Population pharmacokinetic analysis of cisplatin and its metabolites in cancer patients: possible misinterpretation of covariates for pharmacokinetic parameters calculated from the concentrations of unchanged cisplatin, ultrafiltered platinum and total platinum.

Abstract

Usually, total and filtered platinum concentrations in plasma are monitored after cisplatin administration. However, these concentrations represent a mixture of unchanged cisplatin and metabolites. In this work, we studied population pharmacokinetic analysis based on these platinum concentrations. Twenty-seven patients (23 males, four females) were administered cisplatin (60-100 mg/m2) with intravenous constant infusion for 90 min. Blood samples were taken at about three points per patient. The concentrations of cisplatin and platinum in the plasma were determined by high-performance liquid chromatography and atomic absorption spectrometry, respectively. Population pharmacokinetic analysis was performed using the program NONMEM (Version V) with the one- or two-compartment model with zero-order infusion. The clearance and volume of distribution for all platinum species studied were significantly related to the body surface area of the patients. Only the clearance of filtered platinum was significantly related to urinary N-acetyl-beta-D-glucosaminidase and the other covariates were not related to these pharmacokinetic parameters with respect to unchanged cisplatin and total platinum concentrations. The dosage regimen based on the filtered platinum concentration which is usually monitored may result in possible misinterpretation because the detected covariate is different between unchanged cisplatin and filtered platinum.