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<inf>c>0.05μM</inf>), which is a common threshold for paclitaxel. A dosing algorithm was developed based on the population distribution of paclitaxel T<inf>c>0.05μM</inf> and the correlation between paclitaxel T<inf>c>0.05μM</inf> 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<inf>c>0.05μM</inf>. By using an empirical dosing algorithm to target an average paclitaxel T<inf>c>0.05μM</inf> 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.

Bayesian dosing, Neurotoxicity, Paclitaxel, Single sampling strategy, Therapeutic drug monitoring
dx.doi.org/10.1007/s00280-015-2724-9, hdl.handle.net/1765/91599
Cancer Chemotherapy and Pharmacology
Department of Clinical Chemistry

Kraff, S, Nieuweboer, A.J.M, Mathijssen, A.H.J, Baty, F, de Graan, A.J.M, van Schaik, R.H.N, … Joerger, M. (2015). Pharmacokinetically based dosing of weekly paclitaxel to reduce drug-related neurotoxicity based on a single sample strategy. Cancer Chemotherapy and Pharmacology, 75(5), 975–983. doi:10.1007/s00280-015-2724-9