A physiologically based pharmacokinetic - pharmacodynamic modelling approach to predict incidence of neutropenia as a result of drug-drug interactions of paclitaxel in cancer patients

Mailys De Sousa Mendes, Oliver Hatley, Katherine Linda Gill, Karen Rowland Yeo, Alice Ban Ke
European Journal of Pharmaceutical Sciences 2020 May 18, 150: 105355
Paclitaxel is the backbone of standard chemotherapeutic regimens used in a number of malignancies and is frequently given with concomitant medications. Newly developed oncolytic agents, including tyrosine kinase inhibitors are often shown to be CYP3A4 and P-gp inhibitors. The aim of this study was to develop a PBPK model for intravenously administered paclitaxel in order to predict the incidence of neutropenia and to estimate the DDI potential as a victim drug. The dose-dependent effects on paclitaxel plasma protein binding, volume of distribution and drug clearance were considered for dose levels of 80 mg/m2 , 135 mg/m2 and 175 mg/m2 . A pharmacodynamics model that incorporate the impact of paclitaxel on the neutrophil was developed. The relative metabolic clearance via CYP3A4 and CYP2C8, the renal clearance as well as P-gp mediated biliary clearance were incorporated in the model in order to assess the neutropenia in the presence of DDI. The developed PBPK-PD model was able to recover the drop in neutrophils observed after the administration of 175mg/m2 of paclitaxel over a 3-h duration. The mean nadir observed was 1.9 × 109 neutrophils/L and was attained after 10 days of treatment, and a fraction of 47% of the population was predicted to have at some point a neutropenia including 12% with severe neutropenia. In the case of concomitant administration of ketoconazole, 39% of the population was predicted to suffer from severe neutropenia. In summary, PBPK-PD modeling allows a priori prediction of DDIs and safety events involving complex combination therapies which are often utilized in an oncology setting.

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