PHARMACOKINETIC AND PHARMACODYNAMIC EVALUATION OF THE TOPOISOMERASE INHIBITOR IRINOTECAN IN CANCER-PATIENTS

Purpose: We conducted a pharmacokinetic and pharmacodynamic evaluation of irinotecan (CPT-11) and determined the effect of race and sex on d isposition and toxicity of CPT-11. We tested the efficacy of acetamino phen (AAP) to phenotype SN-38 glucuronidation. Patients and Methods: F orty patients received a dose of 145 mg/m(2) of CPT-11 as a 90-minute infusion. Total CPT-11, SN-38, and SN-38G were quantitated in plasma a nd urine samples. Following administration of 1 g AAP, urinary concent rations of AAP and AAP-glucuronide (AAP-G) were assessed. Results: CPT -11 exhibited a mean elimination half-life (t(1/2)) of 8.8 hours, an a verage clearance (CL) of 14.6 L/h/m(2), and a mean volume of distribut ion at steady-state (Vd(ss)) of 136 L/m(2). SN-38 and SN-38G had low p lasma availabilities (3% and 10% relative to CPT-11), with mean t(1/2) values of 11.6 and 10.5 hours, respectively. Urinary recovery account ed for 15% of the dose. Race and sex had no effect on the plasma avail ability of CPT-11, SN-38, and SN-38G. The applicability of biliary ind ex (BI) in predicting dose-limiting intestinal toxicity was validated, patients who developed grade 3 or 4 toxicity had significantly higher index values compared with patients with grade 0 to 2 toxicity (P = . 001). There was no difference in the incidence and severity of toxicit y based on race and sex. AAP was a poor predictor of SN-38 glucuronida tion. Conclusion: The high degree of interpatient variability in param eter estimates suggests pharmacogenetic variation or differential indu ction or inhibition of the sequential metabolic pathway of CPT-11, as well as variability in transport systems, The low urinary recovery ind icates substantial biliary excretion and supports the significant corr elation between intestinal toxicity and BI. Black patients are not at increased risk of: toxicity, An assessment of individual differences i n SN-38 conjugation remains to be established. (C) 1997 by American So ciety of Clinical Oncology.