Physiologically Based Absorption Modelling to Explore the Impact of Food and Gastric pH Changes on the Pharmacokinetics of Entrectinib

AbstractEntrectinib is a potent and selective tyrosine kinase inhibitor (TKI) of TRKA/B/C, ROS1, and ALK with both systemic and CNS activities, which has recently received FDA approval for ROS1 fusion-positive non-small cell lung cancer and NTRK fusion-positive solid tumors. This paper describes the application of a  physiologically based biophamaceutics modeling (PBBM) during clinical development to understand the impact of food and gastric pH changes on absorption of this lipophilic, basic, molecule with reasonable permeability but strongly pH-dependent solubility. GastroPlus™ was used to develop a physiol ogically based pharmacokinetics (PBPK) model integratingin vitro andin silico data and dissolution studies andin silico modelling in DDDPlus ™ were used to understand the role of self-buffering and acidulant on formulation performance. Models were verified by comparison of simulated pharmacokinetics for acidulant and non-acidulant containing formulations to clinical data from a food effect study and relative bioavailability studies wit h and without the gastric acid–reducing agent lansoprazole. A negligible food effect and minor pH-dependent drug-drug interaction for the market formulation were predicted based on biorelevantin vitro measurements, dissolution studies, andin silico modelling and were confirmed in clinical studies. These outcomes were explained as due to the acidulant counteracting entrectinib self-buffering and greatly reducing the effect of gastric ...
Source: The AAPS Journal - Category: Drugs & Pharmacology Source Type: research