title: Pharmacokinetically based dosing of weekly paclitaxel to reduce drug-related neurotoxicity based on a single sample strategy.
abstract: OBJECTIVE
  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.
authors.affiliation: Institute of Pharmacy, Clinical Pharmacy, University of Bonn, An der Immenburg 4, 53121, Bonn, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Kraff
authors.forename: Annemieke J M
authors.initials: AJ
authors.lastname: Nieuweboer
authors.forename: Ron H J
authors.initials: RH
authors.lastname: Mathijssen
authors.forename: Florent
authors.initials: F
authors.lastname: Baty
authors.forename: Anne-Joy
authors.initials: AJ
authors.lastname: de Graan
authors.forename: Ron H N
authors.initials: RH
authors.lastname: van Schaik
authors.forename: Ulrich
authors.initials: U
authors.lastname: Jaehde
authors.forename: Markus
authors.initials: M
authors.lastname: Joerger
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D003198:Computer Simulation; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D020258:Neurotoxicity Syndromes / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D017239:Paclitaxel