PHARMACOKINETIC INTERRELATIONSHIPS OF IRINOTECAN (CPT-11) AND ITS 3 MAJOR PLASMA METABOLITES IN PATIENTS ENROLLED IN PHASE-I II TRIALS/

Irinotecan (CPT-11) is an analogue of 20(S)-camptothecin with promisin g activity against several tumor types, In patients, CPT-11 is metabol ized to 7-ethyl-10-hydroxycamptothecin (SN-38) and to the beta-glucuro nide of SN-38, Recently, we identified an additional metabolite of CPT -11, 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino] carbonyloxy camptothecin (APC; L, P, Rivory et al., Cancer Res., 56: 3689-3694, 19 96), The aim of this study was to investigate the interrelationships o f all four compounds to identify factors that might be responsible for the large interpatient variability in CPT-11 and SN-38 kinetics, The plasma kinetics of CPT-11? SN-38, the beta-glucuronide of SN-38, and A PC were studied in 19 patients for a total of 33 cycles (115-600 mg/m( 2)), Although the area under the concentration curves (AUCs) of all co mpounds studied increased with dose, there was considerable variabilit y, Ratios of the AUCs of the appropriate compounds were used as estima tes of the major routes of metabolism (conversion of CPT-11 to SN-38, metabolism of CPT-11 to APC, and glucuronidation of SN-38), Each ratio varied more than 10-fold across the patient population, and the appar ent extent of conversion of CPT-II to SN-38 was highest at the 115 mg/ m(2) dose level. Interestingly, AUC(SN-38) was greater in patients wit h both high AUC(CPT-11) and AUC(APC). We conclude that the variability of the pharmacokinetics of CPT-11 and SN-38 is likely to be due to ex tensive interpatient differences in the pathways implicated in the met abolism of CPT-11.