Andrea Henrich (1,2) , Markus Joerger (3), Wilhelm Huisinga (4), Charlotte Kloft (1), Zinnia P. Parra-Guillen (1)
(1) Dept. Clinical Pharmacy & Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, Germany, (2) Graduate Research Training program PharMetrX, Germany, (3) Dept. of Oncology & Haematology, Cantonal Hospital, St Gallen, Switzerland and (4) Institute of Mathematics, Universitaet Potsdam, Germany
Objectives: Paclitaxel (PTX) exhibits complex pharmacokinetics (PK) with high interindividual variability and also severe toxicity, namely neutropenia, which makes PTX an appealing drug for dose individualisation. The concentration time-course of PTX and the resulting neutropenia was previously described by a PK/pharmacodynamic (PD) model, and a dose individualisation algorithm was built considering sex and age as covariates [1]. Subsequently, a clinical trial (CEPAC-TDM) was initiated to evaluate whether the proposed dosing algorithm was able to reduce grade 4 neutropenia without reducing treatment efficacy. The aim of the work here presented is to externally validate the previously described PK/PD model using the data collected from the CEPAC-TDM study.
Methods: Data from the CEPAC-TDM study was obtained for the analysis. Briefly, patients were randomised into 2 arms, each comprising 183 patients. In Arm A, standard PTX dose (200 mg/m2) in combination with a platinum-based drug was administered 3-weekly for up to 6 cycles, while in Arm B the previously published algorithm was used to select initial and subsequent doses. PTX plasma concentrations 24 h after PTX administration were available only for Arm B. Shortly before and 15 days after the drug administration, neutrophil concentrations for both arms were obtained. PTX and neutrophil concentrations were visually explored and the performance of the previously published model was evaluated using basic goodness of fit plots and visual predictive checks (NONMEM 7.2, PsN 4.2 and Xpsose4 4.5.3).
Results: Patients in Arm A were exposed to higher PTX doses overall. In this arm, females exhibited more profound neutropenia than men. While in Arm B, in which dose was individualised from the beginning based on sex and age, comparable exposure and neutrophil time course were observed. The results from the performed evaluation showed a model misspecification at the pharmacodynamics level. In addition, bone marrow exhaustion was identified which could partly explain the less predictive performance of the model in the later cycles.
Conclusions: Based on the external evaluation results, the proposed PK/PD model needs to be refined to take into account bone marrow exhaustion. In a next step, the refined model will be used to re-evaluated the dosing algorithm.
References:
[1] M. Joerger, S. Kraff, A.D.R. Huitema, et al. Evaluation of a pharmacology-driven dosing algorithm of 3-weekly paclitaxel using therapeutic drug monitoring: a pharmacokinetic-pharmacodynamic simulation study. Clin Pharmacokinet (2012) 51(9): 607–17.
Reference: PAGE 24 () Abstr 3460 [www.page-meeting.org/?abstract=3460]
Poster: Drug/Disease modeling - Oncology