Population pharmacokinetics of total and unbound plasma cisplatin in adult patients.

Abstract

To investigate the pharmacokinetics of unbound (ultrafilterable) and total plasma platinum using a population approach and to identify patient characteristics that may influence the disposition of the drug. Pharmacokinetic and demographic data were collected from adult patients treated with 30-min daily infusions of cisplatin for various malignancies. Unbound and total platinum concentration-time data were analysed using a nonlinear mixed effects model. Data from 43 patients were available for analysis. A linear two-compartment model best described total and unbound platinum plasma concentration-time data. The mean population estimates for total and unbound drug were, respectively, 0.68 and 35.5 l h(-1) for clearance and 21.1 and 23.4 l for central distribution volume (V(1)). Unbound clearance (CL) was dependent on body surface area (BSA) and creatinine clearance, and V(1) was dependent on BSA. The elimination rate constant for plasma-bound platinum (modelled as metabolite formation) was 0.014 h(-1). The pharmacokinetic parameter, f(m)/V(m), a measure of the clearance of unbound platinum due to irreversible plasma binding, was related to serum protein concentration and to the inverse of dose per m(2). The covariate modelling of CL, V(1) and f(m)/V(m) improved the intersubject variabilities associated with these parameters. The final pharmacokinetic models were validated using 200 bootstrap samples from the original datasets. The results support the conventional dose adjustment of cisplatin based on BSA. They also support the need for a dose reduction in case of renal insufficiency.