Excel-Based Tool for Pharmacokinetically Guided Dose Adjustment of Paclitaxel.

Abstract

Neutropenia is a frequent and severe adverse event in patients receiving paclitaxel chemotherapy. The time above a paclitaxel threshold concentration of 0.05 μmol/L (Tc > 0.05 μmol/L) is a strong predictor for paclitaxel-associated neutropenia and has been proposed as a target pharmacokinetic (PK) parameter for paclitaxel therapeutic drug monitoring and dose adaptation. Up to now, individual Tc > 0.05 μmol/L values are estimated based on a published PK model of paclitaxel by using the software NONMEM. Because many clinicians are not familiar with the use of NONMEM, an Excel-based dosing tool was developed to allow calculation of paclitaxel Tc > 0.05 μmol/L and give clinicians an easy-to-use tool. Population PK parameters of paclitaxel were taken from a published PK model. An Alglib VBA code was implemented in Excel 2007 to compute differential equations for the paclitaxel PK model. Maximum a posteriori Bayesian estimates of the PK parameters were determined with the Excel Solver using individual drug concentrations. Concentrations from 250 patients were simulated receiving 1 cycle of paclitaxel chemotherapy. Predictions of paclitaxel Tc > 0.05 μmol/L as calculated by the Excel tool were compared with NONMEM, whereby maximum a posteriori Bayesian estimates were obtained using the POSTHOC function. There was a good concordance and comparable predictive performance between Excel and NONMEM regarding predicted paclitaxel plasma concentrations and Tc > 0.05 μmol/L values. Tc > 0.05 μmol/L had a maximum bias of 3% and an error on precision of <12%. The median relative deviation of the estimated Tc > 0.05 μmol/L values between both programs was 1%. The Excel-based tool can estimate the time above a paclitaxel threshold concentration of 0.05 μmol/L with acceptable accuracy and precision. The presented Excel tool allows reliable calculation of paclitaxel Tc > 0.05 μmol/L and thus allows target concentration intervention to improve the benefit-risk ratio of the drug. The easy use facilitates therapeutic drug monitoring in clinical routine.