{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T13:58:08Z","timestamp":1792159088809,"version":"4.4.0"},"reference-count":29,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T00:00:00Z","timestamp":1792108800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T00:00:00Z","timestamp":1792108800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Translational Sci"],"published-print":{"date-parts":[[2026,11]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Brain metastases (BMs) represent a major clinical challenge due to their high incidence in cancers such as non\u2010small cell lung cancer (NSCLC) and breast cancer, and the limited efficacy of systemic therapies resulting from inadequate drug penetration across the blood\u2013brain barrier. Although several brain\u2010penetrant 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\u2010response relationship across brain\u2010penetrant small\u2010molecule TKIs. Fourteen TKIs were identified based on guideline\u2010recommended 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\u2010to\u2010plasma unbound concentration ratios (\n                    <jats:italic>K<\/jats:italic>\n                    <jats:sub>p,uu,CSF<\/jats:sub>\n                    ) in humans. Key intracranial exposure metrics, including the CSF steady\u2010state trough and average concentrations relative to IC\n                    <jats:sub>50<\/jats:sub>\n                    (\n                    <jats:italic>C<\/jats:italic>\n                    <jats:sub>min,ss<\/jats:sub>\n                    \/IC\n                    <jats:sub>50<\/jats:sub>\n                    and\n                    <jats:italic>C<\/jats:italic>\n                    <jats:sub>ave,ss<\/jats:sub>\n                    \/IC\n                    <jats:sub>50<\/jats:sub>\n                    ) and the percentage of the steady\u2010state dosing interval during which CSF concentrations remained above IC\n                    <jats:sub>50<\/jats:sub>\n                    (T%\u2009&gt;\u2009IC\n                    <jats:sub>50<\/jats:sub>\n                    ), were derived and correlated with intracranial outcomes from published clinical studies. Overall, significant positive correlations were observed between intracranial exposure metrics and both intracranial objective response rate (ORR) and complete response rate (CR). Greater exposure coverage above IC\n                    <jats:sub>50<\/jats:sub>\n                    was associated with improved intracranial efficacy. This work demonstrates a positive intracranial exposure\u2010response relationship across brain\u2010penetrant TKIs and provides a quantitative benchmark to inform dose selection beyond traditional plasma exposure metrics. These findings highlight the importance of achieving sufficient CNS drug concentrations to optimize the therapeutic effect in patients with BMs.\n                  <\/jats:p>","DOI":"10.1111\/cts.70744","type":"journal-article","created":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T13:41:22Z","timestamp":1792158082000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Systematic Intracranial Exposure\u2010Response Evaluation of Brain\u2010Penetrant Inhibitors: Informing Dose Selection for Brain Metastases"],"prefix":"10.1111","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-8768-673X","authenticated-orcid":false,"given":"Yuqian","family":"Zhao","sequence":"first","affiliation":[{"name":"Clinical Pharmacology Genentech, Inc.  South San Francisco California USA"},{"name":"University of Pittsburgh  Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5903-721X","authenticated-orcid":false,"given":"Weize","family":"Huang","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology Genentech, Inc.  South San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,16]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.pharmthera.2016.10.011","article-title":"Treatment of Brain Metastases in the Modern Genomic Era","volume":"170","author":"Dagogo\u2010Jack I.","year":"2017","journal-title":"Pharmacology & Therapeutics"},{"issue":"3","key":"e_1_2_8_3_1","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1016\/j.trecan.2018.01.003","article-title":"The Evolving Landscape of Brain Metastasis","volume":"4","author":"Valiente M.","year":"2018","journal-title":"Trends Cancer"},{"issue":"11","key":"e_1_2_8_4_1","doi-asserted-by":"crossref","first-page":"1511","DOI":"10.1093\/neuonc\/nox077","article-title":"Incidence and Prognosis of Patients With Brain Metastases at Diagnosis of Systemic Malignancy: A Population\u2010Based Study","volume":"19","author":"Cagney D. 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