Population pharmacokinetics and pharmacodynamics of irinotecan (CPT-11) and active metabolite SN-38 during phase I trials

Abstract

168 pharmacokinetic data sets were obtained in 107 patients (97 first courses, 43 second courses, 23 third courses, 4 fourth courses, and 1 fifth course). Rebound concentrations of CPT-11 were frequently observed at about 0.5 to 1 h following the end of the i.v. infusion, which is suggestive of enterohepatic recycling of the drug. Model-independent analysis yielded the following mean population pharmacokinetic parameters for CPT-11: a terminal half-life of 10.8 h, a mean residence time (MRT) of 10.7 h, a volume of distribution at steady state (Vdss) of 150 L/m2, and a total body clearance of 14.3 L/m2/h. Model-dependent analysis disclosed a CPT-11 plasma disposition as either biphasic or triphasic with a mean terminal half-life of 12.0 h. The volume of distribution Vdss (150 L/m2) and total body clearance (14.8 L/m2/h) yielded almost identical values to the above model-independent analysis. The active metabolite SN-38 presented rebound concentrations in many courses at about 1 h following the end of the i.v. infusion which is suggestive of enterohepatic recycling. The mean time at which SN-38 maximum concentrations was reached was at 1 h since the beginning of the 0.5 h infusion (i.e., 0.5 h post i.v.). SN-38 plasma decay followed closely that of the parent compound with a mean apparent terminal half-life of 10.6 h. Mean 24 h CPT-11 urinary excretion represented 16.7% of the administered dose, whereas metabolite SN-38 recovery in urine was minimal (0.23% of the CPT-11 dose). The number of CPT-11 treatments did not influence pharmacokinetic parameters of either the parent compound or metabolite SN-38. Although CPT-11 pharmacokinetics presented an important interpatient variability, both CPT-11 maximum concentrations (Cmax) and the CPT-11 area under the plasma concentration versus time curves (AUC) increased proportionally and linearly with dosage (Cmax, r = 0.78, p < 0.001); CPT-11 AUC, r = 0.88, p < 0.001). An increase in half-life and MRT was observed at higher dosages, although this did not influence the linear increase in AUC as a function of dose. The volume of distribution at steady state (Vdss) and the total body clearance (CL) were not affected by the CPT-11 dose. Metabolite SN-38 AUC increased proportionally to the CPT-11 dose (r = 0.67, p < 0.001) and also with the parent compound AUC (r = 0.75, p < 0.001) (ABSTRACT TRUNCATED)

Correlation between plasma concentration ratios of SN-38 glucuronide and SN-38 and neutropenia induction in patients with colorectal cancer and wild-type UGT1A1 gene

“…The contribution of plasma SN-38 concentrations in CPT-11-related side-effects is well recognized (5,6). In the present study, a significant correlation was obtained between plasma SN-38 concentrations and neutropenia induction (Fig.…”

“…However, in clinical practice, the adjustment of the optimal dose of CPT-11 for an individual patient remains unclear, since pharmacokinetic parameters of CPT-11, as well as the incidence of CPT-11-related side effects, are markedly varied among patients (1,3,5,6). The clinical significance of inherited genetic polymorphisms of UGTs involved in SN-38 glucuronidation is well recognized in association with CPT-11-induced side effects (2,(7)(8)(9)(10)(11).…”

Population pharmacokinetics in phase I drug development: a phase I study of PK1 in patients with solid tumours

“…Although it has been suggested that this methodology may be useful for dose escalation designs where many concentrations fall below assay limits (Schoemaker and Cohen, 1996), many population studies to date have focused on sparse data collected during Phase III of drug development or routine clinical practice (Samara and Granneman, 1997). The population approach has been applied in cancer chemotherapy, especially for drugs such as carboplatin (Chatelut et al, 1995), docetaxel (Bruno et al, 1996) and etoposide (Nguyen et al, 1998) and in the analysis of phase I data (Chabot et al, 1995;Launay Iliadis et al, 1995). Limited sampling strategies employing Bayesian approaches have also been used to estimate population parameters during early drug development (Jodrell et al, 1994;Reyno et al, 1995;McLeod et al, 1996;Piscitelli et al, 1997).…”

66 Clinical validity of new genetic biomarkers of irinotecan neutropenia: An independent replication study

“…Moreover, we are confident that dosing heterogeneity did not significantly confound our replication results because irinotecan has been shown to demonstrate dose linear pharmacokinetics over a wide range of doses. 38 Regarding our statistical approach, the assessment of replicated associations is not based on hypothesis testing, and therefore using P-values as our main criteria for replication would have been inappropriate. Moreover, given the influence of sample size on P-values, utilization of Pvalues as the main criteria for replication could have resulted in false negative results.…”