ArticleClinical and translational science2026
A Systematic Intracranial Exposure-Response Evaluation of Brain-Penetrant Inhibitors: Informing Dose Selection for Brain Metastases.
Article in Clinical and translational science, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Brain metastases (BMs) represent a major clinical challenge due to their high incidence in cancers such as non-small cell lung cancer (NSCLC) and breast cancer, and the limited efficacy of systemic therapies resulting from inadequate drug penetration across the blood-brain barrier. Although several brain-penetrant tyrosine kinase inhibitors (TKIs) have been developed, the quantitative relationship between intracranial drug exposure and intracranial clinical response has not been well established, leaving an important gap in dose selection strategies. In this study, we systematically evaluated the intracranial exposure-response relationship across brain-penetrant small-molecule TKIs. Fourteen TKIs were identified based on guideline-recommended therapies for BMs. For each drug, plasma and cerebrospinal fluid (CSF) pharmacokinetic profiles were simulated using published population pharmacokinetic models, with CSF exposures extrapolated using known unbound plasma fractions and CSF-to-plasma unbound concentration ratios (K
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