Predicting the efficacy of an oral paclitaxel formulation (DHP107) through modeling and simulation.

ABSTRACT

PURPOSE: DHP107 is an oral paclitaxel under development. The present study characterized the pharmacokinetic properties of DHP107 and predicted the efficacy in comparison to that of intravenous paclitaxel, using modeling and simulation of data from the early phase of clinical development. METHODS: In the first-in-human study of the pharmacokinetic characteristics of DHP107 and intravenous paclitaxel, patients received DHP107 60 to 600 mg/m(2), followed by intravenous paclitaxel 175 mg/m(2). Using the pharmacokinetic model of DHP107 from the present analysis and from a previously published pharmacodynamic analysis of the association between paclitaxel concentration and neutropenia, phase I clinical trial for DHP107, with a modified Fibonacci dose escalation scheme, were simulated to predict the maximal tolerated dose (MTD). Additional simulations of paclitaxel concentration over time were conducted to compare the efficacy of DHP107 with that of intravenous paclitaxel, based on time over minimum effective concentration. FINDINGS: In the clinical trial simulation, 480 mg/m(2) was the most frequently predicted MTD of DHP107. In the simulations for efficacy, the times over minimum effective concentration with DHP107 at the predicted MTD were greater than those of intravenous paclitaxel in weekly regimens. IMPLICATIONS The findings from this analysis suggest the possibility of efficacy of DHP107 in weekly regimens and provides a scientific rationale for further development. Based on findings from modeling and simulation, DHP107 was predicted to be more efficacious compared with intravenous paclitaxel in weekly regimens, and this finding should be confirmed in further clinical trials.