to plasma proteins is much lower. Possibly, this property accounts for the more efficacious penetration of topotecan in cerebrospinal fluid,181, 182 pleural fluid, and ascites183 than occurs with other camptothecin derivates. Furthermore, the plasma pharmacokinetics of topotecan did not change due to the presence of third spaces (i.e., ascites and/or pleural effusion).183 The ratio between the exposure to topotecan in the third space and in the plasma compartment was 55%. Consequently, topotecan can be safely administered to patients with malignant ascites and pleural effusion, and it might contribute to local tumor effects due to its substantial penetration in the third space.183
Figure 17.2 Structures of topotecan metabolites.
Recently, an N-desmethyl metabolite of topotecan was characterized184 and found to be present at relatively low concentrations in human plasma, urine, and feces after i.v. administration of topotecan (Fig. 17.2).152 Although a specific interaction with drug metabolism enzymes has not been established, preliminary clinical data suggest enhanced topotecan clearance in pediatric patients simultaneously receiving treatment with agents that induce hepatic cytochrome P-450 enzymes, such as dexamethasone, phenobarbital, and phenytoin.185 Furthermore, a very low topotecan clearance was described in another patient who was taking terfenadine simultaneously.161 These observations are consistent with a potential drug interaction at the level of CYP3A; however, additional studies on the metabolism and excretion of topotecan and its potential for drug interactions are clearly warranted.186
Topotecan and its main metabolite can also undergo further metabolism into a UGT-mediated glucuronide product (i.e., topotecan-O-glucuronide and N-desmethyl topotecan-O-glucuronide).187 This is a reversible transformation because β-glucuronidase is able to reform topotecan and N-desmethyl topotecan. Because topotecan is metabolized in the liver only to a minor extent, it is not surprising that the pharmacokinetics in patients with impaired liver function did not significantly differ from those in patients with normal hepatic function.188 In contrast, patients with moderately impaired renal function had significantly reduced plasma clearance.189 As a consequence, dose modifications are recommended for patients with impaired renal function and are not required for patients with liver dysfunction.
Elimination of the lactone form is thought to result mainly from the rapid hydrolysis to the carboxylate species followed by renal excretion of the open-ring metabolite.154 Overall, 25 to 49% of the dose administered is excreted as total drug (lactone plus carboxylate) in the urine over a 24-hour period,155 with a few studies performed in pediatric patients reporting recovery of over 90% of the administered drug during more prolonged urinary collection periods.190, 191Furthermore, approximately 18% and 33% of the i.v. and oral dose of topotecan, respectively, was excreted unchanged in the feces. As mentioned earlier, in patients with impaired renal function, the clearance of total topotecan is reduced—there is a 33% decrease in patients with a creatinine clearance (CrCl) ranging from 40 to 59 mL/minute and a 75% decrease in patients with a CrCl ranging from 20 to 39 mL/minute—compared with patients with normal renal function (i.e., CrCl ≥ 60 mL/minute).189 In patients with reduced renal clearance of topotecan, a second plasma peak was seen after the end of infusion due to increased bile excretion, which, in turn, leads to enterohepatic recycling.192 Nevertheless, this is likely not of clinical relevance. Because altered clearance of topotecan has been observed in patients with impaired renal function,189 dosage adjustments for this special population have been recommended (see earlier section). Topotecan was concentrated in the bile at levels 1.5 times higher than simultaneous plasma concentrations in one patient with an external biliary drainage catheter, which suggests that excretion through this route may also be important.126 As expected, no change in topotecan kinetics was observed in a clinical study of patients with moderately impaired hepatic function.188
Pharmacodynamic correlations between parameters of systemic drug exposure and topotecan drug effects have been observed inconsistently.19, 193, 194 In a pediatric study, the topotecan total (lactone plus carboxylate) AUC and lactone plasma AUC correlated with the percentage change in the platelet count and the granulocyte count after a 72-hour drug infusion.161 Similar correlations between leukocyte or granulocyte counts and total topotecan AUC or topotecan dose have been reported after a 30-minute infusion of topotecan given daily for 5 days,154 after 20-minute infusions every 3 weeks,126 and after 24-hour continuous infusions.156 In each case, measurement of the total topotecan plasma concentration was as informative about drug effects as the lactone drug levels. Thus, the need to measure lactone drug concentrations has been questioned by some investigators.119 Finally, although interpatient variability in topotecan plasma concentrations is high, the total variability in hematologic toxicity in patients is relatively low when the drug is administered according to standard dosing guidelines.155 Thus, therapeutic drug monitoring is not useful for this agent. In a clinical study examining sequences of topotecan and cisplatin, the prior administration of cisplatin resulted in substantially greater hematologic toxicity.195 A pharmacokinetic interaction causing a transient reduction in topotecan clearance when this agent was administered after i.v. cisplatin was thought to be related to subclinical renal tubular toxicity induced by the platinum analog,195 although this could not be confirmed in subsequent studies.196, 197 More recently, it has been suggested that the administration of topotecan on days 1 to 4 and docetaxel on day 4 resulted in an approximately 50% decrease in docetaxel clearance and was associated with increased neutropenia.198
The dosage regimen of topotecan approved for clinical use is 1.5 mg/m2 per day given as a 30-minute i.v. infusion daily for 5 days every 3 weeks. Dose-related, reversible, and noncumulative myelosuppression is the most important side effect of topotecan.199 Neutropenia—the nadir is usually approximately 9 days after the start of the treatment, and the median duration is approximately 7 to 10 days—occurred more frequently and is often more severe than thrombocytopenia. Also, neutropenia was more severe in heavily pretreated patients than in minimally pretreated patients.199 Besides myelosuppression, stomatitis (24 to 28% of patients) and late-onset diarrhea (40%) were noted at higher doses.19 Other nonhematological toxicities reported included alopecia (76 to 82% of patients), nausea (75 to 78%), vomiting (53 to 64%), fatigue (30 to 41%), and asthenia (21 to 22%) (reviewed in reference 199).
Numerous phase I clinical trials with topotecan using different schedules of drug administration have been performed.155 Based on the in vitro data on long-term exposure and the fact that efficacy of the drug has been demonstrated to be dependent on the schedules of administration, two schedules have been selected for phase II studies. First, a 30-minute i.v. infusion daily for 5 consecutive days every 3 weeks at a dose of 1.5 mg/m2 per day has been used. In this schedule, the dose-limiting toxicity is short-lasting, noncumulative myelosuppression.119, 120, 200 Nonhematological toxicities are usually mild and reversible and include nausea, vomiting, fatigue, alopecia, and sometimes diarrhea. Phase II studies with the drug administered in this schedule revealed response rates ranging from 9.5 to 25% in pretreated patients with ovarian cancer and response rates of 10 to 39% in patients with SCLC.201, 202, 203 In addition, a comparative, randomized, multicenter trial in which patients with recurrent ovarian cancer were treated showed that topotecan was at least as effective as paclitaxel in terms of response rate (20% vs. 13%), median duration of response, and median time to progression.204, 205, 206, 207, 208, 209, 210 In other tumor types, topotecan was much less active124, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231 (see below). A summary of the safety profiles and clinically observed toxicities is provided in Tables 17.5 and 17.4, respectively.232, 233
Second, as mentioned previously, various schedules focusing on the continuous infusion of topotecan have been studied, including a 24-hour infusion weekly and every 3 weeks; a 72-hour infusion administered weekly, every 14 days, and every 21 days; a 120-hour infusion every 3 to 4 weeks; and 21-day low-dose continuous infusion every 4 weeks. In addition to the dose-limiting toxicity of leukocytopenia, the longest infusion schedules also induce thrombocytopenia.
With the continuous i.v. administration for 21 days every 28 days, the MTD was 0.53 mg/m2 per day.122 The steady-state lactone topotecan was only approximately 4 ng/mL. No consistent relationship between drug level and hematological toxicity was found. Of interest, the phase I study showed several partial tumor responses in tumor types that were initially chemotherapy-resistant.122 In a phase II study with this regimen in patients with progressive and platinum refractory ovarian cancer, the response rate was 37%.234
In order to mimic a prolonged exposure regimen and based on the relatively short half-life of the drug (average 2.4 hours), a twice daily oral administration schedule for 21 days every 28 weeks was studied.135 The dose-limiting side effect was diarrhea, at a dose of 0.6 mg/m2 twice daily. It occurred in 55% of patients, with day 15 as the median day of onset (range, 12 to 20) and mean period of resolution of 8 days (range, 7 to 16). Administration of high-dose loperamide did not limit the diarrhea.135 The hematological toxicity was mild and consisted mainly of neutropenia (35%).
TABLE 17.5 SAFETY GUIDELINES FOR THE USE OF TOPOTECAN
Because of this diarrhea occurring beyond day 15, and in view of the emerging insights that topoisomerase I inhibition might be no longer optimal after 14 days of continuous drug administration, a shorter schedule was investigated.234, 235 Patients were treated once daily or twice daily for 10 days every 21 days.235 In the once daily regimen, dose-limiting thrombocytopenia and diarrhea was seen at a dose of 1.6 mg/m2 per day. The dose-limiting toxicities (DLTs) were similar, occurring at a dose of 0.8 mg/m2 twice a day.
Because of the persistence of diarrhea as a side effect in the 10-day schedule, a 5-day schedule was studied.236 The DLT was neutropenia, similar to the i.v. drug use, with a nadir between day 8 and 15 and a median duration of 6 days (range, 2 to 12). Nonhematological toxicities were mild to moderate. Moderate to severe diarrhea (grade 2 or above) was observed in 21% of the patients, and this event was self-limiting. The recommended dose was 2.3 mg/m2 per day. Assuming an average body surface area in patients of 1.75 m2, the recommended dose of 2.3 mg/m2 per day equals a fixed dose of 4 mg per day. Pharmacokinetics and toxicity were studied at this fixed dose in order to ascertain whether dosing based on per square meter offered any advantage over flat dosing, but such an advantage was not found.165, 236, 237
In summary, hematologic toxicity is more pronounced with the shorter oral regimens but is still mostly mild and noncumulative, whereas diarrhea is a severe and intractable side effect of more prolonged daily administration.238 An analysis of the pharmacokinetic-pharmacodynamic relationships revealed that the total AUC per course did not differ between the various regimens, and in an analysis of the time over the threshold concentration of 1 ng/mL, it appeared that the daily times 5 schedule provided the best systemic exposure and toxicity profile.239
In acute leukemia, the MTD of a daily 30-minute i.v. infusion for 5 consecutive days every 3 weeks was 4.5 mg/m2 per day.240 The DLT at higher dose levels was a complex of symptoms, consisting of high fever, rigors, precipitous anemia, and hyperbilirubinemia. Although the precise etiology of these adverse effects was not known, it was believed that high doses of topotecan had induced an acute hemolytic reaction.
The antitumor activity of topotecan, given as a single agent using various schedules of administration, was established in a variety of phase II studies, including ovarian cancer (overall response rate [OR], 14 to 38%), small-cell lung cancer (OR, ~39%; reviewed in references 241 and 242), NSCLC (OR, ~13%; reviewed in reference 243), breast cancer (OR, ~10%),222 myelodysplastic syndrome (complete response rate [CR], ~37%),244 and chronic myelomonocytic leukemia (CR, ~27%245; reviewed in 246). Marginal activity was seen in head and neck cancer,219, 247 prostate cancer,248 pancreatic cancer,224, 231 gastric cancer,225, 226 esophageal carcinoma,217 hepatocellular carcinoma,227 and recurrent malignant glioma191, 215 and when topcotecan was used as consolidation treatment after first-line standard chemotherapy for ovarian cancer.249
In a phase III study, the daily times 5 i.v. topotecan regimen was compared with paclitaxel (3-hour infusion of 175 mg/m2 per day every 3 weeks) in ovarian cancer. In this disease, topotecan and paclitaxel where equally effective with regard to response rates, progression-free survival, and overall survival.204, 250The median duration of response was 26 weeks (range, 7 to 84 weeks) for topotecan and 22 weeks (range, 9 to 67 weeks) for paclitaxel. The respective median times to progression were 19 weeks (range, <1 week to 93 weeks) and 15 weeks (range, <1 week to 77 weeks), while the median survival was 63 weeks (range, <1 week to 122 weeks) versus 53 weeks (range, <1 week to 130 weeks).125
In an open-label, multicenter study comparing the activity and tolerability of oral versus i.v. topotecan, 266 patients with relapsed epithelial ovarian cancer after failure of one platinum-based regimen, which could have included a taxane, were randomized to both arms.141 Oral versus i.v. doses of topotecan were administered as 2.3 mg/m2 per day and as 1.5 mg/m2 per day, respectively, for 5 consecutive days every 3 weeks. The principal toxicity was noncumulative myelosuppression, although moderate to severe neutropenia was less frequently seen in patients treated with oral topotecan. Furthermore, grade 3 and 4 gastrointestinal toxicity was slightly higher in the oral treatment arm. No difference in response rates between the two treatment arms was reported. Although a small, statistically significant difference in survival favored the i.v. formulation (58 weeks) over the oral formulation (51 weeks) (P = .033), in the context of second-line palliative treatment for ovarian cancer, this outcome has only limited clinical significance.141 For this reason, oral topotecan could be an alternative treatment modality in this setting because of its convenience and good tolerability. Its definite place has to be clarified in further studies.
Another phase III study compared single agent topotecan with combination chemotherapy consisting of cyclophosphamide, doxorubicin, and vincristine (CAV) in 211 patients with SCLC relapsing after first-line platinum-based chemotherapy.251 Although the response rate, time to disease progression, and overall survival were similar, the palliation of disease-related symptoms was better with topotecan.251 In a randomized trial performed by the Eastern Cooperative Oncology Group (ECOG), topotecan was compared with best support of care in patients with extensive SCLC. In this trial, topotecan was administered as consolidation therapy after response induction with cisplatin and etoposide.201 Although topotecan induced a moderate increase in the time to disease progression, it did not improve survival.201 Finally, similar to the study of ovarian cancer, oral topotecan was compared to i.v. administration of topotecan in patients with relapsed and chemosensitive SCLC. The oral formulation was found to be similar in efficacy, result in less severe neutropenia, and possess superior drug administration convenience.140 Based on these data, topotecan has been approved by the FDA for the treatment of recurrent SCLC in the US.252
Although topotecan has shown some activity against hematological malignancies, its use for this specific indication needs to be further explored in research.253 As indicated, the complete remission rate is interesting in myelodysplastic syndromes (MDSs) (37%) and in chronic myelomonocytic leukemia (CMML) (27%).121, 254 Of note, the presence of a mutation of the ras-oncogene seems to predict insensitivity to topotecan treatment in CMML. In relapsed or resistant multiple myeloma, the overall response rate was 16% (95% CI, 7 to 31%). Responses have lasted 70 to more than 477 days, with a median progression-free survival of 13 months and a median survival time of 28 months.228, 229
Irinotecan (7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin, CPT-11) (Fig.17.1) was the first camptothecin derivative with increased aqueous solubility to enter clinical trials. These began in the 1980s in Japan, where the drug was developed by the Daiichi Pharmaceutical and Yakult Honsha companies. Irinotecan hydrochloride became commercially available in Japan for treatment of lung cancer (SCLC and NSCLC), cervical cancer, and ovarian cancer in 1994. In 1996 irinotecan was approved in the US for use in patients with advanced colorectal cancer refractory to 5-FU, and in 2000 it was approved as a component of first-line therapy in combination with 5-FU/LV for the treatment of metastatic colorectal cancer or for patients who have progressed following initial 5-FU-based therapy. Irinotecan is unique in that it must first be converted by a carboxylesterase-converting enzyme to the active metabolite SN-38 (Fig.17.3).255, 256 SN-38 is the major metabolite believed to be responsible for irinotecan's biologic effects. Key features of irinotecan are listed inTable 17.6.
Dosages and Routes of Administration
The most commonly used schedules of irinotecan administration are a 30- or 90-minute i.v. infusion of 125 mg/m2 given weekly for 4 of every 6 weeks or 350 mg/m2 given every 3 weeks. In Japan, regimens of 100 mg/m2 every week or 150 mg/m2 every other week also have been used. The weekly times 4 schedule is more popular in North America, and the every-3-week schedule was developed predominantly in Europe. None of these regimens shows clear superiority with regard to antitumor efficacy in comparative clinical studies.257, 258 Other short infusion schedules tested clinically include daily infusions for 3 days259and infusions every 2 weeks.260
Figure 17.3 Genes involved in irinotecan (CPT-11) activation (modified from reference 337).
Because of the schedule-dependent activity of irinotecan seen in preclinical studies, protracted or repeated irinotecan dosing schedules have been tested in phase I trials. These included short 1-hour infusions of 20 mg/m2 per day daily for 5 days261 and a continuous infusion over 4 days,262 over 7 days,263 or over 14 days.264 The dose-limiting toxicity for all of these protracted administration schedules is diarrhea, with myelosuppression being less common than with the weekly or every-3-weeks short infusion schedules. Despite the somewhat low recommended dosages associated with these protracted administration schedules, the conversion of irinotecan to the active metabolite SN-38 is relatively more efficient. The AUC proportions of SN-38 relative to irinotecan range from 16 to 28%; these values are much greater than the 3 to 4% proportional AUC values of SN-38 to irinotecan seen during weekly or every-3- weeks short infusion schedules, and they are consistent with an increased efficiency of irinotecan enzymatic activation.257 I.p. dosing, 265, 266 intraarterial dosing,267 and oral dosing of irinotecan266, 268, 269, 270, 271, 272 are also under investigation and represent potential strategies for the more convenient delivery of protracted low doses of irinotecan to patients.
Both irinotecan and its active metabolite SN-38 circulate in plasma after drug administration. Like all camptothecins, irinotecan and SN-38 both contain a terminal α-hydroxy lactone ring that is unstable in aqueous solutions and undergoes rapid nonenzymatic hydrolysis to the open-ring carboxylate (Fig.17.1). The early pharmacokinetic studies of irinotecan used assays that measured only total (lactone and carboxylate) concentrations of irinotecan and SN-38; however, more recent assays have been validated that can separate both lactone and carboxylate forms (reviewed in reference 148). Virtually all of these assays use reversed-phase HPLC with fluorescence detection. Rapid precipitation of plasma samples with ice cold methanol or acetonitrile (or both) is used to trap the camptothecins in their relative lactone and carboxylate forms, which are later resolved on a reversed-phase HPLC column.148 Careful attention to sample storage conditions is important for preventing interconversion of the lactone and carboxylate drug species. Newer assays have also been developed for the determination of more recently recognized irinotecan metabolites, including 10-O-glucuronyl-SN-38 (SN-38G),273, 274 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]-carbonyloxycamptothecin (APC), and 7-ethyl- 10-(4-amino-1-piperidino)-carbonyloxycamptothecin (NPC) (Fig. 17.3).275 Recently, assays for measuring irinotecan and SN-38 in saliva276 and erythrocytes have also been reported.277
TABLE 17.6 KEY FEATURES OF IRINOTECAN
After short i.v. infusions of irinotecan, both the parent drug and SN-38 are measurable in plasma as the lactone and open-ring carboxylate species (Fig. 17.3). After approximately 1 hour, however, the levels of SN-38 tend to be 50 to 100 times lower than the irinotecan plasma levels, and the overall AUC proportion of SN-38 relative to irinotecan is only approximately 4%.257 In most259, 278, 279, 280, 281 but not all282 reports, irinotecan and SN-38 plasma concentrations and AUC increased proportionally with increasing dose, which suggests linear pharmacokinetics. Peak plasma levels of irinotecan occurred immediately after the end of the infusion period, whereas SN-38 peak levels tended to occur approximately 2.2 ± 0.1 hours later (range, 1.6 to 2.8 hours).280 Extremely high interpatient variability in the plasma concentrations of irinotecan and SN-38 is common, although the reasons for this are only partially defined and appear unrelated to body-size measures.283, 284
The kinetics of irinotecan and SN-38 have been fitted to a biexponential or triexponential model in most studies.257 For short i.v. infusions, the mean terminal elimination half-life for irinotecan lactone was approximately 6.8 hours (range, 5.0 to 9.6 hours). The plasma half-life of the active metabolite, SN-38 lactone, however, was relatively long compared with that of the other camptothecins; the terminal half-life was approximately 10.4 hours (range, 9.1 to 11.5 hours) for SN-38 lactone. The prolonged duration of exposure to SN-38 is probably a function of its sustained production from irinotecan in tissues, because direct injection of SN-38 into rats resulted in extremely rapid plasma clearance, with a half-life of only 7 minutes.285, 286
Figure 17.4 Metabolic pathways of irinotecan (CPT-11) (modified from reference 257).
Race, gender, and renal function do not appear to alter the clinical pharmacology of irinotecan.287, 288 However, decreased total irinotecan clearance has been modestly correlated with abnormalities in liver function such as increased serum bilirubin and γ-glutamyl transpeptidase levels in population pharmacokinetic studies.287, 289 These same hepatic abnormalities also correlated with an increased ratio of SN-38 to irinotecan AUC (metabolic ratio), an observation that can be explained by increased conversion of irinotecan to SN-38 or decreased clearance of the SN-38 metabolite, or both.
Several groups have attempted to use population pharmacokinetic analysis using nonlinear mixed effect modeling and Bayesian approaches to predict irinotecan pharmacokinetic profiles.287, 290, 291, 292 Limited sampling strategies have also been developed; most have recommended two293, 294, 295 or three296, 297, 298 sampling times to reliably estimate irinotecan, SN-38, or SN-38G AUC values. All have attempted to estimate total irinotecan and SN-38 pharmacokinetic parameters, and none have distinguished between the lactone and carboxylate drug species. A few of these limited sampling methods have been applied to clinical studies of the pharmacokinetics of irinotecan in larger patient populations.299
Compared with topotecan, relatively large amounts of both irinotecan and SN-38 in plasma are present in the lactone form. The irinotecan lactone AUC ranged from 33 to 44% of the total irinotecan AUC, and for SN-38 the lactone percentage was even greater, ranging from 30 to 74% in most studies.257 Thus, compared with other camptothecins, relatively large amounts of the SN-38 circulate in plasma as the biologically active lactone, which may be relevant to irinotecan's clinical activity.
One potential explanation for variation in the lactone to carboxylate ratios for different camptothecins is their differential protein binding. It has been shown that the equilibrium ratio in plasma between the carboxylate and lactone forms of different camptothecin derivatives was greatly affected by their relative degree of albumin binding.118 For drugs such as camptothecin or 9-AC, the albumin-binding affinity of the open-ring carboxylate was over 200 times greater than the lactone affinity.118 The overall plasma protein binding for SN-38 is higher than that for irinotecan, with 92 to 96% of total SN-38 being protein-bound in laboratory plasma incubation experiments, compared with 30 to 43% for irinotecan.300 Serum albumin was the major protein to which both SN-38 and irinotecan were bound.
Thus, several factors in the clinical pharmacology of irinotecan may contribute to its greater antitumor activity relative to other camptothecin derivatives. One is the longer half-life of the active metabolite SN-38.301 As discussed earlier, this may be due to the slow conversion of irinotecan to SN-38 and enterohepatic recirculation. The second factor is the relatively large amount of circulating SN-38 that is present as the active lactone form. Finally, as discussed previously, the topoisomerase I–DNA cleavable complexes induced by SN-38 are extremely stable compared with those of other camptothecin analogs.110 All of these factors probably contribute to the clinical antitumor activity of irinotecan.
Because of the greater difficulty in analytic determination of the unstable lactone species in plasma, several investigators have questioned the value of measuring lactone versus total (lactone plus carboxylate) plasma concentrations for pharmacokinetic studies.302 In any individual, the ratio of lactone to total drug is relatively constant; however, variation between different individuals may be quite high. Nonetheless, pharmacodynamic studies performed to date have not shown a superiority for lactone compared to total plasma drug measurements in predicting clinical drug effects.257
Although the most common route of irinotecan administration is i.v., oral formulations have been tested in preclinical268 and clinical studies (reviewed in reference 238). In nude mice, oral administration of irinotecan is active and well tolerated,266, 268, 303, 304 although the bioavailability in animals is only 12 to 21%.269 The amount of SN-38 generated from oral administration of irinotecan, however, was threefold higher than that from i.v. administration when the molar AUC ratios of SN-38 to irinotecan were compared.269 Extensive first-pass metabolism of irinotecan to SN-38 in the intestine and liver was proposed as a potential explanation. In a clinical phase I study, oral irinotecan at 20 to 100 mg/m2 per day for 5 days every 3 weeks was well tolerated.271 Because of the occurrence of dose-limiting age-related delayed diarrhea, the recommended phase II oral dosage was 66 mg/m2 per day for patients younger than 65 years and 50 mg/m2 per day for older patients. As seen in earlier animal studies, higher molar AUC ratios of SN-38 to irinotecan were generated by the oral route, consistent with greater metabolic conversion of irinotecan to SN-38. I.p. administration has also been examined, and there is evidence that it may result in more efficient activation of irinotecan to SN-38 than i.v. routes of administration.265, 266, 305, 306
Little is known about the tissue penetration and distribution of irinotecan, although the volume of distribution at steady state is large, with mean values ranging from 76 to 157 L/m2 for total irinotecan. In rhesus monkeys, the CSF penetration of irinotecan was only 14 ± 3% of the plasma exposure, which is less than observed for topotecan,182 and SN-38 was not detectable in the CSF. In nude mice, repeated daily i.p. administration of irinotecan resulted in high prolonged irinotecan and SN-38 concentrations in the intestine307; however, penetration into other tissue compartments was not measured. Interestingly, when SN-38 instead of irinotecan was directly administered i.v. to rats, very little tissue accumulation was observed, which suggests that peripheral tissue conversion of irinotecan to the active metabolite may be potentially important for generating its clinical activity.285
In a phase II clinical study, i.v. irinotecan at 60 mg/m2 combined with cisplatin was given to patients with malignant pleural mesothelioma, and pleural fluid pharmacokinetics were monitored in three patients.308 Irinotecan was detectable in pleural fluid as early as 1 hour after an i.v. infusion, with peak levels occurring after 6 hours. The active metabolite SN-38 was also detected within 1 hour after the end of an infusion; by 6 hours the SN-38 pleural fluid concentrations mirrored plasma concentrations and continued to do so for the remainder of the monitoring period, which lasted 24 to 48 hours. The maximal pleural concentrations of irinotecan and SN-38 were 37% and 76% of the plasma concentrations of drug, respectively. Thus, excellent penetration into the pleural fluid compartment was observed in this study. Dosing guidelines for patients with large third-space fluid collections such as pleural effusions and ascites are not available; however, no clinical reports have been published of excessive irinotecan toxicity in these patients.308
Irinotecan is extensively metabolized to a number of active and inactive metabolites (Fig.17.3). This creates the potential for clinically important variability in the kinetics of this agent. Irinotecan carboxylesterase–converting enzyme metabolizes irinotecan to SN-38, which, in turn, is conjugated by liver UDP glucuronosyl transferases (UGTs) to form an inactive β-glucuronic acid derivative, SN-38G. The total amount of SN-38 generated in individual patients is highly variable,257 which suggests that variations in carboxylesterase-converting enzyme activity may be important in determining irinotecan response and toxicity. The relative AUC value of the active metabolite SN-38 to irinotecan varied from 0.9 to 11% in a pharmacokinetic study of different dosages of irinotecan (dose range, 115 to 600 mg/m2).309 Furthermore, this ratio was highest at the lowest doses of irinotecan examined (115 mg/m2), which suggests that less efficient conversion of irinotecan to SN-38 occurred at higher drug concentrations. Alternatively, variations in the clearance of SN-38 via the UGT pathway provide another potential mechanism for variability in irinotecan pharmacokinetics. Irinotecan is also a substrate for metabolism by the cytochrome P-450 system, which creates an additional potential for drug interactions. Collectively, these studies demonstrate that the metabolic pharmacokinetics of irinotecan is complex and may be mediated by several different families of enzymes, including carboxylesterases, cytochrome P-450 enzymes, and glucuronosyl transferases.
In rodents, an irinotecan carboxylesterase–converting enzyme that can hydrolyze irinotecan to SN-38 has been purified from rat serum, and high activity is also found in rat and mouse liver, intestinal mucosa, and other tissues.310 However, carboxylesterase-converting enzyme–specific activity is much lower in human serum311, 312, 313 and in comparable human tissues.314 The main carboxylesterase responsible for the clinical activation of irinotecan in humans has been proposed to be CES2.315, 316 Human liver carboxylesterase activity is found in hepatic microsomal fractions, and this enzyme has been cloned and characterized.317 The high interindividual variation observed in human liver and intestinal microsomal carboxylesterase activity could potentially cause clinically important differences in drug metabolism.318, 319 In human and animal studies, no evidence exists that irinotecan induces hepatic or serum carboxylesterase activity.320
Carboxylesterase activity and irinotecan metabolism have been studied in detail in human liver microsomes.257 Rate-limiting deacylation kinetics were observed, with an initial fast “burst” rate of SN-38 release occurring during the first 10 to 15 minutes of incubation, followed by slower steady-state production of SN-38. The overall activity of irinotecan carboxylesterase–converting enzyme was lower in human liver than in rats, with an apparent Km in humans of 52.9 µmol/L and a Vmax (maximum reaction velocity) of 0.145 nmol/L per hour. A slight inhibition of irinotecan activation by loperamide suggested that a potential drug interaction could occur when this drug was given concomitantly; however, this finding has not been evaluated further in clinical studies.
The difference between irinotecan lactone and carboxylate forms as substrates for carboxylesterase activation was studied further in human liver microsomes.321 Irinotecan lactone was more rapidly metabolized than the carboxylate by approximately twofold, with observed Km values of 23.3 ± 5.3 µmol/L and 48.9 ± 5.5 µmol/L for irinotecan lactone and carboxylate, respectively. Additional studies using the enzyme inhibitor phenylmethyl sulfonyl fluoride suggested that the liver carboxylesterase responsible for SN-38 formation was a serine-dependent hydrolase. Although irinotecan carboxylesterase activity correlated with the carboxylesterase-mediated hydrolysis of para-nitrophenol acetate, this later reaction was over 1 million times more efficient. Thus, irinotecan is a relatively poor substrate for human liver carboxylesterase. High interindividual variability in carboxylesterase-specific activity was seen in 12 different human liver microsomal preparations, with a 5- to 45-fold range of activity depending on the carboxylesterase substrate used.318 This finding suggests that interindividual variation in this enzyme activity may be an important source of pharmacokinetic and pharmacodynamic variability.
An unresolved issue is whether actual irinotecan carboxylesterase-converting enzyme activity within the tumor itself is an important determinant of irinotecan sensitivity. In general, human irinotecan carboxylesterase-activating activity is difficult to measure in human tissues and in plasma because of its low overall level.322 In a study of irinotecan carboxylesterase-converting enzyme activity in 53 human colon tumors, the enzyme-specific activity varied 146- fold.323Some324, 325 but not all87, 303 studies have found a modest correlation between tumor carboxylesterase-converting enzyme activity and sensitivity to irinotecan. Despite this uncertainty, studies of the use of the mammalian liver carboxylesterase gene to sensitize tumors to irinotecan are under investigation in laboratory model systems.326, 327, 328
Under normal circumstances, only a relatively small amount of the total irinotecan metabolized is converted into SN-38. Recently, several additional metabolites of irinotecan have been identified and characterized in human matrices.329 Oxidation of the terminal piperidino ring by hepatic cytochrome P-450 enzymes, in particular CYP3A4, is thought to be responsible for the formation of APC (Fig.17.3).330 Overall, the APC metabolite was at least 100-fold less active than SN-38 as an inhibitor of topoisomerase I,331 and it was found to a poor substrate for conversion to SN-38 by human liver carboxylesterases. In cytotoxicity experiments, APC was also a poor inhibitor of human nasopharyngeal KB cell growth; the concentration showing 50% growth inhibition was comparable to that of irinotecan.331 Although the APC metabolite does not appear to be responsible for any of irinotecan's clinical toxicities or antitumor effects, its formation may represent an important metabolic pathway for irinotecan clearance.
Another piperidino ring metabolite of irinotecan is NPC, which was characterized in the plasma and urine of patients on irinotecan therapy (Fig.17.3).332 Like APC, this derivative is a poor inducer of topoisomerase I–cleavable complexes, but unlike APC, this new metabolite is a weak substrate for CES2 and can be enzymatically converted into SN-38.316, 333 Thus, NPC may contribute to the clinical activity of irinotecan. In plasma, the concentration of NPC is less than that of irinotecan or APC. Additional hepatic metabolites of irinotecan were also found in an analysis of human bile obtained from a patient undergoing irinotecan therapy. At least 16 different irinotecan metabolites were partially identified using highly sensitive liquid chromatography/mass spectroscopy and liquid chromatography/tandem mass spectroscopy techniques.334 These included irinotecan oxidation products involving the C-10 bipiperidine side chain and a decarboxylated camptothecin derivative that lacked the terminal carboxylate group. Alkylated and N-oxidized species were also detected. The exact chemical structure of most of these metabolites and their clinical importance are not yet known, although several metabolites seem to be the result of CYP3A5-mediated conversion.335
Because of the genetic diversity in the genes encoding these proteins,336 it has been suggested that genotyping for CYP3A4 and CYP3A5 variants may be useful for prediction of total hepatic CYP3A activity as well as the pharmacokinetic profile of substrate drugs. However, such studies have demonstrated that genotyping for CYP3A4 and CYP3A5 does not lead to significant correlations with irinotecan pharmacokinetics.337 This may be due to the low allele frequency of most CYP3A variant genotypes in the Caucasian population (e.g., CYP3A4*17, CYP3A4*18, and CYP3A5*1) or may reflect the absence of a clinically important effect on enzyme activity in vivo (e.g., CYP3A4*1B).336 Taking into account that CYP3A is a very complex enzyme system and that it is easily influenced by environmental (i.e., comedication, herbal preparations, and/or food substances) and physiologic factors (i.e., aging, disease state, and altered liver and renal function), the role of CYP3A4/5 genotyping in improving treatment with irinotecan remains doubtful.
Because human hepatic CYP3A appears to be important in the metabolism of irinotecan, the potential exists for serious drug-drug interactions. This enzyme is principally responsible for the metabolism of a large number of commonly prescribed drugs. A number of studies evaluating irinotecan in malignant glioma patients revealed that the clearance of irinotecan was significantly faster in patients who required cotreatment with anticonvulsants and glucocorticoids—inducers of CYP3A4—than in patients who did not receive such concomitant treatment.338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348 A recent investigation also indicates that a significant interaction occurs between irinotecan and the herbal product St. John's wort, likely because of CYP3A4 induction, resulting in 42% decreased circulating concentrations of SN-38.349 In contrast, inhibition of CYP3A4 activity by agents like ketoconazole350 or cyclosporin A351 has been shown to lead to substantially increased exposure to SN-38. It has also been suggested that both irinotecan and SN-38 are mechanism-based inactivators of CYP3A4,352 although the clinical relevance of this finding is unknown.
UGT-Mediated Metabolism of SN-38
The major metabolite of SN-38 is the glucuronidated derivative SN-38G,285 which is present in the plasma and bile of patients receiving irinotecan chemotherapy (Fig. 17.3).353 In pharmacokinetic studies, the peak SN-38G concentrations were seen 10 to 20 minutes after the end of a 90-minute irinotecan infusion.354 The amount of SN-38G increased from time zero up to 1 hour postinfusion; this was followed by a gradual decline so that by 5 to 6 hours postinfusion the ratio of SN-38G to SN-38 stabilized at 4:1 or 5:1. The decrease in plasma concentrations of SN-38G tended to parallel the decrease in SN-38 over time.301 These data are consistent with the view that UGT is the rate-limiting step responsible for the elimination of the SN-38 active metabolite.353
UGT may also represent a potentially exploitable target for modulating SN-38 pharmacokinetics. In mice, coadministration of irinotecan with valproic acid, an inhibitor of glucuronidation, markedly decreased the amount of SN-38G formed, and it increased the systemic exposure to SN-38 2.7-fold.355 In contrast, coadministration with phenobarbital, which enhances hepatic glucuronidation, increased the plasma AUC for SN-38G and decreased that for SN-38.355 If these same drug interactions occur in humans as well as in mice, then a potential strategy for using such agents is suggested, such as administering phenobarbital to decrease gastrointestinal toxicity by increasing SN-38 detoxification.
The UGT isoforms UGT1A1, UGT1A3, UGT1A6, UGT1A7, and UGT1A9 have all been implicated in the glucuronidation of SN-38 in in vitro studies using hepatic liver microsomes.79 It has been suggested that patients with Gilbert's syndrome, who are genetically deficient in UGT1A1 and have impaired bilirubin conjugating activity, may be at risk for severe irinotecan-induced diarrhea because of an inability to conjugate and detoxify SN-38. The genetic defect in Gilbert's syndrome, which can occur in up to 15% of the population and may be clinically silent, most commonly results from the presence of an additional TA repeat [(TA)7TAA] (UGT1A1*28) in the promoter region of UGT1A1.356, 357 In a retrospective case control study of 26 Japanese patients who experienced greater toxicity following irinotecan treatment, multivariate analysis suggested that a heterozygous or homozygous genotype for UGT1A1*28 would be a significant risk factor for severe toxicity by this drug.358 Shortly thereafter, a prospective clinical pharmacogenetic study of 20 patients being treated with irinotecan for solid tumors found that one seventh of heterozygotes experienced grade 4 diarrhea, one fourth of the homozygote variant demonstrated grade 3 neutropenia, while another homozygote demonstrated both grade 3 diarrhea and grade 4 neutropenia.359 The findings have been independently confirmed by several investigators337, 360, 361, 362, 363, 364 and have been propagated as a rationale for performing pretreatment genetic testing on patients receiving irinotecan.
Collectively, the data suggest that much of the variability in irinotecan pharmacokinetics is related to variations in its enzymatic metabolism. The existence of multiple polymorphic metabolic pathways for irinotecan and its metabolites makes this a complex area to study, but ongoing research may provide a better understanding of the clinical impact of these pathways in irinotecan chemotherapy.
Deconjugation of SN-38G
Because hepatic glucuronidation followed by biliary excretion of SN-38G is a major route of drug elimination, the presence of bacterial β-glucuronidase in the intestinal lumen can potentially contribute to irinotecan's gastrointestinal toxicity. Hydrolysis of the inactive glucuronidated SN-38G by bacterial enzymes can release unconjugated SN-38, which results in prolonged exposure of the gastrointestinal mucosa to the active metabolite. This process can also enhance reabsorption of the unconjugated SN-38 from the intestinal lumen via enterohepatic circulation. Inhibition of bacterial β-glucuronidase, however, might prevent deconjugation of SN-38G and promote fecal elimination of drug, thereby lessening gastrointestinal toxicity. Consistent with this hypothesis was the finding that the Chinese herbal medicine Kampo, which contains baicalin, a β-glucuronidase inhibitor, substantially reduced the severity of irinotecan-induced diarrhea in rats.365 In animal studies, antibiotic administration also protected against drug-associated diarrhea, presumably by altering the gut microbial flora and decreasing intestinal β-glucuronidase activity.366, 367 Coadministration of penicillin and streptomycin sulfate with irinotecan to rats markedly reduced drug-induced diarrhea and cecal damage. Pharmacodynamic studies in these rats receiving both irinotecan and antibiotics showed no difference in blood pharmacokinetics but demonstrated an 85% reduction in SN-38 concentrations within the large intestine.366, 367 A similar approach in humans treated with the antibiotic neomycin has been shown to safely alleviate irinotecan-associated diarrhea without diminishing clinical efficacy.368
In addition to hepatic metabolism, elimination of irinotecan and its metabolites also occurs by urinary and fecal excretion. Fourteen percent to 37% of the administered irinotecan dose was excreted unchanged in the urine over 48 hours after a short 90-minute infusion.278, 280 Only approximately 0.26% of the administered dose, however, was excreted as SN-38.278, 280 Biliary secretion of irinotecan, SN-38, and SN-38G also appears to be a substantial mechanism of drug elimination. Biliary drug concentrations were measured in two patients; the total irinotecan concentration was 10 to 113 times higher and the SN-38 biliary concentration was 2 to 40 times higher than the simultaneous plasma drug.278, 354 For two other patients, quantitative collection of bile from percutaneous catheters was performed for up to 48 hours after a single dose of irinotecan.354 The percentage of the total dose administered that was excreted into the bile as either irinotecan, SN-38, or SN-38G ranged from 24 to 50%.
Biliary transport of irinotecan and its metabolites by the canalicular multispecific organic anion transporter (cMOAT, ABCC2) has been extensively studied using isolated canalicular membrane vesicles obtained from rat liver.369, 370 The ABCC2 system is believed to be responsible for the biliary secretion of irinotecan carboxylate, SN-38 carboxylate, and the carboxylate and lactone forms of SN-38G, but other transport systems in the bile canaliculi may also exist, including ABCG2371, 372 but not ABCB1.373
Theoretically, another way of reducing gastrointestinal toxicity is to reduce the amount of free SN-38 in bile by blocking biliary excretion of SN-38 and SN-38G.374 Cyclosporin A can reduce bile flow and inhibit bile canalicular active transport, and thus it is a potential modulator of SN-38–induced toxicity. Coadministration of cyclosporin A with irinotecan in rats was found to increase the AUCs of irinotecan, SN-38, and SN-38G by 3.4-fold, 3.6-fold, and 1.9-fold, respectively.375 Overall, nonrenal clearance of irinotecan decreased by 81%, with no change in the calculated volume of distribution, and the terminal half-life of SN-38 increased by approximately twofold. The AUC ratio of SN-38 to irinotecan in plasma was not altered, but the AUC ratio of SN-38 to SN-38G did increase. All of these observations are consistent with cyclosporin-induced inhibition of biliary canalicular transport of irinotecan, SN-38, and SN-38G; however, the precise transport systems affected by this modulation have not been fully characterized. Nonetheless, these observations suggest another possible strategy for reducing the gastrointestinal toxicities of irinotecan.
Fecal loss also contributes to the elimination of irinotecan and its metabolites from the body. In one study, which included 10 patients, the total excretion of irinotecan, SN-38, SN-38G, APC, and NPC in urine accounted for 28.1 ± 10.6% of the administered dose, whereas recovery from feces accounted for 24.4 ± 13.3%.376 Thus, the total mass balance of known metabolites accounted for only approximately 50% of the total administered dose, which indicates the likely existence of other as yet unidentified metabolites of irinotecan, although a better drug yield was obtained in a small study in which radiolabeled irinotecan was administered.377
The major clinical toxicity of irinotecan is delayed diarrhea, which is believed to result from direct effects of the active metabolite SN-38 on the intestinal epithelium. As previously described, glucuronidation of SN-38 may prevent this toxicity by decreasing the relative amount of biologically active unconjugated SN-38 in the bile and small intestine. In an attempt to identify patients at risk for severe delayed diarrhea during irinotecan therapy, a biliary index was developed to estimate the relative amount of free and unconjugated SN-38 in the biliary system using measured plasma drug concentrations.374 The biliary index was defined as the product of the AUC of irinotecan and the ratio of the AUC of SN-38 to that of SN-38G. In the original study, nine patients with grade 3 to 4 diarrhea had higher biliary indices (which indicated relatively more unconjugated SN-38 in the bile) than 12 patients with grade 0 to 2 diarrhea.374 Estimation of the biliary index initially required substantial numbers of pharmacokinetic blood samples to determine the AUCs of irinotecan, SN-38, and SN-38G. However, a limited sampling strategy for estimating the biliary index was recently developed that requires only two blood samples obtained at 3.5 and 7.5 hours after a 90-minute infusion of irinotecan.288, 378 Thus, the biliary index may be able to be estimated during week 1 of therapy, and if it is highly elevated, immediate dosage adjustments can be instituted to decrease the incidence of severe diarrhea. Nevertheless, other studies using a variety of different schedules of administration have not confirmed the utility of the biliary index in predicting clinically significant diarrhea.299, 379, 380
Other pharmacodynamic studies have attempted to correlate the AUC of irinotecan or SN-38 with clinical drug toxicities, with varying results. In early studies of irinotecan in Japan, no correlation between irinotecan or SN-38 AUCs and myelosuppression or diarrhea was noted.282 In later studies, a strong correlation between the degree of leukopenia and the AUC of irinotecan was reported, whereas the severity of diarrhea correlated better with SN-38 kinetics.311 Other studies have also found pharmacodynamic correlations between the irinotecan AUC and myelosuppression279, 287, 299, 381 and/or between the SN-38 AUC and myelosuppression.279, 280, 287, 299, 379, 381 For severe diarrhea, inconsistent associations with the irinotecan AUC259, 279, 281, 381 and with the SN-38 AUC278,279 or SN-38G AUC380 have also been reported. Similarly, tumor response does not correlate with plasma pharmacokinetic parameters. Finally, although SN-38 lactone is believed to the biologically active species, measurement of SN-38 lactone kinetics has not been superior to total drug (lactone and carboxylate) measurements in predicting pharmacodynamic end points.302
Dosage Adjustments for Abnormal Organ Function
When grade 3 neutropenia or delayed diarrhea occurs, the dose of irinotecan should be reduced by 25 mg/m2 on the weekly schedule or by 50 mg/m2 on the every-3-weeks schedule. If grade 4 neutropenia or diarrhea occurred during the previous cycle, the dose of irinotecan should be reduced by 50 mg/m2 on either schedule. A new course of therapy should not be initiated until any prior neutropenia or diarrhea has resolved. Patients at increased risk for severe diarrhea include those who have had prior pelvic radiation, have poor performance status, are age 65 years or older, or have Gilbert's syndrome.382
In pharmacokinetic studies, modest changes in renal function do not appear to affect irinotecan plasma concentrations.383 In contrast, various studies suggest that elevated bilirubin levels are associated with a decrease in irinotecan clearance and an elevated AUC ratio of SN-38 to irinotecan.289, 291, 301, 383, 384Therefore, extreme caution is warranted in administering irinotecan to patients with impaired hepatic function and hyperbilirubinemia, and a 1.75-fold (43%) reduction in irinotecan dose has been recommended in patients with bilirubin values 1.51 to 3.0 times the upper limit of normal.383, 384
Phase I studies were performed first in Japan, later in the US and Europe. The recommended regimen of irinotecan in the US is 125 mg/m2 administered as a 90-minute i.v. infusion once weekly for 4 or 6 weeks.278 In Europe, the approved administration schedule of irinotecan is 350 mg/m2 given as an i.v. infusion over 60 to 90 minutes once every 3 weeks,280 while a recent reevaluation indicated a MTD of 320 mg/m2, or 290 mg/m2 in patients with prior abdominal/pelvic radiation therapy.385 Finally, in Japan the administration schedule of irinotecan was developed as 100 mg/m2 every week or 150 mg/m2 every other week.282 Remarkably, the dose intensity of all applied dosage regimens of irinotecan is approximately 100 mg/m2 per week, which suggests a schedule independency. This phenomenon might be explained by the long half-life of SN-38, which is achieved after a single dosage of irinotecan.301 Although the half-life of SN-38 does not fully support this approach, in an effort to further explore the possible therapeutic advantage of prolonged exposure to camptothecins, protracted or repeated dosing regimens of irinotecan have been studied (see above).
In the US phase I clinical trials, the maximum dose-intensity of irinotecan was achieved with short-time i.v. infusion once every 2 or 3 weeks (mean dose-intensity [DI], 125 mg/m2 per week; range, 80 to 167 mg/m2 per week), whereas the lowest dose-intensity was achieved with continuous i.v. infusion (DI, range 27 and 47 mg/m2 per week).386 In the weekly times 4 schedule and the daily i.v. infusion over 3 or 5 consecutive days, the mean calculated dose-intensity was 83 mg/m2 per week (range, 73 to 100 mg/m2 per week). Thus, the maximum dose-intensity achieved with prolonged exposure schedules of irinotecan is 2 to 3 times lower than that achieved with short-infusion administration. But as indicated previously, irinotecan is more effectively converted to SN-38 during protracted i.v. infusion.
The principal DLT for all schedules used was delayed diarrhea, with or without neutropenia.257 The frequency of severe diarrhea (grade 3 or 4) was reported as 35% in the phase I studies. The incidence of this toxicity can be reduced by more than 50% if an intensive treatment with loperamide is used, as described in the safety guidelines in Table 17.7. Neutropenia is typically dose-related, is generally of brief duration and noncumulative, and occurred in 14 to 47% of patients treated once every 3 weeks and less frequently using the weekly schedule (12 to 19%).387, 388, 389, 390 In approximately 3% of patients, the neutropenia was associated with fever. In one phase I study, where irinotecan was given as a 96-hour continuous infusion for 2 weeks every 3 weeks, thrombocytopenia was also dose-limiting.262 Due to inhibition of acetylcholinesterase activity by irinotecan within the first 24 hours after dosing of the drug, an acute cholinergic reaction can be observed. The symptomatology of this syndrome, as well as the other nonhematologic toxicities of irinotecan, is summarized in Table 17.8.
Phase II studies consistently revealed response rates of 10 to 35% to single-agent irinotecan in advanced or metastatic colorectal cancer (reviewed in reference 391) independent of the applied schedules. There was no apparent difference between the applied schedules with respect to the median remission duration and median survival time, respectively 6 to 8 months and 8 to 13 months.391, 392, 393
TABLE 17.7 SAFETY GUIDELINES FOR THE USE OF IRINOTECAN
In a randomized phase III study comparing treatment with irinotecan given as a 300 to 350 mg/m2 i.v. infusion every 3 weeks to best supportive care in patients refractory to previous treatment with 5-FU–based chemotherapy, the one-year survival rate was significantly greater for the irinotecan-treated group than for the control group, 36% and 14% (P <.01), respectively.387 Another randomized phase III study, comparing treatment with irinotecan to three different continuous i.v. infusion schedules of 5-FU in patients with previously treated advanced colorectal cancer, revealed a survival advantage for the irinotecan-treated group in comparison to the 5-FU–treated group.388 The one-year survival rates were 45% and 32%, respectively (P <.05). Apart from colorectal cancer antitumor activity, single-agent irinotecan was also moderately active in phase II studies in several other solid malignancies, including breast cancer,212 relapsed or refractory non-Hodgkin's lymphomas,394 and SCLC395 (reviewed in reference 396).
TABLE 17.8 MAIN TOXICITIES OF IRINOTECAN
Based on the activity data in colorectal cancer derived from phase I/II studies on the combination of irinotecan with 5-FU/LV, two randomized phase III studies were performed comparing this combination to single agent 5-FU/LV in the first-line treatment of metastatic colorectal cancer.108, 109 Saltz et al. randomized 683 patients to receive either a weekly times 4 regimen of a 90-minute i.v. infusion of irinotecan at a dose of 125 mg/m2 and a 15-minute i.v. infusion of LV at a dose of 20 mg/m2, followed by 5-FU i.v. bolus at a dose of 500 mg/m2 (arm A, n = 231); conventional low-dose 5-FU/LV (arm B, n = 226); or irinotecan at a dose of 125 mg/m2 for 4 consecutive weeks every 6 weeks (arm C, n = 226).397 An intention-to-treat analysis showed that the combination of irinotecan and 5-FU/LV (arm A) yielded a significantly higher remission rate (P <.001), significantly longer progression-free survival (P = .004), and significantly longer median survival (P = .04) than single-agent 5-FU/LV (arm B). There was no difference between single-agent irinotecan (arm C) and 5-FU/LV (arm B) in terms of overall response rate, median time to disease progression, and median overall survival time.397
Severe diarrhea (grade 3 or 4) (arm A, 23%; arm B, 13%; arm C, 31%) and grade 4 neutropenia (arm A, 42%; arm B, 24%; arm C, 12%) were the most prominent toxicities in this study, but these side effects did not preclude the administration of approximately 75% of the prescribed doses of irinotecan and 5-FU.397 The reverse side of the study was the bias of unreported toxic deaths in the combination treatment arm (arm A).
Douillard et al. randomized 385 patients to the combination of irinotecan and an infusional schedule of 5-FU.398, 399 The regimens were once weekly, irinotecan 80 mg/m2 with 5-FU 2,300 mg/m2 by 24-hour infusion and leucovorin (LV) 500 mg/m2 (arm A1), or every 2 weeks, irinotecan 180 mg/m2 on day 1 with 5-FU 400 mg/m2 bolus and 600 mg/m2 by 22-hour infusion, and LV 200 mg/m2 on day 1 and 2 (arm A2).398 For the control arm (arm B), the regimens were once weekly, 5-FU 2600 mg/m2 by 24-hour infusion and LV 500 mg/m2 (arm B1), or every 2 weeks, 5-FU and LV at the same doses and administration as in arm A2.398 Although there was a good balance between both treatment arms for known risk factors, the number of primary rectal cancers in arm A was slightly higher. Compared with the study by Saltz et al., in this study proportionally more patients had received prior adjuvant 5-FU–based chemotherapy (10% and 25%, respectively). An objective response rate of 41% was reported in treatment arm A (combination irinotecan with 5-FU and LV), compared with 23% in the schedule of 5-FU and LV alone (arm B) (P <.001). Also, the median time to disease progression (P <.001) and median survival time (P <.028) were statistically significant in favor of the combination treatment arm (arm A) compared with the control arm (arm B). The overall treatment response rates were 51% for arm A1 and 38% for arm A2. For the weekly single-agent 5-FU and LV (arm B1) and biweekly 5-FU/LV (arm B2), the overall response rates were 29% and 21%, respectively. More severe neutropenia (29% vs. 21%, P <.01) and more severe diarrhea (24% vs. 11%) were seen in the combination arm (arm A) than in the control arm (arm B). The neutropenia was not significantly associated with fever or infection.
In a multiregression Cox model analysis, the influence of baseline characteristics of patients on the efficacy of the cytotoxic therapy in terms of time to progression and survival was determined. This analysis revealed that excellent performance status (WHO 0 vs. 1 or more), extent of organ involvement (1 vs. 2 or more sites), and normal values for lactate dehydrogenase (LDH), bilirubin, and leucocytes were the major prognostic factors for longer overall survival.391A significant prolongation of time to progression adjusted for normal values of LDH and disease extent (only one organ site) (P = .0001) was established for the combination irinotecan and 5-FU/LV compared with single-agent 5-FU/LV in both studies.391
Combined analysis of both studies confirmed that the addition of irinotecan to 5-FU/LV significantly increases response rate, median time to disease progression, and median time of survival, and thus patients with excellent prognostic characteristics will have received a survival benefit from this combination therapy.391 The above-mentioned treatment schedules used in both studies are approved by the FDA as first-line chemotherapy for patients with metastatic colorectal cancer.391 Yet randomized trials to evaluate the merits of this combination in the adjuvant setting are ongoing.399 Furthermore, clinical trials evaluating the antitumor efficacy of irinotecan in combination with the oral fluoropyrimidine capecitabine, which may replace infusional 5-FU, are currently in progress, as are studies evaluating the addition of monoclonal antibodies like bevacizumab to irinotecan-based regimens for metastatic colorectal cancer.400 Oxaliplatin (see Chapter 14) was approved for use in combination with FU/LCV in 2004 and may replace irinotecan as the preferred partner in colon cancer treatment.
Other Combination Chemotherapy Trials
The combination of irinotecan and raltitrexed was evaluated in two phase I studies, and asthenia was found to be the dose-limiting toxicity in both studies. The recommended doses were irinotecan 350 mg/m2 and raltitrexed 3 mg/m2 once every 3 weeks.401, 402 All phase I studies on the combination of irinotecan and cisplatin, except for one, focused on fractioned dose schedules for both agents (reviewed in reference 403). Neutropenia (grade 4 in 35% of the patients) and diarrhea were the dose-limiting toxicities. In only 4% of all patients was neutropenia complicated by fever. A 33% and 65% increase in the dose intensity of irinotecan could be achieved by adding G-CSF to schedules, with neutropenia as the dose-limiting toxicity.404, 405 Only one phase I study involved the 3 weekly administration and studied the relevance of sequence of drug administration.406 Patients were randomized to receive irinotecan immediately followed by cisplatin in the first course, and the reversed sequence in the second course, or vice versa. Significant differences in toxicity between the treatment schedules were not observed. Neither could a pharmacokinetic interaction be discerned. In addition, irinotecan had no influence on the platinum DNA-adduct formation in peripheral leukocytes in either sequence.406 Apparently there is no administration sequence that should clearly be favored for this particular topoisomerase I inhibitor.
Phase II studies of this combination indicate high levels of activity in various tumors, but none of these studies were randomized, so their interpretation is difficult.252 A Phase III study using this combination as first-line chemotherapy for patients with extensive SCLC showed a significant improvement in the 1-year survival rate (60%) in comparison with conventional treatment with etoposide and cisplatin (40%) (P = .005).407
The combination of irinotecan and oxaliplatin was evaluated in several studies using a once-every-2-weeks schedule and a once-every-3-weeks schedule, with neutropenia and a combination of diarrhea and neutropenia as dose-limiting side effects, respectively.408, 409, 410, 411, 412 Remarkably, the interaction of both drugs showed acute cholinergic toxicities, whose severity is potentiated by oxaliplatin.413 The recommended dose of oxaliplatin is 85 mg/m2 for both schedules. The recommended dose of irinotecan is 175 mg/m2 for the once-every-2-weeks schedule and 200 mg/m2 for the once-every-3-weeks. In a phase II study in patients with advanced colorectal cancer, this combination was compared with raltitrexed as first-line treatment. The combination showed an acceptable toxicity profile after dose-reduction of irinotecan to 150 mg/m2 once every 3 weeks.410
In phase I and/or II studies, irinotecan has also been combined with numerous other cytotoxic and noncytotoxic agents, including etoposide,414, 415carboplatin,416, 417, 418 docetaxel,419, 420, 421, 422, 423 paclitaxel,424, 425 gemcitabine,426 and mitomycin-C,427, 428 and in a triplet combination with carboplatin and docetaxel.429, 430 The various combination treatment regimens with irinotecan have previously been reviewed extensively.252
The compound 9-NC (RFS2000, rubitecan, Orathecin) is a camptothecin analog (Fig. 17.1, Table 17.9) that has a nitro group in the C-9 position and is highly insoluble in water. 9-NC is partially metabolized in vivo to an active metabolite, 9-AC.431, 432 Since nearly all human cells are able to convert 9-NC to 9-AC, including tumor cells, it has been difficult to identify whether the 9-NC–mediated antitumor activity is directly associated with the parent drug alone, 9-AC alone, or the combination of both. Most likely the antitumor activity is associated with both 9-NC and 9-AC. However, because in patients most of the drug remains in the 9-NC form, the antitumor activity may be predominantly due to 9-NC.
In preclinical studies, 9-NC has shown excellent anticancer activity in nude mice bearing human tumor xenografts, including breast cancer,433, 434 ovarian cancer,435 and melanoma.436, 437 It is predominantly being developed clinically as an oral agent to mimic the protracted schedule and maximize patient convenience,438 in spite of extensive inter- and intrapatient variability in bioavailability.439 The recommended dose of 9-NC orally is 1.5 mg/m2 per day for 5 days each week for 8 weeks. This regimen has been used in phase I440, 441, 442 and phase II studies in patients with solid tumors and leukemia443, 444, 445, 446,447, 448 and in phase III studies in patients with newly diagnosed and refractory pancreatic cancer.449 Administration of aerosolized liposomal 9-NC in the treatment of advanced pulmonary malignancies is also being evaluated.450, 451, 452, 453, 454, 455
In a phase II trial of 9-NC at a dosage of 1.5 mg per m2 per day daily for 5 days each week, a response rate of 32% (95% CI, 20 to 45%) was seen in 60 evaluable patients with advanced pancreatic cancer.456 Phase III studies of 9-NC administered orally daily for 5 days per week in patients with newly diagnosed and refractory pancreatic cancer have also been completed, although only the results of the randomized phase III study of 9-NC versus best choice in patients with refractory pancreatic cancer have been reported.449 In patients with measurable disease (59%), there were 12 independently verified (i.e., blinded radiology reviewed) responders of 9-NC (2 CR and 10 PR), for an overall response rate of 11%, compared with one responder (<1%, 1 CR) for patients treated on the best alternative chemotherapy arm (P <0.001). The median progression-free survival (PFS) was significantly longer for the 9-NC arm (58 days) than for the best alternative chemotherapy (48 days) (P = 0.003). 9-NC was well tolerated as < 5% of patients discontinued treatment due to toxicity. The results of this study support the notion that 9-NC has an acceptable risk-benefit ratio, is convenient to use, and can achieve tumor growth control in a disease with few treatment options.
Phase II studies of single-agent 9-NC have been performed in patients with various solid tumors. 9-NC has achieved antitumor activity in patients with refractory ovarian cancer443 and refractory gastric cancer.457 However, 9-NC has been shown to be inactive against metastatic colorectal cancer,458 advanced glioblastoma multiforme,459 soft-tissue sarcoma,446 urothelial tract cancers,447 and SCLC.448 9-NC has also been evaluated in patients with chronic myeloid leukemia, chronic myelomonocytic leukemia (CML), and myelodysplastic syndromes.460 Although the response rate in Ph-positive CML is low, one cytogenetic response was noted. Further studies are needed to better define the dose and schedule of 9-NC for the treatment of CML and MDS.460 An evaluation of the feasibility of combining 9-NC with other cytotoxic agents, including gemcitabine461 and capecitabine441 in patients with solid tumors, is currently ongoing.
TABLE 17.9 KEY FEATURES OF SYNTHETIC DERIVATIVES OF CAMPTOTHECIN
9-AC is a camptothecin derivative (Fig. 17.1, Table 17.9) with impressive preclinical activity in human xenograft models of colon cancer,109, 462 malignant melanoma,436 prostate cancer,463 breast cancer,433 ovarian cancer,435 acute leukemia,464 bladder cancer,465 and CNS metastatic tumors.462 In three human colon cancer xenografts, 9-AC was highly active, exhibited minimal systemic toxicity, and produced a better antitumor response than a panel of nine anticancer agents, including 5-FU, doxorubicin, melphalan, methotrexate, vincristine, vinblastine, and several nitrosourea compounds.109
Clinical testing of 9-AC began in 1993 with initial phase I trials of the drug administered as a 72-hour infusion every 2 weeks466 or 3 weeks.467, 468 This schedule was selected because of the preclinical studies demonstrating that prolonged drug exposures were needed to see any biologic effect and that short i.v. infusions had no activity in animal models.469 More recently, other schedules of 9-AC administration have been developed, including a prolonged 120-hour infusion weekly,470 a 24-hour infusion weekly for 4 of 5 weeks,471 and a short i.v. infusion daily for 5 days every 3 weeks.472 On all of these schedules, the major dose-limiting toxicities are neutropenia and, to a lesser extent, thrombocytopenia. Other common toxicities included anemia, fatigue, nausea and vomiting, diarrhea, alopecia, and mucositis. The compound 9-AC is not associated with pulmonary toxicity or hemorrhagic cystitis, and the diarrhea is much less severe than that seen with irinotecan. Phase I trials involving pediatric patients473 and acute leukemia patients474 have also been completed. Oral administration475, 476 and i.p. schedules for 9-AC have also been studied.477
In pharmacokinetic studies, the amount of 9-AC that is present in plasma relative to the total drug level (lactone plus carboxylate) is quite low, with most reported values below 10%.117 This observation is consistent with earlier studies demonstrating that 9-AC lactone exhibits greater instability in human plasma than do other camptothecin derivatives such as topotecan or irinotecan.478 Most of the reported terminal elimination half-lives for total 9-AC in plasma have been in the range of 7 to 10 hours.479 Reports suggest that patients receiving anticonvulsant medications may have increased clearance and lower plasma drug levels of 9-AC.480 In pharmacodynamic studies, 9-AC steady-state plasma concentrations481, 482 and AUC471, 472, 483 correlated with the dose-limiting toxicity of neutropenia.
In phase II studies of 72-hour infusions of 9-AC administered at 50 to 59 µg/m2 per hour every 2 weeks to 16 previously treated patients with metastatic colorectal cancer, no responses were observed, and the myelosuppressive toxicity was substantial.484 Grade 4 neutropenia occurred in 56% of patients, and febrile neutropenia occurred in 31%. In another trial in which 17 previously untreated patients with this disease were given a lower dose of 35 µg/m2 per hour for 72 hours every 2 weeks, no responses were observed.485 In heavily pretreated patients with relapsed or refractory lymphoma administered 9-AC at 40 µg/m2 per hour over 72 hours every 3 weeks with G-CSF support,486 the response rate was 25% (95% CI, 13 to 41%), with 10 partial responses seen in 40 evaluable patients. The median duration of response was 5 months (range, 1 to 10 months), and the median survival time was 12.5 months. In 58 untreated patients with advanced NSCLC treated with 46 to 59 µg/m2 per hour over 72 hours every 2 weeks, the overall response rate was 8.6% (95% CI, 2.9 to 19%),487 and the median survival was 5.4 months. Again, myelosuppressive toxicity was substantial, with grade 4 neutropenia seen in 31% of patients overall. Using similar treatment schedules, 9-AC was found to have minimal activity in refractory breast cancer488 and metastatic colorectal cancer.489 Thus, in phase II trials, the antitumor activity of 9-AC on the 72-hour infusion schedule has been disappointing. Efforts to improve its activity include the development of longer infusion schedules.470 Seventeen previously untreated patients with metastatic colorectal cancer were given 9-AC as a 120-hour infusion at 20 µg/m2per hour for 120 hours every week for 3 of 4 weeks; however, no responses occurred.490
Thus, despite its impressive preclinical activity in human colon cancer xenograft models, 9-AC has not shown effective antitumor activity in the clinical studies completed to date. One potential explanation for this discrepancy may be the inability to achieve the necessary plasma drug concentrations needed for antitumor efficacy.491 Because human bone marrow stem cells are more sensitive to 9-AC than is murine bone marrow, dose-limiting myelosuppression made it impossible to achieve the same plasma drug concentrations in humans that were associated with optimal antitumor efficacy in the preclinical animal models.492
EXATECAN MESYLATE (DX-8951f)
The hexacyclic camptothecin analog exatecan mesylate (DX-8951f) ([1S,9S]-1-amino-9-ethyl-5-fluoro-1,2,3,9,12,15-hexahydro-9-hydroxy-4-methyl-10 H,13H-benzo[de]-pyrano[3′,4′:6,7]-indolizino[1,2-b]quinoline-10,13-dione monomethane sulfonate, dihydrate) is a synthetic derivative with an amino group at C-1 and a fluorine atom at C-5 (Table 17.9). The compound has increased aqueous solubility in comparison with other camptothecin analogs. As exatecan does not require enzymatic activation, inter-individual variability in efficacy and side effects might be reduced as compared to some prodrug analogs.493 The anhydrous free-base form of the drug is referred to as DX-8951. The lactone form of DX-8951 is hydrolyzed into an open-ring hydroxy-acid form, comparable with most other camptothecins. Similarly, the lactone and hydroxy-acid form coexist in solution according to a reversible pH-dependent equilibrium.494, 495
Exatecan showed superior and a broader spectrum of antitumor activity in vitro and in vivo in comparison with some other camptothecin analogs tested.496,497, 498, 499, 500, 501, 502 Comparable with other camptothecin derivatives, exatecan is metabolized by CYP3A4 and CYP1A2, resulting in the formation of at least two hydroxylated metabolites referred to as UM-1 and UM-2.503 The antitumor activity of these metabolites is much less potent than the parent compound itself.494, 504
Phase I clinical studies included DX-8951f administered as a 30-min i.v. infusion once every week505 or every 3 weeks,506, 507 as a 30-min i.v. infusion daily for 5 days508 or 7 days every 3 weeks,509 as a 24-hour continuous i.v. infusion every week510 or every 3 weeks,511 and as a protracted 5- to 21-day infusion.512
Reversible, noncumulative, and dose-related neutropenia was the DLT in all schedules.505, 506, 507, 508, 509, 510, 511, 512 With the prolonged continuous infusion schedules, thrombocytopenia was an added DLT, especially in heavily pretreated patients.511, 512 Neutrophil and platelet count nadirs occurred between days 10–15, with recovery by day 22. Non-hematological toxicities included mild to moderate gastrointestinal toxicity (nausea, vomiting, stomatitis, diarrhea), fatigue, asthenia and alopecia.505, 506, 507, 508, 510, 511, 512 Transient and reversible liver dysfunction was also observed and in a Japanese study this event was dose-limiting at the dose of 6.65 mg/m2.506, 508 In advanced leukemia, stomatitis was dose limiting.509 Remarkably, the MTD in leukemia (0.9 mg/m2/daily for 5 days) is almost double of that observed in solid tumors.509
For phase II clinical trials, the 30-min infusion regimen with daily administration for 5 consecutive days every 3 weeks was selected because this schedule in phase I studies showed the most prominent signs of antitumor activity. However, at this dose and schedule, DX-8951f appears to lack significant activity in metastatic breast cancer,513 NSCLC,514 advanced ovarian cancer,515 and colorectal cancer.516
Like exatecan, lurtotecan (GI147211, GG211) is a hexacyclic camptothecin analog currently under clinical investigation as an anticancer drug (Table 17.9). Lurtotecan is a water-soluble, totally synthetic derivative with a dioxalane moiety between C-10 and C-11.517 Because of the agent's low oral bioavailability,518lurtotecan has been evaluated clinically in various phase I trials using a 30-minute i.v. infusion given daily for 5 consecutive days519, 520 or a 72-hour521 or 21-day522 continuous i.v. infusion. The dose-limiting toxicity in all schedules was myelosuppression, including severe neutropenia and thrombocytopenia. Nonhematological toxicities were various and only mild to moderate. In phase II trials, lurtotecan has shown only modest activity in breast cancer, colorectal cancer, NSCLC,523 and SCLC.524 Overall, the data suggest that the hematological toxicity profile, antitumor activity, and pharmacokinetic profiles closely resemble those observed with topotecan.525
Gimatecan (ST1481) is an orally administered camptothecin with a relatively long plasma half-life (>80 hours; Table 17.9).526 Gimatecan lacks schedule-dependency and has a favorable in vivo therapeutic index in several human tumor xenografts.527, 528 Thus, several schedules of orally administered gimatecan have been evaluated in phase I studies. Gianni and colleagues evaluated gimatecan administered orally daily for 5 days for 1 week (schedule A), 2 weeks (schedule B), or 3 weeks (schedule C), repeated every 4 weeks.529 The qualitative toxicity pattern was similar in all schedules, and late onset thrombocytopenia followed by neutropenia was dose limiting in all schedules. The MTD on schedule A was 5.6 mg/m2 per cycle, and on schedule B and C it was 7.2 mg/m2 per cycle. Partial responses were documented in patients with NSCLC, breast cancer, and rhabdomyosarcoma.
A phase I/II study of gimatecan administered orally once a day for 5 consecutive days repeated every 28 days was performed in patients with recurrent malignant glioma where the dose was independently escalated based on concurrent use of enzyme-inducing anticonvulsants (EIAEDs).530 The mean ± SD terminal half-lives in the EIAED and non-EIAED groups were 6.3 ± 4.7 hours and 71 ± 28 hours, respectively. In addition, the AUC of day 5 in the EIAED group was 81% lower than in the non-EIAED group. Thus, the apparent clearance of gimatecan is markedly increased in patients coadministered EIAEDs. In addition, the authors concluded that the drug is well tolerated and shows initial promise in the treatment of patients with malignant glioma.
Due to the long plasma half-life, Zhu and colleagues performed a phase I trial of gimatecan administered orally once a week for 3 of 4 weeks at doses from 0.26 to 1.32 mg/m2 per week, without significant toxicity.531 Gimatecan was rapidly absorbed and slowly eliminated, with a mean apparent half-life of 108 ± 40 hours. The authors concluded that administration of gimatecan orally once a week at doses that are well tolerated provides continuous exposure to potentially effective plasma concentrations of the drug.
Diflomotecan (BN80915) belongs to the class of fluorinated homocamptothecins (Table 17.9). Homocamptothecins are synthetic, water-insoluble camptothecin analogs with a stabilized lactone ring due to modification of the naturally occurring 6-membered ring into a 7-membered ring by insertion of a methylene spacer between the alcohol and the carboxyl moiety.532 The inductive effect from the electronegative oxygen of the adjacent hydroxyl group causes higher reactivity of the carboxyl group of camptothecins. By inserting a methylene spacer between the carboxylic and alcoholic functions of the E ring, it was believed that the electronic influence of the hydroxyl group was removed.533 The alcohol moiety was seen as an important structure for stabilizing the cleavable complex, because neither deshydroxy-camptothecin nor the nonnatural enantiomer of camptothecin is biologically active.533 Since a one-carbon ring expansion is chemically termed a homologation, these new lactone- or E-ring modified compounds were named homocamptothecins.
In comparison with most other camptothecins, which show rapid hydrolysis of the lactone moiety until a pH and protein–dependent equilibrium has been reached, homocamptothecins display a slow and irreversible hydrolytic lactone-ring opening.534 This key feature, irreversibility of the E-ring opening, may lead to reduced toxicity.
Diflomotecan has entered phase I clinical testing. Oral diflomotecan administered once daily for 5 days every 3 weeks, was limited by dose-dependent myelosuppression.535 Other toxicities observed were gastrointestinal (i.e., mild nausea and vomiting, alopecia, and fatigue). The recommended dose for phase II studies is 0.27 mg given once daily for 5 days every 3 weeks.
Oral diflomotecan exerts an apparent linear, dose-independent pharmacokinetic profile over a large dose range studied, with high inter- and intrapatient variability. It was also reported that flat dosing of oral diflomotecan resulted in the same variation in AUC as dosing per square meter would have done, as already established for many other cytotoxic agents.237 The oral bioavailability (F) of diflomotecan at the recommended dose was 67.1%, which is much better than for other oral topoisomerase I inhibitors such as topotecan (F = 30 to 44%)134, 136 and 9-AC (F = 48.6%).536 Preliminary pharmacogenetic analysis has indicated that the ABCG2 421C>A genotype significantly affects the systemic disposition of diflomotecan.537 This suggests that, in the future, population pharmacokinetic studies incorporating this pharmacogenetic information might enable a reduction in interindividual pharmacokinetic variability.
SILATECANS AND HOMOSILATECANS
Since the closed, active lactone ring is a structural requirement for effective biologic activity of the camptothecins,115 many researchers have investigated various modifications of the camptothecins in an effort to promote lactone stability yet retain antitumor efficacy. One approach to synthesize a more stable topoisomerase I inhibitor has included structural modifications that eliminate the highly preferential binding of the carboxylate form to HSA and thus reduce the rate of hydrolysis. In addition, the discovery of lactone stabilization through lipid bilayer partitioning has led to the design of more lipophilic analogs in order to promote partitioning of these agents into the lipid bilayers of erythrocytes and protect the active lactone form from hydrolysis.538
The synthesis of 7-silycamptothecins by adding a silyl group at position 7 with various substitutions at position 10 has demonstrated increased stability of the lactone ring.539, 540 The addition of a silyl group may limit drug inactivation by both protein binding and hydrolysis of the lactone ring and may also enhance lipophilicity, which would increase in vivo activity while possibly limiting toxicity.541 The majority of these new compounds demonstrate potencies comparable to or better than other camptothecin derivatives. Two of the leading members of this class, DB-67 and karenitecin (BNP1350), are in preclinical and phase II development, respectively. Preclinical nonhuman primate and phase I clinical studies of karenitecin indicated the percent lactone was 104% and 87 ± 11%, respectively.542, 543 DB-67 was found to have antitumor activity more potent than that of topotecan and at least comparable to that of SN-38 against a panel of five high-grade glioma cell lines.541 Although the results of this study are promising for the future treatment of human gliomas, it is unclear if the increased stability of the lactone ring in human blood and its potentially increased lipophilicity will translate into increased activity in humans. One potential problem is that silatecans have low penetration into the CSF.542
Homocamptothecins have been further modified to form homosilatecans.544 In addition to the expanded β-hydroxylactone E ring, each of the homosilatecans also contains a silylalkyl functionality at the 7-position. As with the silatecans, this functionality group increases the lipophilicity while reducing the strength of carboxylate interactions with HSA. Two homosilatecans, DB-90 and DB-91, contain amino and hydroxyl groups at the 10-position, respectively, to further reduce binding of the carboxylate form to HSA. Homosilatecans display improved lipophilicity and stability in human whole blood compared with camptothecin and topotecan. Interestingly, homosilatecans display similar stability in human and mouse blood, which contrasts with the interspecies variations in blood stability observed for camptothecins.544 Thus, preclinical animal modeling and efficacy studies with the homosilatecans may be predictive of their use in a clinical setting.
ALTERNATIVE FORMULATIONS AND PRODRUGS
Several different liposomal formulations of camptothecin analogs, including camptothecin,545 topotecan,546 irinotecan,547 SN-38,548 lurtotecan,549 and 9-NC,451 have been designed. The main goals of these strategies were to overcome the limited water solubility of camptothecins, increase the lactone stability, prolong the duration of exposure in plasma and tumor, and improve the therapeutic index by increasing tumor delivery of the active drug and reducing toxicity. In addition, since camptothecin analogs are topoisomerase inhibitors that exhibit cell cycle–dependent antitumor activity, the prolonged exposures may increase cytotoxic effects.35
Because the oral bioavailability of lurtotecan was previously shown to be highly variable and as low as 10%,518 alternative methods of drug administration are currently being developed, including a new liposomal formulation (OSI-211; also known as NX 211). Preclinical data have been generated demonstrating that this unilamellar liposomal formulation of lurtotecan has a significant therapeutic advantage over the free drug, showing increased antitumor activity in xenograft models, which is consistent with increased systemic exposure and enhanced tumor-specific delivery of the drug.550 Based on these exciting data, phase I clinical trials have been performed, with OSI-211 given to cancer patients as a 30-minute infusion either once551 or daily for 3 days every 3 weeks.552,553, 554 As expected, the dose-limiting toxicities in these trials were neutropenia and thrombocytopenia, and pharmacological findings seem to agree with the preclinical profile of this agent. Indeed, the clearance of total lurtotecan following administration of OSI-211 was approximately 25-fold slower than that of the free drug,551 which might prove to be beneficial for the pharmacodynamic outcome of treatment. A phase II study in which OSI-211 was delivered at a dose of 2.4 mg/m2 on days 1 and 8 of a 3-week schedule lacked significant activity in patients with topotecan-resistant ovarian cancer.555 Clinical evaluation of this agent in other patient populations and/or with alternative schedules is currently ongoing.
SN-38, the active metabolite of irinotecan, thus far has not been used as an anticancer drug due to poor solubility in any pharmaceutically acceptable solvent as well as its rapid elimination.285 An alternative i.v. formulation involving liposomal encapsulation of SN-38 has been recently presented.548 The liposomal formulation of SN-38 overcomes the need for administration of the prodrug, irinotecan, and the variability associated with irinotecan administration and subsequent formation of SN-38 by CES2. SN-38 has low affinity to lipid membranes, and it tends to precipitate in aqueous phase, resulting in very low drug-to-liposome entrapment. A novel liposomal formulation of SN-38 has been developed to overcome these issues.548 In this liposomal formulation, SN-38 drug partitions into the bilayer of the liposome. As a result, SN-38 in biological solutions (e.g., blood or plasma) may be immediately released from the liposome. Thus, SN-38 is likely to predominantly exist in the circulation as released, nonencapsulated SN-38. In view of the important role of UGT1A1*28 in SN-38 elimination, pharmacogenetic analyses of UGT1A1*28 have been implemented prospectively as part of a phase I study of liposomal encapsulated SN-38 in patients with advanced cancer.556
Pegylation of liposomes (Stealth(R)) was initially developed to avoid uptake of liposomes by the mononuclear phagocyte system (MPS), thus allowing liposomes to remain in the circulation for longer periods of time than nonpegylated liposomes.557, 558, 559 Stealth liposomal CKD602 (S-CKD602) is a liposomal formulation similar to Stealth liposomal doxorubicin (Doxil)560: the drug is contained in the core of the liposome, and the outer layer of the liposomal bilayer contains a phospholipid covalently bound to methoxypolyethylene glycol (MPEG). The purpose of the encapsulating CKD602 in a Stealth liposome is to maintain the lactone stability, prolong the elimination half-life in plasma, increase the drug exposure in the tumor, and potentially improve antitumor efficacy. In preclinical studies, S-CKD602 produced significantly enhanced antitumor efficacy over that of nonliposomal CKD602 in human xenograft models of ovarian, melanoma, colon, and SCLC carcinomas.561, 562 S-CKD602 is currently being evaluated in a phase I study.
Polyethylene Glycol-Conjugated Prodrugs
An alternative strategy to optimize the therapeutic indices and feasibility of administering camptothecin involves conjugating camptothecin to a chemically modified polyethylene glycol (PEG) macromolecule.563, 564, 565 The highly water soluble and stable prodrug pegylated camptothecin (PEG-CPT, EZ-246, Prothecin) undergoes enzymatic hydrolysis that releases camptothecin in tissues and biological fluids. An advantage of this approach is that the acylated camptothecin prodrug maintains the E ring in its desired active lactone form.564 Selective tumor distribution may also occur as a result of the high molecular and specific physiochemical properties of PEG-camptothecin, which potentially results in enhanced vascular permeation and intratumoral retention. Furthermore, PEG-camptothecin has demonstrated an impressive and broad spectrum of antitumor activity in xenograft models.564
In a phase I study in patients with advanced solid tumors, the recommended dose of PEG- camptothecin was 7,000 mg/m2 as a 1-hour infusion every 3 weeks.566 The primary toxicity was myelosuppression; cystitis, nausea, vomiting, and diarrhea were also observed but were rarely severe. The plasma dispositions of PEG-camptothecin and released camptothecin are complex, reflecting the interplay between both forms. The elimination half-life (77 ± 37 hour) of PEG- camptothecin is significantly longer than that reported for most other camptothecin analogs.566 In addition, released camptothecin accumulated slowly in plasma. A phase II study of PEG-camptothecin in patients with adenocarcinoma of the stomach and gastroesophageal junction reported responses in 4 of 15 patients.567 The regimen was well tolerated, with a low incidence of grade 3 and 4 toxicities. Two subjects developed grade 2 cystitis and also reported dehydration.
Over the past several years, the camptothecins have evolved from an experimental class of antitumor agents into established agents with documented clinical utility in the treatment of human malignancies. Despite our growing understanding of the pharmacology of the topoisomerase I inhibitors, several important issues must still be resolved. One is to determine the optimal method of combining these agents with other active drugs or treatment modalities such as radiation and biologic agents. Current laboratory and clinical investigations of camptothecin drug combinations may help guide further clinical development in this area. A more difficult question is why marked differences exist in the clinical activity of different camptothecin derivatives. Agents such as camptothecin and 9-AC are potent inhibitors of topoisomerase I at the molecular level, yet their clinical utility appears to be much less than that of topotecan or irinotecan. Some of this variation may be related to the clinical pharmacology of these agents, but pharmacologic differences do not fully explain the differences in clinical efficacy. Further studies of their molecular pharmacology and a clearer understanding of the relevant molecular determinants of response to the topoisomerase I poisons may help to clarify these issues and aid development of even more effective topoisomerase I poisons.
Almost 40 years after they first showed promising anticancer activity in a National Cancer Institute screening program, the camptothecins are established agents for the treatment of human cancer. Nonetheless, we are still learning how to optimally incorporate these agents into effective cancer treatments. The development of the camptothecins has also helped to elucidate the basic function of the topoisomerase I protein at the molecular level, and these agents have provided investigators with a valuable research tool for studying this important enzyme. The documented clinical activity of the camptothecins has highlighted topoisomerase I as a key target for cancer chemotherapy and has thereby allowed the development of completely new pharmacologic strategies for the treatment of human cancer.
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