Population pharmacokinetic model for topotecan derived from phase I clinical trials

Purpose: To characterize the pharmacokinetics of topotecan in a population model that would identify patient variables or covariates that appreciably impacted on its disposition. Patients and Methods: All data were collected from 82 patients entered in f our different phase I trials that were previously reported as separate stud ies from 1992 to 1996. All patients received topotecan as a 30-minute const ant-rate infusion on a daily-times-five schedule and were selected for this study because their daily dose did not exceed 2.0 mg/m(2). Among the 82 pa tients were 30 patients classified as having renal insufficiency and 13 pat ients with hepatic dysfunction. The population pharmacokinetic model was bu ilt in sequential manner, starting with a covariate-free model and progress ing to a covariate model with the aid of generalized additive modeling. Results: A linear two-compartment model characterized total topotecan plasm a concentrations (n = 899). Four primary pharmacokinetic parameters (total clearance, volume of the central compartment, distributional clearance, and volume of the peripheral compartment) were related to various combinations of covariates. The relationship for total clearance (TVCL [L/h] = 32.0 +/- [0.356(WT - 71) + 0.308(HT - 168.5) - 8.42(SCR - 1.1)] x [1 + 0.671 sex]) was dependent on the patients' weight (WT), height (HT), serum creatinine ( SCR), and sex and had a moderate ability to predict (r(2) = 0.64) each pati ent's individual clearance value. The addition of covariates to the populat ion model improved the prediction errors, particularly for clearance. Remov al of 10 outlying patients from the analysis improved the ability of the mo del to predict individual clearance values (r(2) = 0.77). Conclusion: A population pharmacokinetic model for total topotecan has been developed that incorporates measures of body size and renal function to pr edict total clearance. The model can be used prospectively to obtain a revi sed and validated model that can then be used to design individualized dosi ng regimens. J Clin Oncol 18:2459-2467. (C) 2000 by American Society of Cli nical Oncology.