PHARMACOKINETICS AND PHARMACODYNAMICS OF IRINOTECAN DURING A PHASE-IICLINICAL-TRIAL IN COLORECTAL-CANCER

Purpose: A pharmacokinetic study was performed during a phase II clini cal trial of irinotecan (CPT-11) to confirm the pharmacokinetic profil e of this drug and its metabolite and to investigate interpatient and intrapatient pharmacokinetic variations and pharmacokinetic-pharmacody namic relationships. Patients and Methods: Twenty-six men and 21 women (mean age, 61 years) with metastatic colorectal cancer, performance s tatus less than 3 (World Health Organization [WHO] scale), and normal renal and hepatic function were administered CPT-11 (350 mg/m(2)) by 3 0-minute intravenous (IV) infusion every 21 days. CPT-11 and its metab olites SN-38 and SN-38 glucuronide (SN-38G) were determined by high-pe rformance liquid chromatography (HPLC) using fluorimetric detection. R esults: The mean CPT-11 clearance and area under the concentration-tim e curve (AUC) were 15.2 L/h . m(2) and 24,769 ng . h/mL, respectively. The large difference in SN-38 and SN-38G AUCs (559 v 2,283 ng . h/mL) was suggestive of extensive glucuronidation of SN-38. Interindividual variation in the metabolic ratio ([AUC(SN-38) + AUC(SN-38G)]/AUC(CPT- 11)) was marked (coefficient of variation [CV] = 51.6%] compared with intrapatient variation in this variable (CV = 32.6%). A significant re lationship existed between percentage reduction in neutrophil count an d the AUC of CPT-11 (r = .597, P < .001) and SN-38 (r = .559, P < .001 ). No relationship was identified between any pharmacokinetic paramete r and delayed diarrhea or therapeutic outcome. Conclusion: Interindivi dual variations in the metabolic ratio suggest interpatient variation in carboxylesterase activity. Furthermore, glucuronidation of SN-38 ma y also be in part responsible for the large interpatient variability i n the total SN-38 AUC. Conversely, low intrapatient variation of this parameter was observed in this study, which indicates a lack of autoin duction of the carboxylesterase system. The relationship between neutr openia and both CPT-11 and SN-38 pharmacokinetic parameters confirms t he results of previous studies. (C) 1996 by American Society of Clinic al Oncology.