ArticleClinical cancer research : an official journal of the American Association for Cancer Research2022
Mechanistic Modeling of Central Nervous System Pharmacokinetics and Target Engagement of HER2 Tyrosine Kinase Inhibitors to Inform Treatment of Breast Cancer Brain Metastases.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers, 1 of them a synthesis that pooled it.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
17 citing papers in PubMed, 1 synthesis or guideline pooled it, 23 citations in OpenAlex.
- Tyrosine kinase inhibitors in HER2-positive breast cancer brain metastases: A systematic review and meta-analysis.Cancer medicine · 2023Pooled it
- Phase I/II and window-of-opportunity study of pamiparib and metronomic temozolomide for recurrent isocitrate dehydrogenase mutant gliomas.Neuro-oncology · 2026Trial
- Intranasal drug delivery to the brain for neurodegenerative diseases: Current efforts and challenges in delivery platforms and modeling.Advanced drug delivery reviews · 2026Review
- Clinical Features, Molecular Biology, and the Metastatic Microenvironment in Lung Cancer Brain Metastases: Implications for Treatment Decisions.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Review
- SpatialCNS-PBPK: An R/Shiny Web-Based Application for Physiologically Based Pharmacokinetic Modeling of Spatial Pharmacokinetics in the Human Central Nervous System and Brain Tumors.CPT: pharmacometrics & systems pharmacology · 2025Article
- Mechanistic Modeling of Spatial Heterogeneity of Drug Penetration and Exposure in the Human Central Nervous System and Brain Tumors.Clinical pharmacology and therapeutics · 2025Article
- Review
- Case Report: Pathological complete response yet early brain relapse in HER2-positive breast cancer: a case-based review.Frontiers in immunology · 2025Review
- Anti-HER2-targeted therapies: effects on humanFrontiers in drug delivery · 2025Article
- Nanotechnology Platform for the Delivery of Docetaxel and Tyrosine Kinase Inhibitors for HER2-Positive Breast Cancer Therapy.Pharmaceutical nanotechnology · 2025Article
- Depicting Biomarkers for HER2-Inhibitor Resistance: Implication for Therapy in HER2-Positive Breast Cancer.Cancers · 2024Review
- Integrated PBPK-EO modeling of osimertinib to predict plasma concentrations and intracranial EGFR engagement in patients with brain metastases.Scientific reports · 2024Article
- Realizing the promise of Project Optimus: Challenges and emerging opportunities for dose optimization in oncology drug development.CPT: pharmacometrics & systems pharmacology · 2024Review
- Mechanistic Modeling of Intrathecal Chemotherapy Pharmacokinetics in the Human Central Nervous System.Clinical cancer research : an official journal of the American Association for Cancer Research · 2024Article
- Prognostic Factors Influencing Progression-Free Survival in HER2-Positive Metastatic Breast Cancer Patients Who Were Treated With A Combination of Lapatinib and Capecitabine.European journal of breast health · 2023Article
- Durable responses in patients with HER2+ breast cancer and leptomeningeal metastases treated with trastuzumab deruxtecan.NPJ breast cancer · 2023Article
- Individualize management for advanced breast cancer with pyrotinib-based anti-HER2 therapy: a case report.Translational breast cancer research : a journal focusing on translational research in breast cancer · 2023Article
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
Abstract
purposeThis 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
designDrug-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.
resultsPBPK 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.
conclusionsThe 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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.