TY  - JOUR
A1  - Gerner, Bettina
A1  - Scherf-Clavel, Oliver
T1  - Physiologically based pharmacokinetic modelling of Cabozantinib to simulate enterohepatic recirculation, drug−drug interaction with Rifampin and liver impairment
JF  - Pharmaceutics
N2  - Cabozantinib (CAB) is a receptor tyrosine kinase inhibitor approved for the treatment of several cancer types. Enterohepatic recirculation (EHC) of the substance is assumed but has not been further investigated yet. CAB is mainly metabolized via CYP3A4 and is susceptible for drug–drug interactions (DDI). The goal of this work was to develop a physiologically based pharmacokinetic (PBPK) model to investigate EHC, to simulate DDI with Rifampin and to simulate subjects with hepatic impairment. The model was established using PK-Sim® and six human clinical studies. The inclusion of an EHC process into the model led to the most accurate description of the pharmacokinetic behavior of CAB. The model was able to predict plasma concentrations with low bias and good precision. Ninety-seven percent of all simulated plasma concentrations fell within 2-fold of the corresponding concentration observed. Maximum plasma concentration (C\(_{max}\)) and area under the curve (AUC) were predicted correctly (predicted/observed ratio of 0.9–1.2 for AUC and 0.8–1.1 for C\(_{max}\)). DDI with Rifampin led to a reduction in predicted AUC by 77%. Several physiological parameters were adapted to simulate hepatic impairment correctly. This is the first CAB model used to simulate DDI with Rifampin and hepatic impairment including EHC, which can serve as a starting point for further simulations with regard to special populations.
KW  - physiologically based pharmacokinetic (PBPK) modeling
KW  - Cabozantinib
KW  - enterohepatic recirculation
KW  - drug–drug interactions (DDIs)
KW  - liver impairment
KW  - cytochrome P450 3A4 (CYP3A4)
KW  - pharmacokinetics
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-239661
SN  - 1999-4923
VL  - 13
IS  - 6
ER  -