Publication

Pharmacokinetically based dosing of weekly paclitaxel to reduce drug-related neurotoxicity based on a single sample strategy

Journal Paper/Review - Mar 12, 2015

Units
PubMed
Doi

Citation
Kraff S, Nieuweboer A, Mathijssen R, Baty F, de Graan A, van Schaik R, Jaehde U, Jörger M. Pharmacokinetically based dosing of weekly paclitaxel to reduce drug-related neurotoxicity based on a single sample strategy. Cancer Chemother Pharmacol 2015
Type
Journal Paper/Review (English)
Journal
Cancer Chemother Pharmacol 2015
Publication Date
Mar 12, 2015
Issn Electronic
1432-0843
Brief description/objective

PURPOSE
The present simulation study was initiated to develop a limited sampling strategy and pharmacokinetically based dosing algorithm of weekly paclitaxel based on pharmacokinetic (PK) and chemotherapy-induced peripheral neuropathy (CIPN) data from a large database.

METHODS
We used paclitaxel plasma concentrations from 200 patients with solid tumors receiving weekly paclitaxel infusions to build a population PK model and a proportional odds model on CIPN. Different limited sampling strategies were tested on their accuracy to estimate the individual paclitaxel time-above-threshold-concentration of 0.05 µmol/L (T c>0.05µM), which is a common threshold for paclitaxel. A dosing algorithm was developed based on the population distribution of paclitaxel T c>0.05µM and the correlation between paclitaxel T c>0.05µM and CIPN. A trial simulation based on paclitaxel PK and CIPN was performed using empirical Bayes estimations, applying the proposed dosing algorithm and a single 24-h paclitaxel PK sample.

RESULTS
A single paclitaxel plasma concentration taken 18-30 h after the start of chemotherapy infusion adequately predicted T c>0.05µM. By using an empirical dosing algorithm to target an average paclitaxel T c>0.05µM between 10 and 14 h, Bayesian simulations of repetitive (adapted) dosing suggested a potential reduction of grade 2 CIPN from 9.6 to 4.4 %.

CONCLUSIONS
This simulation study proposes a pharmacokinetically based dosing algorithm for weekly paclitaxel and shows potential improvement of the benefit/risk ratio by using empirical Bayesian models.