TY - JOUR T1 - Semi-mechanistic bone marrow exhaustion pharmacokinetic/pharmacodynamic model for chemotherapy-induced cumulative neutropenia JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.117.240309 SP - jpet.117.240309 AU - Andrea Henrich AU - Markus Joerger AU - Stefanie Kraff AU - Ulrich Jaehde AU - Wilhelm Huisinga AU - Charlotte Kloft AU - Zinnia Patricia Parra-Guillen Y1 - 2017/01/01 UR - http://jpet.aspetjournals.org/content/early/2017/06/09/jpet.117.240309.abstract N2 - Paclitaxel is a commonly used cytotoxic anticancer drug with potentially life-threatening toxicity at therapeutic doses and high interindividual pharmacokinetic variability. Thus, drug and effect monitoring is indicated to control dose-limiting neutropenia. A dose individualization algorithm was developed by Joerger et al. based on a pharmacokinetic/pharmacodynamic (PK/PD) model describing paclitaxel and neutrophil concentrations. Further, the algorithm was prospectively compared in a clinical trial against standard dosing (CEPAC-TDM study, npatients=365, ncycles=720) but did not substantially improve neutropenia. This might be caused by misspecifications in the PK/PD model underlying the algorithm, especially without consideration of the observed cumulative pattern of neutropenia or the platinum-based combination therapy, both impacting neutropenia. The aim of this work was to externally evaluate the original PK/PD model for potential misspecifications and to refine together with considering the cumulative neutropenia pattern and the combination therapy. For PK (nsamples=658), an underprediction was observed and the PK parameters were re-estimated using the original estimates as prior information. Neutrophil concentrations (nsamples=3274) were overpredicted by the PK/PD model especially for later treatment cycles, when the cumulative pattern aggravated neutropenia. Three different modelling approaches (two from literature, one newly developed) were investigated and the newly developed one, implementing the bone marrow hypothesis semi-physiologically, was superior. This model further included an additive effect for toxicity of the carboplatin combination therapy. Overall, a physiologically plausible PK/PD model was developed that can be used for dose adaptation simulations and prospective studies to further improve paclitaxel-carboplatin-combination therapy. ER -