TY  - JOUR
A1  - Henrich, Andrea
A1  - Joerger, Markus
A1  - Kraff, Stefanie
A1  - Jaehde, Ulrich
A1  - Huisinga, Wilhelm
A1  - Kloft, Charlotte
A1  - Parra-Guillen, Zinnia Patricia
T1  - Semimechanistic Bone Marrow Exhaustion Pharmacokinetic/Pharmacodynamic Model for Chemotherapy-Induced Cumulative Neutropenia
JF  - Journal of Pharmacology and Experimental Therapeutics
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. Joerger et al. (2016) developed a dose individualization algorithm based on a pharmacokinetic (PK)/pharmacodynamic (PD) model describing paclitaxel and neutrophil concentrations. Furthermore, the algorithm was prospectively compared in a clinical trial against standard dosing (Central European Society for Anticancer Drug Research Study of Paclitaxel Therapeutic Drug Monitoring; 365 patients, 720 cycles) 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. This work aimed to externally evaluate the original PK/PD model for potential misspecifications and to refine the PK/PD model while considering the cumulative neutropenia pattern and the combination therapy. An underprediction was observed for the PK (658 samples), the PK parameters, and these parameters were re-estimated using the original estimates as prior information. Neutrophil concentrations (3274 samples) were over-predicted by the PK/PD model, especially for later treatment cycles when the cumulative pattern aggravated neutropenia. Three different modeling approaches (two from the literature and one newly developed) were investigated. The newly developed model, which implemented the bone marrow hypothesis semiphysiologically, was superior. This model further included an additive effect for toxicity of 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.
Y1  - 2017
U6  - https://doi.org/10.1124/jpet.117.240309
SN  - 0022-3565
SN  - 1521-0103
VL  - 362
IS  - 2
SP  - 347
EP  - 358
PB  - American Society for Pharmacology and Experimental Therapeutics
CY  - Bethesda
ER  -