Physiologically Based Pharmacokinetic Modelling of Cabozantinib to Simulate Enterohepatic Recirculation, Drug–Drug Interaction with Rifampin and Liver Impairment

Abstract

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 (Cmax) 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 Cmax). 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.

Prediction for optimal dosage of pazopanib under various clinical situations using physiologically based pharmacokinetic modeling

“…Currently, these parameter changes have been applied to multiple PBPK models (see Supplementary Table S4 ). However, most published papers for PBPK models of hepatic impairment have not taken into account absorption changes between impaired and normal hepatic function ( Morcos et al, 2018 ; Gerner and Scherf-Clavel, 2021 ; Fan et al, 2022 ).…”

“…In this simulation, the used physiological parameters in patients with hepatic impairment were taken from the published papers ( Heimbach et al, 2021 ; Willmann et al, 2021 ). The plasma protein scale factor (PPSF) in PK-Sim ® was modified to describe changes in plasma albumin protein concentration and unbound PAZ fraction ( Gerner and Scherf-Clavel, 2021 ). Based on the following equation derived from the paper ( Johnson et al, 2010 ), PPSF was estimated.…”

Cabozantinib-Loaded PLGA Nanoparticles: A Potential Adjuvant Strategy for Surgically Resected High-Risk Non-Metastatic Renal Cell Carcinoma

“…In current clinical practice, the CZ tablet formulation (Cabometyx™) was approved at a dose of 60 mg daily for treating advanced RCC. CZ at 2–2.5 mg/kg per day is equivalent to 15–20 mg per day in humans [ 67 , 73 ], and previous preclinical in vivo studies using oral CZ monotherapy (once daily oral gavage of 10–60 mg/kg CZ) have demonstrated its anticancer effects in mouse models of various tumor types, including RCC Renca cell lines [ 41 , 67 ]. For example, a recent study using the subcutaneous Renca model demonstrated the CZ (10 mg/kg, once per day by gavage for 14 days)-mediated tumor growth inhibition through triggered infiltration of both antineoplastic neutrophils/T cells into the tumor bed and significantly enhanced the cytotoxicity of tumor-infiltrated T cells [ 67 ].…”

Physiologically based pharmacokinetic modelling and simulation to predict the plasma concentration profile of schaftoside after oral administration of total flavonoids of Desmodium styracifolium

“…Nevertheless, there was still an overestimation in schaftoside plasma concentration especially for C max . According to the literature, intestinal absorption may be limited by solubility, thus imposing an upper limit on the absorption of compounds ( Gerner and Scherf-Clavel, 2021 ). Even so, the predicted C max and AUC 0-t values of schaftoside after oral administration of TFDS in rats were within ∼1.5-fold of the observed values, which met the acceptance criteria (<2-fold).…”

“…There are some limitations to this study. One limitation which might reduce the applicability of the model was the lack of iv data of schaftoside in human ( Gerner and Scherf-Clavel, 2021 ). Although the rat PBPK model utilized the iv and oral plasma concentration-time profiles of schaftoside and TFDS, the establishment of human PBPK model only based on the oral data of schaftoside after oral administration of TFDS.…”