Annals of oncology : official journal of the European Society for Medical Oncology
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Clinical Trial Controlled Clinical Trial
Population pharmacokinetics and pharmacodynamics of irinotecan (CPT-11) and active metabolite SN-38 during phase I trials.
Irinotecan (CPT-11) is a novel water-soluble camptothecin derivative selected for clinical testing based on its good in vitro and in vivo activity in various experimental systems, including pleiotropic drug-resistant tumors. Its mechanism of action appears mediated through topoisomerase I inhibition. The purpose of this study was to describe CPT-11 and active metabolite SN-38 population pharmacokinetics, examine patient characteristics that may influence pharmacokinetics, and to investigate pharmacokinetic-pharmacodynamic relationships that may prove useful in the future clinical management of this drug. ⋯ 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)
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We conducted a phase I and pharmacokinetic study to determine the maximum tolerable dose (MTD), toxicities, pharmacokinetic profile, and antitumor activity of Irinotecan (CPT-11) in patients with refractory solid malignancies. ⋯ The MTD for CPT-11 administered in a 3 consecutive-days-every-3 weeks schedule in this patient population is 115 mg/m2/day. The recommended dose for phase II studies is 100 mg/m2/day.