Pocket Oncology (Pocket Notebook Series), 1st Ed.

ANTIMETABOLITES

Angela G. Michael

Cytarabine (ara-C, Cytosar-U)

Dosing/dose adjustments: Standard dose: 100–200 mg/m2/d 24 h CIVI × 5–7 d. High dose: 1500–3000 mg/m2 IV q12h × 3 d. No renal or hepatic dose adjustments recommended (use w/caution).

PK/PD: Wide & rapid distribution, crosses BBB (conc. 40–50% plasma), hepatic metabolism, eliminated via deamination in liver, plasma, & peripheral tissue, T1/2 1–3 h

Adverse effects: Myelosuppression (DLT, black box warning (BBW), nadir biphasic 7–9 d/15–24 d), N/V (low-to-mod. emetogenic potential), diarrhea, GI ulceration, ↑ LFTs, neurotoxicity (cerebellar dysfunction, reversible, high dose), rash, conjunctivitis (high dose)

Drug-drug interactions (DDI): Cyclophosphamide (fatal CMP, case reports), MTX (↑ formation of ara-CTP), fludarabine (↑ formation of ara-CTP), gentamicin (potential ↓ efficacy of gentamicin), digoxin (↓ absorption of digoxin)

Clinical pearls: Can be administered as IT Rx. Ppx corticosteroid (0.1% dexamethasone 1–2 gtt every 6 h during & 2–7 d after) w/high dose.

Gemcitabine (Gemzar)

Dosing/dose adjustments: Pancreatic CA: 1000 mg/m2 IV weekly × 7 wks, w/1 wk rest; NSCLC: 1000 mg/m2 IV d 1, 8, 15 every 28 d; breast CA: 1250 mg/m2 IV d 1, 8 every 21 d (w/paclitaxel) OR 800 mg/m2 IV d 1, 8, 15 every 28 d; Ovarian CA: 1000 mg/m2 IV d 1, 8 every 21 d. No renal or hepatic dose adjustments recommended.

PK/PD: Intracellular metabolism by nucleoside kinases, renal excretion (92–98%), T1/2 metabolite 1.7–19.4 h

Adverse effects: Myelosuppression (DLT,  w/infusional), edema, flu-like syndrome, ↑ LFTs, ↑ Tbili, pneumonitis, infusion rxn, proteinuria, N/V (low emetogenic potential), TTP/HUS (rare)

DDI: Cisplatin (↓ clearance of gemcitabine)

Clinical pearls: Irritant, radiation sensitizer (caution w/thoracic RT)

Azacytidine (5-Azacytidine, Vidaza)

Dosing/dose adjustments: 75 mg/m2/d SQ/IV × 7d every 4 wks, ↑ dose to 100 mg/m2/d if no response after 2 cycles. Caution in pts w/renal & hepatic dysfunction. Adjust dose for tox (hematologic, ↑ BUN/Cr).

PK/PD: Does not cross BBB, hepatic metabolism via hydrolysis, bioavailability SQ ∼89%, renal excretion (50–85%), T1/2 ∼4 h

Adverse effects: Myelosuppression, N/V (mod. emetogenic potential), pyrexia, HA, dizziness, ↑ LFTs, rigors, arthralgia

DDI: No significant drug interactions

Clinical pearls: Use w/caution in pts w/altered mental status

Decitabine (Dacogen)

Dosing/dose adjustments: 15 mg/m2 every 8 h × 3 d every 6 wks OR 20 mg/m2 daily × 5 d every 28 d. No renal or hepatic dose adjustments recommended. Hold/adjust dose for tox (hematologic, serum creatinine (SCr) ≥2 mg/dL, ALT, TBili ≥2 × ULN, active or uncontrolled infxn).

PK/PD: Metabolism via deamination, T1/2 ∼30–35 min

Adverse effects: Myelosuppression (up to 90%, recovery 28–50 d), nausea (40–42%), diarrhea (28–34%), pyrexia (up to 53%), HA (23–38%), insomnia, fatigue, petechiae (12–39%), ↑ glu, ↑ Tbili, ↓ Mg, ↓ K

DDI: No significant drug interactions

Methotrexate (MTX, Trexall)

Dosing/dose adjustments: Dosing dependent on malignancy, range 30–40 mg/m2/wk to 100–12000 mg/m2 IV once. CrCl 10–50 mL/min: 50% of dose; CrCl <10 mL/min: Avoid; HD: 50% of dose. TBili 3.1–5 mg/dL or LFTs >3× ULN: 75% of dose; TBili >5 mg/dL: Avoid.

PK/PD: Extensive distribution into third-space fluids (effusions, ascites, ↑ T1/2), renal excretion (80–90% as unchanged drug)

Adverse effects: Myelosuppression, mucositis, N/V, nephrotoxicity (intratubular precipitation, direct tubular toxin), ↑ LFTs, ↑ Tbili, neurotoxicity

DDI: Probenecid, PCN, ceph., ASA, NSAIDs, sulfonamides (↓ excretion of MTX), asparaginase (↓ MTX activity), leucovorin (↓ MTX activity)

Clinical pearls: Vigorous hydration & urinary alkalinization should be implemented during Rx (↓ incidence of renal failure), requires administration of leucovorin rescue (doses >500 mg/m2)

Pemetrexed (Alimta)

Dosing/dose adjustments: 500 mg/m2 d 1 every 21 d. Renal: CrCl < 45 mL/min: Avoid. Concomitant NSAID: CrCl 45–79 mL/min & NSAID w/short T1/2 (ibuprofen, indomethacin, ketoprofen, ketorolac): Avoid NSAID 2 d prior, d of & 2 d post-Rx; Any CrCl & NSAID w/long T1/2 (nabumetone, naproxen, oxaprozin, piroxicam): Avoid NSAID 5 d prior, d of & 2 d post-Rx. Hepatic: Grade 3–4 ↑ LFTs: 75% of dose. Adjust dose for tox (hematologic, mucositis, diarrhea, neurotoxicity).

PK/PD: Renal excretion, T1/2 3.5 h (↑ 5.3–5.8 h CrCl 40–59 mL/min)

Adverse effects: Myelosuppression (DLT), mucositis, hand-foot syndrome, anorexia, fatigue, GI tox, ↑ LFTs

DDI: Probenecid, PCN, ceph., ASA, NSAIDs (↓ renal excretion)

Clinical pearls: Folic acid 400–1000 μg daily (7 d prior, during Rx & 21 d after last dose), cyanocobalamin 1000 μg IM (7 d prior, every 3 cycles) to prevent GI tox. Dexamethasone 4 mg PO twice daily (start d prior to Rx × 3 d) for prev of cutaneous rxns.

Pralatrexate (Folotyn)

Dosing/dose adjustments: 30 mg/m2 IV weekly × 6 wks, 1 wk rest. Use caution in renal impairment. TBili > 1.5 mg/dL or AST/ALT > 2.5 × ULN: Omitted in trials, use w/caution. Grade 3 hepatotoxicity (on tx): Hold, ↓ to 20 mg/m2; grade 4 hepatotoxicity (on tx): D/C. Adjust dose for tox (hematologic, mucositis)

PK/PD: 67% protein bound, renal excretion (35%), T1/2 12–18 h

Adverse effects: Mucositis (DLT), myelosuppression (DLT), ↑ LFTs, anorexia, fatigue, edema, rash, ↓ K, nausea, cough, epistaxis, night sweats

DDI: Probenecid, PCN, ceph., aspirin, NSAIDs (↓ renal excretion)

Clinical pearls: Folic acid 1–1.25 mg/d (10 d prior, during Rx & 30 d after last dose), cyanocobalamin 1000 μg IM (w/in 10 wk prior, every 8–10 wks) to prevent GI tox

Cladribine (Leustatin)

Dosing/dose adjustments: 0.09 mg/kg/d IVCI × 7d. Renal: CrCl 10–50 mL/min: 75% of dose; CrCl < 10 mL/min: 50% of dose; CAPD: 50% of dose. Caution in pts w/hepatic dysfunction.

PK/PD: Bioavailability ∼50%, penetrates CSF (conc. ∼25% plasma), renal excretion, T1/2 5.4 h

Adverse effects: Myelosuppression (BBW, dose-dependent, prolonged), neurotoxicity (BBW, dose-related, doses above FDA recs, including paraparesis), renal tox (BBW, dose-related, doses above FDA recs), HA, dizziness, fever (33–69%), fatigue (11–45%), prolonged lymphopenia

DDI: Live vaccines (vaccinial infxn may occur)

Clofarabine (Clolar)

Dosing/dose adjustments: ALL (£21 y): 52 mg/m2/d × 5 d every 2–6 wks; AML (induction): 30 mg/m2/d × 5d; AML (consolidation): 20 mg/m2/d × 5d. Use w/caution in renal & hepatic impairment.

PK/PD: Intracellular metabolism to active metabolite, renal excretion, T1/2 5 h in children, 7 h in adults, ↑ in elderly/renal impairment

Adverse effects: Myelosuppression (DLT), N/V (mod. emetogenic potential), diarrhea, SIRS, ↑ opportunistic infxn, renal tox, ↑ LFTs/Tbili (w/i 10 d, duration ≤15 d), cardiac tox

DDI: Warfarin (↑/↓ warfarin effects), nephrotoxins (cum. nephrotoxicity)

Clinical pearls: Consider ppx corticosteroids (hydrocortisone 100 mg/m2 d 1–3, prev of capillary leak/SIRS)

Fludarabine (Fludara)

Dosing/dose adjustments: 20–30 mg/m2 IV × 3–5 d every 28 d (dosing varies based on malignancy) OR 40 mg/m2 PO d 1–5 every 28 d. CrCl 50–79 mL/min: ↓ dose to 20 mg/m2; CrCl 30–49 mL/min: ↓ dose to 15 mg/m2; CrCl < 30 mL/min: Avoid use. No hepatic dose adjustments recommended.

PK/PD: Extensive tissue distribution, dephosphorylated in plasma → active metabolite → phosphorylated in cells, renal excretion (60%), T1/2 ∼20 h

Adverse effects: Myelosuppression (DLT, BBW, nadir 10–14 d, recovery 5–7 wks), immunosuppression, N/V (low emetogenic potential), fever (60–69%), fatigue, diarrhea, weakness, cough (10–44%), PNA, infxn (33–44%), AIHA

DDI: Pentostatin (fatal pulm tox, BBW), Imatinib (↓ fludarabine effects), live vaccines (vaccinial infxn may occur)

Clinical pearls: Recommend antiviral & antipneumocystis ppx w/use

Nelarabine (Arranon)

Dosing/dose adjustments: 1500 mg/m2/dose d 1, 3, 5 every 21 d until transplant, progression or unacceptable tox. Use caution in CrCl < 50 mL/min (↓ ARA-G clearance). Closely monitor w/mod.-sev. hepatic impairment (Tbili > 3 × ULN). Consider delay or D/C for tox (neurotoxicity, hematologic).

PK/PD: Hepatic metabolism (ARA-G), T1/2 ∼2–3 h (metabolite)

Adverse effects: Myelosuppression, neurotoxicity (DLT, BBW, somnolence, HA, seizures, fatigue, hypoesthesia, D/C if ≥grade 2), ↑ LFTs, ↑ Tbili, ↑ K, myalgia, arthralgia, cough, dyspnea, blurred vision

DDI: Pentostatin (↓ conc. of nelarabine), live vaccines (vaccinial infxn may occur)

Pentostatin (Nipent)

Dosing/dose adjustments: 4 mg/m2 every 2 wks. Use w/caution in pts w/CrCl <60 mL/min. No hepatic dose adjustments recommended.

PK/PD: Renal excretion w/in 24 h, T1/2 3–7 h (↑ 4–18 h CrCl < 50 mL/min)

Adverse effects: Myelosuppression (nadir 7 d), CNS tox (BBW, higher than rec. dose), hepatotoxicity (BBW, higher than rec. dose), pulm tox (BBW, higher than rec. dose), nephrotoxicity (BBW, higher than rec. dose),fever, fatigue, HA, rash, ↑ LFTs, myalgia, cough, infxn

DDI: Fludarabine (fatal pulm tox), carmustine, etoposide, high-dose cyclophosphamide (fatal pulm edema & HoTN)

Capecitabine (Xeloda)

Dosing/dose adjustments: 1000–1250 mg/m2 PO twice daily × 2 wks every 21 d. Renal: CrCl 30–50 mL/min: 75% of dose; CrCl < 30 mL/min: Use contraindicated. Caution in hepatic dysfunction. Adjust dose for tox (hematologic) w/docetaxel or ixabepilone.

PK/PD: Bioavailability ∼ 80%, protein binding < 60%, hepatic & tissue metabolism (active metabolite: 5-FU), renal excretion (96%), T1/2 0.5–1 h

Adverse effects: Diarrhea, hand-foot syndrome, myelosuppression, mucositis, neurologic tox, coronary vasospasm

DDI: Oral anticoagulants (↑ levels of anticoagulants), phenytoin (↑ levels of phenytoin), leucovorin (↑ tox of capecitabine)

Clinical pearls: Oral prodrug of 5-FU, converted via three-step activation process. Available as 150 mg & 500 mg tablets. Take w/in 30 min after a meal, DPD deficiency (prolonged clearance, ↑ tox), radiation sensitizer

Fluorouracil (5-FU, Adrucil)

Dosing/dose adjustments: Intravenous push (IVP): 325–425 mg/m2/d × 5 d every 28 d OR 500 mg/m2/wk × 6 wks; IVCI: 750–1000 mg/m2/d × 5 d every 21–28 d OR 1200 mg/m2/d × 2 d. Use w/caution in pts w/renal impairment & avoid use w/Tbili >5 mg/dL.

PK/PD: Extensive tissue distribution, saturable catabolism, excretion via metabolism, lung, & urine, T1/2 8–14 min after bolus

Adverse effects: Diarrhea (DLT), mucositis (DLT), N/V (low emetogenic potential), myelosuppression (bolus > IVCI), neurotoxicity, coronary artery vasospasm, conjunctivitis, hand-foot syndrome (IVCI > bolus), alopecia, nail changes

DDI: CYP2C9 substrates (↓ substrate levels), oxaliplatin (↓ TS), cimetidine (↓ clearance of 5-FU), oral anticoagulants (↑ levels of anticoagulants), leucovorin (↑ tox of 5-FU)

Clinical pearls: DPD deficiency (prolonged clearance, ↑ tox), predictors of ↑ tox (↑ age, female, poor PS), radiation sensitizer

Mercaptopurine (6-MP, Purinethol)

Dosing/dose adjustments: 1.5–2.5 mg/kg/d oral (duration dependent on malignancy). CrCl < 50 mL/min: Every 48 h. No hepatic dose adjustments recommended.

PK/PD: Erratic PO absorption, oxidized via xanthine oxidase

Adverse effects: Myelosuppression, GI tox (N/V, anorexia, diarrhea, stomatitis), cholestatic jaundice, ↑ risk of infxn

DDI: Allopurinol (≠ mercaptopurine tox, reduce dose by 50–75%)

Clinical pearls: TPMT deficiency (reduce dose to 5–25% of standard dose)

Thioguanine (6-TG, Tabloid)

Dosing/dose adjustments: 60 mg/m2/d × 14d. No renal dose adjustments recommended. Hepatotoxicity (on tx, including VOD): D/C.

PK/PD: Erratic PO absorption, hepatic metabolism via TPMT, T1/2 5–9 h

Adverse effects: Myelosuppression, GI tox (N/V, anorexia, diarrhea, stomatitis), cholestatic jaundice, ↑ risk of infxn, 2° malignancy

DDI: No significant drug interactions

Clinical pearls: TPMT deficiency (reduce dose to 5–25% of standard dose)

Hydroxyurea (Droxia, Hydrea)

Dosing/dose adjustments: 20–30 mg/kg oral daily (CML, solid tumors) OR 50– 100 mg/kg until WBC <100 K. Titrate dosing for WBC & plt count. CrCl 10–50 mL/min: 50% of dose; CrCl < 10 mL/min: 20% of dose; HD: Administer dose after HD on HD d. No hepatic dose adjustments recommended. Adjust dose for tox (rash, GI, mucositis, hematologic).

PK/PD: Readily absorbed, widely distributed including CSF, 75–80% protein bound, metabolism via hepatic & GI tract, renal excretion, T½ ∼2–4 h

Adverse effects: Myelosuppression (DLT, primarily granulocytopenia w/in 2–5 d), GI ulceration, skin pigmentation, rash, squamous carcinoma (skin)

DDI: Didanosine, Stavudine (↑/↓ conc. of hydroxyurea, fatal pancreatitis), radiation (↑ tissue Sn to radiation)

Clinical pearls: Available as 200 mg, 300 mg, 400 mg, & 500 mg capsules

Info. based on publicly available drug inserts from Allos, Bedford, Berlex, Bristol Meyers-Squibb, Celgene, Centocor Ortho-Biotech, Eisai, Genzyme, GlaxoSmithKline, Hoffman-LaRoche, Hospira, Lilly, and Teva.