Limited sampling models for topotecan pharmacokinetics

Abstract

Background: Limited sampling models for the estimation of the topotecan Area Under the concentration versus time Curve (AUC) and its lactone ring opened form (AUC Tm), from one or more plasma concentration determinations, are desired for further population-kinetic studies.

Patients and methods: The models were developed and validated using 34 pharmacokinetic curves in 19 patients who participated in a phase I study.

Results: A single point model was selected as optimal: AUC (mumol/L.min) = 499 (min).C2h (mumol/L) +0.85 (m2/mg.mumol/L.min).dose(mg/m2), and for topotecan-metabolite (Tm), AUC Tm (mumol/L.min) = 55.1 (min).CTm2h (mumol/L) -0.011 (m2/mg.mg.mumol/L.min).dose (mg/m2), where C2h is the plasma concentration (mumol/L) of topotecan at 2 h after the end of a 30-min infusion, and CTm2h the concentration of the opened form at the same time point. The models are valid for dosages ranging from 0.5 to 1.5 mg/m2/day and proved to be unbiased (MPE% = -1.8% and -9.3%, respectively) and precise (RMSE% = 17.9% and 22.7%, respectively). From the predicted AUCs, the clearance (Cl = dose (mumol)/AUC(mumol/L.min)) could also reliably be predicted, as well as the total AUC (AUC+AUC Tm) RMSE% = 17.1% and MPE% = -0.02%). Half-life values could not be predicted with acceptable precision and accuracy.

Conclusion: The limited sampling models presented may useful for future studies focused on pharmacokinetic/pharmacodynamic relationships of topotecan in large populations.