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Abstract
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 overpredicted 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.
Footnotes
- Received February 28, 2017.
- Accepted June 5, 2017.
C.K. and W.H. are supported by grants from an industry consortium comprising AbbVie Deutschland GmbH & Co. KG, Boehringer Ingelheim Pharma GmbH & Co. KG, Grünenthal GmbH, F. Hoffmann-La Roche Ltd., Merck KGaA, and Sanofi. C.K. is supported by grants from the Innovative Medicines Initiative Joint Undertaking (DDMoRe: Drug Disease Modelling Resources) and Diurnal Ltd.
C.K. and Z.P.P.-G. are co-senior authors.
Part of this work was previously presented at the following meetings:
Henrich A, Joerger M, Huisinga W, Kloft C, and Parra-Guillen ZP (2015) External evaluation of a PK/PD model describing the time course of paclitaxel and neutropenia in patients with advanced non-small cell lung cancer. 24th Population Approach Group Europe (PAGE); 2015 Jun 02-05; Hersonissos, Greece.
Henrich A, Joerger M, Huisinga W, Kloft C, and Parra-Guillen ZP (2015) Dose-individualisation of paclitaxel in patients with advanced non-small cell lung cancer: exploiting modelling and simulation to refine dosing algorithm. Annual Meeting of the Central European Society of Anticancer Drug Research (CESAR); 2015 Sep 17-19; Innsbruck, Austria.
↵Henrich A, Joerger M, Kraff S, Jaehde U, Huisinga H, Kloft C, and Parra-Guillen ZP (2016) PK/PD model extension to characterise bone marrow exhaustion in cancer patient making use of a prior paclitaxel PK model. 25th Population Approach Group Europe (PAGE); 2016 Jun 07-10; Lisbon, Portugal. PAGE 25: 5879 [www.page-meeting.org/?abstract=5879], (2016).
Henrich A, Joerger M, Huisinga W, Parra-Guillen ZP, and Kloft C (2016) Semi-mechanistic PK/PD modelling to characterise long-term deterioration of neutropenia in cancer patients. Annual Meeting of the Central European Society of Anticancer Drug Research (CESAR); 2016 Sep 08-10; Munich, Germany.
Henrich A, Joerger M, Huisinga W, Kloft C, and Parra-Guillen ZP (2016) Characterisation of bone marrow exhaustion and long-term neutropenia by applying PK/PD modelling. Annual Meeting of the Deutsche Pharmazeutische Gesellschaft (DPhG); 2016 Oct 04-07; Munich, Germany.
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- Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics
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