Irinotecan, CPT-11 (Camptosar)
Dosing/dose adjustments: 125 mg/m2 × 4 wks w/2 wks rest or 240–350 mg/m2 every 3 wks. Homozygous for UGT1A1*28 allele (FDA-approved test available to detect allele) and hepatic impairment (Tbili > ULN): ↓ dose, no specific adjustments suggested.
PK/PD: Extensive extravascular distribution, active drug (SN-38) hepatically glucuronidated via UGT1A1, renal excretion (25%), remainder eliminated via hepatic metabolism & biliary excretion, T1/2 6–12 h (irinotecan), 10–20 h (SN-38)
Adverse effects: Diarrhea (DLT, early & delayed), myelosuppression, abdominal pain, N/V (mod. emetogenic potential), alopecia, weakness, ↑ LFTs & Tbili
DDI: CYP3A4 inducers (↓ conc. of irinotecan), azole antifungals (↑ conc. of irinotecan)
Clinical pearls: Diarrhea <24 h: Acute cholinergic effect produced by inhibition of acetylcholinesterase by prodrug, treat w/atropine. Diarrhea > 24 h: Mucosal cytotoxicity, treat w/loperamide and/or octreotide.
Dosing/dose adjustments: 1.5 mg/m2 over 30 min daily × 5 d w/2 wk rest or 2.3 mg/m2/d PO × 5 d w/2 wk rest. Renal (IV): CrCl 30–60 mL/min: 75% of dose, CrCl 10–30 mL/min: 50% of dose & CrCl < 10 mL/min: 25% of dose; (PO): CrCl 30–49 mL/min: ↓ dose to 1.8 mg/m2/d.
PK/PD: Rapid oral absorption w/40% bioavailability, widely distributed w/significant CSF penetration (CSF conc. ∼30% of plasma), metabolism via rapid plasma hydrolysis to inactive metabolite, renal excretion, T1/2 (IV) 2–3 h, (PO) 3–6 h
Adverse effects: Myelosuppression (DLT/BBW, nadir 9–14 d), N/V (low emetogenic potential), diarrhea, low-grade fever, fatigue, alopecia, skin rash, HA, transient ↑ LFTs
DDI: P-gp inhibitors (ketoconazole, saquinavir, ritonavir, ↑ conc. of topotecan)
Clinical pearls: Do NOT administer w/neutrophils <1500/mm3 & plts <100000/mm3. Myelosuppression ↑ w/extensive prior radiation or previous bone-marrow suppressive chemotherapy. Risk of thrombocytopenia ↑ w/extensive prior carboplatin tx.
Etoposide, VP-11 (Toposar, VePesid)
Dosing/dose adjustments: 50–120 mg/m2/d IV × 3 d every 3–4 wks or PO dosing 2 × IV dosing (round to nearest 50–50-mg capsules). Use IBW to dose. TBili 1.5–3 mg/dL or AST 60–180: 50% of dose, TBili >3 mg/dL or AST >180: Safety unknown. CrCl <15 mL/min: 50% of dose.
PK/PD: Oral bioavailability 50%, poor BBB penetration (CSF conc. <5% of plasma), highly protein bound (94–98%), hepatically metabolized via CYP3A4/5, renal excretion (56%), T1/2 IV 4–11 h
Adverse effects: Myelosuppression (DLT/ BBW, nadir 7–14 d), N/V (low-to-mod. emetogenic potential), ↑ LFTs, HA, HoTN during infusion, alopecia, rash, urticaria, pruritus, fever, 2° malignancy
DDI: Strong CYP3A4 inhibitors (ketoconazole, clarithromycin, ↑ conc. of etoposide), CYP3A4 inducers (rifampin, phenytoin, ↓ conc. of etoposide). P-gp inhibitors (↑ conc. of etoposide).
Clinical pearls: Giving etoposide phosphate ↓ the rate of skin changes & incidence of rash. Risk of 2° malignancy (AML via 11q23 translocation) usually occurs 2–3 y after administration of etoposide. Slow infusion to ↓ risk of HoTN.
Teniposide, VM-26 (Vumon)
Dosing/dose adjustments: 165 mg/m2/dose d 1, 4, 8, 11 of alternating consolidation cycles. No renal or hepatic dose adjustments recommended. Down syndrome (50% of dose).
PK/PD: Good tissue distribution, limited BBB penetration, highly protein bound (99.4%), extensive hepatic metabolism via CYP3A4, renal excretion (44%), T1/2 5 h
Adverse effects: Myelosuppression (DLT/BBW, nadir 7–10 d), mucositis, diarrhea, N/V (mild-to-mod. emetogenic potential), HoTN during infusion, alopecia, rash, HSR
DDI: Strong CYP3A4 inhibitors (ketoconazole, clarithromycin, ↑ conc. of teniposide), CYP3A4 inducers (rifampin, phenytoin, ↓ conc. of teniposide), P-gp inhibitors (↑ conc. of teniposide)
Clinical pearls: Risk of 2° malignancies > etoposide. HSR including anaphylaxis-like rxns have been reported & have been linked to Cremophor EL in vials.
Info. based on publicly available drug inserts from Pfizer, GlaxoSmithKline & Bristol-Myers Squibb.
Figure 8-1 Cell Cycle-Specific Drugs
Figure 8-2 Mechanism of Action of Antimetabolites