Antiepileptic Drugs, 5th Edition



Chemistry, Biotransformation, and Pharmacokinetics

Dennis R. Doose PhD*

Anthony J. Streeter PhD**

* Associate Director, Global Clinical Pharmacokinetics and Clinical Pharmacology, Johnson & Johnson Pharmaceutical Research and Development, Raritan, New Jersey

** Research Fellow, Department of Drug Metabolism, Johnson & Johnson Pharmaceutical Research and Development, Spring House, Pennsylvania


Topiramate is a structurally novel antiepileptic drug (AED) (1, 2, 3) marketed in the United States under the brand name Topamax. It is marketed in other countries under the brand names Topimax, Topamac, and Epitomax. Chemically, topiramate is a derivative of D-fructose in the pyranose configuration, and it is identified by the names 2,3:4,5-di-O-isopropylidene-β-D-fructopyranose sulfamate or 2,3:4,5-bis-O-(1-methylethylidene)-β-D-fructopyranose sulfamate. Topiramate has the molecular formula C12H21NO8S and a molecular weight of 339.4. Its chemical structure is provided in Figure 78.1.

Topiramate drug substance is a white crystalline powder with a bitter taste. Topiramate is most soluble in alkaline solutions containing sodium hydroxide or sodium phosphate and having a pH of 9 to 10. It is freely soluble in acetone, chloroform, dimethylsulfoxide, and ethanol. The solubility in water is 9.8 mg/mL at room temperature. A saturated aqueous solution has a pH of 6.3. Aqueous solubility is increased by the addition of cosolvents, such as propylene glycol or polyethylene glycol 400, 1,500, 4,000, or 6,000 (4).



After oral administration of any commercial formulation, topiramate is rapidly absorbed, with peak plasma concentration occurring at approximately 2 to 4 hours (5). Although oral bioavailability has not been assessed by a classic intravenous-oral crossover comparison in humans, the absolute bioavailability of orally administered topiramate has been estimated to be 81% to 95% based on pharmacokinetic data obtained from a study in subjects with different degrees of renal impairment (6). Absolute bioavailability was calculated as the inverse of the slope of the linear regression curve fit to oral clearance as a function of renal clearance data. The equation for this relationship is:

where Cl is total body clearance, F is bioavailability, ClR is renal clearance, and ClNR is nonrenal clearance.

The extent of absorption estimated pharmacokinetically is consistent with the results obtained after the oral administration of a 100-mg solution dose of [14C]-topiramate, in which 80.6% of the administered radioactivity was excreted in the urine over 10 days (7). Administration with food slightly slows absorption (11% to 13% decreased mean maximum concentration), but with equivalent extent of absorption (-4% to 13% difference in mean area under the curve) (8). These differences in the rate and extent of absorption are not considered clinically significant.


FIGURE 78.1. Chemical structure of topiramate.



Topiramate is available commercially as coated tablets and as coated beads (sprinkle) in a gelatin capsule. Coated tablets are available in the following strengths and colors: 25-mg white, 100-mg yellow, 200-mg salmon. Because of the bitter taste of topiramate, it is recommended that tablets not be broken (4).

The encapsulated sprinkle formulation is available for those patients who have difficulty in swallowing tablets, such as pediatric and elderly patients, and it is available in 15- and 25-mg strengths (4). Topiramate sprinkle capsules may be swallowed whole or may be administered by carefully opening the capsule and sprinkling the entire contents on a small amount (teaspoon) of soft food. This drug-food mixture should be swallowed immediately and not chewed. It should not be stored for future use. The tablet and sprinkle formulations are bioequivalent (4). Consuming the sprinkle formulation on food or encapsulated results in bioequivalent exposure. Topiramate tablets and sprinkle capsules should be stored in tightly closed containers at controlled room temperature and protected from moisture (4).

Routes of Administration

Topiramate has been evaluated in humans only after oral administration. There are reports of investigating the use of topiramate after gastric tube and rectal administration. At present, however, no definitive information exists on the therapeutic utility of these routes of administration.


FIGURE 78.2. Mean concentration of total radioactivity in blood and selected tissues and organs of female Wistar rats after a single oral 10 mg/kg dose of 14C topiramate.


Plasma Protein Binding

The plasma protein binding of topiramate has been studied in vitro using radiotracer methods and microequilibrium dialysis techniques. Topiramate is poorly bound to plasma proteins. Generally, between 9% and 17% of topiramate over a concentration range of 1 to 250 µg/mL is bound to plasma proteins (unpublished data, R.W. Johnson Pharmaceutical Research Institute). The clinically relevant topiramate plasma concentration range has been found to extend to ≤33 µg/mL.

Cerebrospinal Fluid, Brain, and Other Tissues

Tissue distribution of topiramate was assessed in the female Wistar rat at 1, 6, 24, and 48 hours after single oral administration of [14C]-topiramate by quantitative whole-body autoradiography. The amount of radioactivity was determined by densitometry on the exposed autoradiographs, and the results are presented in Figure 78.2 (unpublished data, R.W. Johnson Pharmaceutical Research Institute). Validating that this study primarily characterized the tissue distribution of topiramate, parallel studies showed by thin-layer chromatography analysis that most (>83%) of the total radioactivity in plasma, liver, and kidney during the first 24 hours after dosing (unpublished data, R.W. Johnson Pharmaceutical Research Institute), and in brain (96%) at 2 hours after administration (9), was unchanged topiramate. Radioactivity was rapidly absorbed and was quickly distributed


into the tissues. The mean concentrations of radioactivity in the brain were less than or equivalent to those in the plasma at 1, 6, 24, and 48 hours after dose administration in both sexes. Exposure of topiramate to the eye was minimal, as evidenced by the low radioactivity detected in this organ. The radioactivity was rapidly eliminated from all tissues, with negligible amounts remaining by 48 hours.

High-affinity, low-capacity binding of topiramate to erythrocytes has been identified. This is postulated to be the result of binding to carbonic anhydrase enzymes present in erythrocytes. In humans, two distinguishable binding sites have been identified, with binding constants of 0.52 and 87 µmol/L (unpublished data, R.W. Johnson Pharmaceutical Research Institute). In blood, this binding rapidly becomes saturated and does not significantly influence systemic clearance at clinically relevant concentrations. As indicated, tissue distribution studies showed that topiramate was most highly concentrated in blood, kidney, liver, and lung. Because these tissues are known to be highly enriched with carbonic anhydrase (10), the higher concentrations in these tissues may be explained by binding to carbonic anhydrase.


Although topiramate has a chemical structure similar to that of carbohydrates, no carrier-mediated transporters appear to be significantly involved in drug absorption because food appears to have only a dilutional effect on the rate of absorption. Similarly, tissue distribution is rapid, with no evidence of transporter-dependent exposure.


FIGURE 78.3. Mean tissue levels of radioactivity in pregnant female Sprague-Dawley rats after a single oral 20 mg/kg dose of [14C]-topiramate.

Transplacental Passage

Transplacental distribution of topiramate was assessed as part of the preclinical evaluation of topiramate (unpublished data, R.W. Johnson Pharmaceutical Research Institute). A single oral dose of [14C]-topiramate (20 mg/kg) was administered to pregnant female Sprague-Dawley rats on day 11 of gestation. Concentrations of total radioactivity in blood, plasma, fetuses, and selected maternal organs were determined by tissue excision and liquid scintillation spectrometry at 1, 6, 24, and 48 hours after administration. The mean data are presented in Figure 78.3.

Radioactivity was found to distribute rapidly into the fetus and all maternal organs. Concentrations of topiramate and total radioactivity in the fetus and most maternal tissues were found to decline with time in parallel with maternal plasma concentrations.

Breast Milk

Öhman et al. (11) described the excretion of topiramate in human breast milk. Two patients receiving topiramate therapy were evaluated. Simultaneous maternal plasma and breast milk sampling 2 to 3 weeks after delivery was conducted. Reported coincident breast milk/maternal plasma concentrations (mol/L) were 7.6/6.3 and 15/17 in the two patients, respectively. The nursing infant:mother plasma concentration ratio was 0.1 to 0.2. Thus, it appears that infants are exposed to marginal pharmacologically significant amounts of topiramate during nursing.





When administered in the absence of enzyme inducers, topiramate is not extensively metabolized. Under this condition, a significant percentage of the dose (~40% in 10 days) is excreted in urine as intact topiramate (7). When it is administered during concomitant therapy with enzyme inducers, the extent of metabolism is significantly greater, but the metabolic profile appears similar. Seven trace metabolites from three types of metabolic pathways—hydroxylation or hydrolysis of the isopropylidene groups, and conjugation (each <3% of the administered radioactivity)—have been identified and characterized (Figure 78.4)


(7,12, 13, 14). The two metabolites retaining most of the parent drug structure, metabolites 2 (unpublished data, R.W. Johnson Pharmaceutical Research Institute) and 5 (15) (Figure 78.4), show little or no anticonvulsant activity in animal tests. The major route of elimination of unchanged topiramate and its metabolites is by the kidney.


FIGURE 78.4. Metabolites: a rearranged product of a hydroxytopiramate (1); 4,5-O-(2-hydroxy-1-methylethylidene)-2,3-O-methylethylidene)-β-D-fructopyranose-1-sulfamate(2); 2,3:4,5-bis-O-(2-hydroxy-1-methylethylidene)-β-D-fructopyranose sulfamate (3); 4,5-O-(1-methylethylidene)-β-D-fructopyranose-1-sulfamate (4); 2,3-O-(1-methylethylidene)-β-D-fructo-pyranose-1-sulfamate (5); 2,3- or 4,5-O-(1-methylethylidene)-β-D-fructopyranose (6); 4,5-O-(2-hydroxy-1-methylethyli-dene)-2,3-O-(1-methyl-ethylidene)-β-D-fructopyranose-1-sulfamate-O-glucuronide (7); 4,5-O-(1-methylethylidene)-β-D-fructopyranose-1-sulfamate-O-glucuronide (8); and 2,3:4,5-bis-O-(1-methylethylidene)-β-D-fructopyranose-1-sulfamate-N-glucuronide (9). Only metabolites 1, 2, 4, 5, 7, 8, and 9 have been detected in humans. Proposed pathways: (A)hydroxylation at the 7- or 8-methyl group followed by rearrangement to yield metabolite 1; (B) hydroxylation at the 10-methyl group to yield metabolite 2, followed by glucuronidation to yield metabolite 7; (C) hydrolysis at the 2,3-O-isopropylidene group to yield metabolite 4, followed by glucuronidation to yield metabolite 8; (D) hydrolysis at the 4,5-O-isopropylidene group to yield metabolite 5; (E) cleavage at the sulfamate group to yield metabolite 6; and (F) N-glucuronidation of topiramate to yield metabolite 9.Metabolite 3 may be the product of a second hydroxylation of either metabolite 1 or metabolite 2.

Genetic Factors

There are no reports of genetic factors that influence the pharmacokinetics of topiramate.


The specific metabolic enzymes responsible for the metabolism of topiramate have not been identified. However, it is evident the enzymes induced by phenytoin and carbamazepine play a major role in the clearance of topiramate when the drug is administered with these agents.

Biliary and Renal Excretion

The major route of elimination of unchanged topiramate and its metabolites is by the kidney. A significant percentage of the dose (~40% in 10 days) is excreted in urine as intact topiramate (7).

The dependence of topiramate pharmacokinetics on renal function and hepatic disease was evaluated in separate studies. In two renal impairment studies, patients with moderate and severe renal impairment (creatinine clearance 30 to 60 mL/min/1.73 m2 and <30 mL/min/1.73 m2) (16) and patients with end-stage renal disease were studied (17). In a third study, patients with moderate to severe hepatic impairment were investigated (18). The results of these studies are summarized in Table 78.1.


Type of Subject


F (%)

V/F (L)

Plasma Protein Binding (%)

Half-life (h)

CL/F (mL/min)

CLR (mL/min)

Healthy subjects and patients with epilepsy without concomitant enzyme inducers





Patients with epilepsy with concomitant enzyme inducers











Severe renal impairment (CLCR <30 mL/min)







Moderate renal impairment (CCR: 30-69 mL/min)





Renal dialysis




Hepatic disease





C, clearance; CCR, creatinine clearance; CL/F, volume of distribution divided by bioavailability; CLR, renal clearance; F, bioavailability; NS, not studied; Tmax, time to maximum plasma concentration, VF, volume of distribution divided by bioavailability.

Considering the high renal clearance of topiramate, it is not surprising that renal impairment significantly decreases apparent clearance and increases half-life. Based on these observations, renally impaired patients accumulate topiramate to a greater extent after multiple doses and require a significantly longer time to reach steady state. Therefore, the administration of topiramate to renally impaired patients should be done starting at lower doses and with longer intervals of dose titration.

Topiramate is cleared by hemodialysis at a rate that is four to six times greater than in an otherwise healthy person. Accordingly, a prolonged period of dialysis may cause topiramate concentration to fall significantly. To avoid rapid drops in topiramate plasma concentration during hemodialysis, a supplemental dose of topiramate may be required. The actual adjustment should take into account the duration of dialysis period, the clearance rate of the dialysis system used, and the effective renal clearance of topiramate in the patient undergoing dialysis.

In hepatically impaired patients, topiramate plasma concentrations may be increased. The mechanism is not well understood. The moderate decrease in apparent clearance with hepatic impairment does not appear to warrant adjustment of the topiramate dosing regimen.

No reports have evaluated the extent of biliary excretion in humans. In a study of bile duct-cannulated Wistar rats administered a single oral [14C]-topiramate dose (10 mg/kg), 37.5% and 5.3% of the radioactive dose was excreted in the bile over 24 hours for males and females, respectively (unpublished data, R.W. Johnson Pharmaceutical Research Institute). Because the extent of metabolism and clearance in the female rat is closer to that in humans, it is possible that biliary excretion could be a minor elimination pathway in clinical use.




Healthy Persons

The pharmacokinetics of topiramate is linear, with dose-proportional increases in plasma concentration. The mean plasma elimination half-life is 21 hours after single or multiple doses. Steady state is thus reached in about 4 days in patients with normal renal function. Apparent oral clearance is ~30 mL/min, most of which is renal clearance (~18 mL/min) (19,20).

Comedicated Epileptic Patients

When topiramate is administered to patients as adjunctive therapy with enzyme-inducing drugs, clearance is significantly increased. In controlled pharmacokinetic interaction studies, mean steady-state concentrations were reported to decrease 48% and 40% when topiramate was administrated with phenytoin and carbamazepine, respectively (21,22). The induced clearance appears to be entirely the result of increased nonrenal clearance, because topiramate renal clearance was comparable when administered alone or with carbamazepine.

When topiramate is administered to patients as adjunctive therapy with non-enzyme-inducing drugs, the pharmacokinetics of topiramate is comparable to that in healthy subjects. Valproic acid and lamotrigine appear to have little effect on the plasma clearance of topiramate (23,24).


The pharmacokinetics of topiramate was evaluated in pediatric subjects with epilepsy (ages 4 to 17 years) who were receiving one or two other AEDs (25). Pharmacokinetic profiles were obtained after 1 week at doses of 1, 3, and 9 mg/kg/day. Clearance was independent of dose. Pediatric patients had a 50% higher clearance and consequently shorter elimination half-life than adults. Consequently, the plasma concentration for the same (mg/kg) dose may be lower in pediatric patients compared with adults. As in adults (discussed in the previous section on comedicated epileptic patients), hepatic enzyme-inducing AEDs decreased the steady-state plasma concentrations of topiramate.

In a separate study, unchanged topiramate and six metabolites were quantified from the urine of children with infantile spasms who were between the ages of 9 and 43 months and who were receiving topiramate doses of 7 to 10 mg/kg/day (unpublished data, R.W. Johnson Pharmaceutical Research Institute). The relative amounts of topiramate and metabolites found in the urine of children with infantile spasms were similar to those observed in adults. Both infants and adults receiving topiramate adjunctive to enzyme-inducing AEDs had a higher proportion of metabolites to parent topiramate in the urine. Two metabolites, topiramate-N-glucuronide and hydroxytopiramate sulfate, were identified in trace amounts (≤8% of total metabolites) in infants but were not detected in adults. Topiramate does not appear to be metabolized significantly differently in infant children compared with adults.

Elderly Patients

The pharmacokinetics of topiramate in elderly subjects (65 to 85 years of age) was evaluated in a controlled clinical study (26). This elderly population had reduced renal function (creatinine clearance of -23%) compared with young adults. After a single oral 100-mg dose, maximum plasma concentrations for elderly and young adults were achieved at approximately 1 to 2 hours. Reflecting the primary renal elimination of topiramate, topiramate plasma concentrations and renal clearance were reduced 21% and 19%, respectively, in elderly subjects, compared with young adults. Similarly, topiramate half-life was longer (13%) in the elderly patients. Reduced topiramate clearance resulted in slightly higher maximum plasma concentration (23%) and area under the curve (25%) in elderly patients than observed in young adults. Topiramate clearance was decreased in the elderly patients only to the extent that renal function was reduced.

Characterized Intersubject Variability and Its Determinants

Aside from the obvious relationship between renal function and elimination pharmacokinetics of topiramate (see the earlier discussion of clearance and half-life in healthy persons), other determinants of pharmacokinetic intersubject variability were evaluated using a population pharmacokinetic analysis (unpublished data, R.W. Johnson Pharmaceutical Research Institute). Mixed effects of sex, age, and race were specifically evaluated. Plasma concentration data obtained during the conduct of three multicenter, well-controlled trials in subjects with refractory partial epilepsy who were taking a maximum of two concomitant AEDs were evaluated (see the description of studies discussed in the section on the relationship between plasma concentration and effect). The population pharmacokinetic model was based on a one-compartment model with first-order absorption and elimination. Parameterization of the model included terms for clearance, apparent volume of distribution, and absorption rate. Weight effects were applied to both clearance and volume terms. The database evaluated consisted of 1,239 plasma concentration measurements from 265 patients. This analysis did not reveal any group at risk of altered pharmacokinetics, although sex was found to have an effect on volume of distribution, with values about 50% lower for females. This finding may be attributed to the higher proportion of body fat in women and is of no clinical consequence because the steady-state concentration of a drug is independent of volume of distribution.




Generally, the pharmacokinetics of topiramate is linear, with dose-proportional increases in plasma concentration. This has been confirmed by comparing steady-state topiramate plasma concentrations achieved among treatment groups in multicenter, well-controlled trials in patients administered topiramate as adjunctive therapy and as monotherapy (unpublished data, R.W. Johnson Pharmaceutical Research Institute). Although the pharmacokinetics is linear, with dose-proportional increases in plasma concentration within the adjunctive and monotherapy regimens, mean steady-state concentrations decreased 40% to 50% when the drug was administrated with concomitant enzyme-inducing AEDs.


The relationship between steady-state topiramate plasma concentration and clinical efficacy and safety was evaluated in three multicenter, well-controlled trials in patients with refractory partial epilepsy who were taking a maximum of two concomitant AEDs (27). Intent-to-treat groups ranged in topiramate dose from 100 to 1,000 mg/day. Patients were titrated in weekly increments to their assigned dose or to their maximum tolerated dose, if less. These patients were maintained at their stable dose for at least 8 weeks. During both the titration period and the stabilization period, single blood samples were taken for topiramate plasma determination at selected clinical visits.

The relationship of clinical efficacy with plasma concentration was evaluated only during the stabilization period. The relationship of clinically relevant adverse events with plasma concentration was evaluated during both the titration and stabilization periods. Although most topiramate-treated patients experienced a decrease in their seizure rates, no consistent relationships were found between this reduction and topiramate plasma concentration. Statistically significantly higher concentrations were observed for the patients who reported central nervous system-related adverse events than for those patients who did not. Despite this correlation, no threshold value could be identified above which central nervous system-related adverse events were more likely to occur.


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