Mechanistic Modeling of Central Nervous System Pharmacokinetics and Target Engagement of HER2 Tyrosine Kinase Inhibitors to Inform Treatment of Breast Cancer Brain Metastases.

ABSTRACT:

Purpose

This study evaluated the central nervous system (CNS) pharmacokinetics and target engagement of lapatinib, neratinib, and tucatinib in patients with cancer, using a physiologically based pharmacokinetic (PBPK) modeling approach.

Experimental design

Drug-specific parameters for in vitro metabolism, binding to plasma proteins and brain tissues, transcellular passive permeability, and interactions with efflux transporters were determined. Whole-body PBPK models integrated with a 4-compartment permeability-limited brain model was developed and verified for predicting plasma and CNS pharmacokinetics. Target engagement ratio (TER), defined as the ratio of the average steady-state unbound drug brain concentration (Css,ave,br) to in vitro IC50 for HER2 inhibition, was used a

SUBMITTER: Li J 

PROVIDER: S-EPMC9357092 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature