Clinical Exploration and Physiologically Based Modelling of the Impact of Hepatic Impairment on Entrectinib Pharmacokinetics

• Published in: Clinical pharmacokinetics Vol. 64; no. 3; pp. 437 - 451
• Main Authors: Ozbey, Agustos C, Meneses-Lorente, Georgina, Simmons, Brian, McCallum, Sam, Annaert, Pieter, Parrott, Neil, Umehara, Kenichi
• Format: Journal Article
• Language: English
• Published: Switzerland Springer Nature B.V 01.03.2025
• Subjects: Administration, Oral; Adult; Aged; Area Under Curve; Benzamides - administration & dosage; Benzamides - blood; Benzamides - pharmacokinetics; Bile; Clinical trials; Computer Simulation; Cytochrome P-450 CYP3A - metabolism; Drug dosages; Enzymes; Female; Humans; Indazoles - administration & dosage; Indazoles - blood; Indazoles - pharmacokinetics; Kinases; Liver; Liver Diseases - blood; Liver Diseases - metabolism; Male; Metabolism; Metabolites; Middle Aged; Models, Biological; Permeability; Pharmacokinetics; Plasma; Simulation; Trends; Tumors

This study investigates the pharmacokinetics (PK) of entrectinib and its metabolite M5 (CYP3A4 substrates) in patients with hepatic impairment (HI) and applies physiologically based pharmacokinetic (PBPK) modelling to understand the observed changes mechanistically. After a single oral administratio...