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 as a predictor of intracranial efficacy.

RESULTS:

PBPK models predicted that following 1 cycle of standard dosing, tucatinib and lapatinib achieved similar Css,ave,br (14.5 vs. 16.8 nmol/L), while neratinib Css,ave,br (0.68 nmol/L) was 20-fold lower. Tucatinib and neratinib were equally potent for HER2 inhibition (IC50, 6.9 vs. 5.6 nmol/L), while lapatinib was less potent (IC50, 109 nmol/L). The model-predicted population mean TER in the human normal brain was 2.1 for tucatinib, but < 0.20 for lapatinib and neratinib.

CONCLUSIONS:

The PBPK modeling suggests that tucatinib induces sufficient HER2 inhibition (TER > 2.0) in not only brain metastases with a disrupted blood-brain barrier (BBB), but also micrometastases where the BBB largely remains intact. These findings, in line with available clinical pharmacokinetics and efficacy data, support the therapeutic value of tucatinib for treatment of brain metastases and warrant further clinical investigation for the prevention of brain metastases in patients with HER2-positive breast cancer.

• Authors: Jing Li, Jun Jiang, Xun Bao, Vineet Kumar, Stephen C Alley, Scott Peterson, Anthony J Lee
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 28 Issue 15 Pg. 3329-3341 (08 02 2022) ISSN: 1557-3265 [Electronic] United States
• PMID: 35727144 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)
• Copyright: ©2022 The Authors; Published by the American Association for Cancer Research.

Chemical References

• Protein Kinase Inhibitors
• Lapatinib
• Receptor, ErbB-2

Topics

• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Brain Neoplasms (secondary)
• Breast Neoplasms (pathology)
• Central Nervous System
• Female
• Humans
• Lapatinib (therapeutic use)
• Protein Kinase Inhibitors (therapeutic use)
• Receptor, ErbB-2 (metabolism)