{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T16:59:45Z","timestamp":1791910785612,"version":"4.3.4"},"reference-count":38,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2022,4,27]],"date-time":"2022-04-27T00:00:00Z","timestamp":1651017600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["accp1.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Clinical Pharma"],"published-print":{"date-parts":[[2022,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Lorlatinib is a third\u2010generation, brain\u2010penetrant anaplastic lymphoma kinase (ALK) and c\u2010ros oncogene\u00a01 (ROS1) tyrosine kinase inhibitor (TKI) with robust intracranial activity in patients with <jats:italic>ALK\u2010<\/jats:italic> or <jats:italic>ROS1\u2010<\/jats:italic>positive non\u2010small cell lung cancer (NSCLC). Data from the ongoing open\u2010label, single\u2010arm, multicenter, phase\u20101\/2 study of lorlatinib in patients with metastatic <jats:italic>ALK\u2010<\/jats:italic> or <jats:italic>ROS1\u2010<\/jats:italic>positive NSCLC were used to further investigate the potential brain penetration of lorlatinib. Patients received escalating lorlatinib doses (10\u2013200\u00a0mg once daily or 35\u2013100\u00a0mg twice daily) or the approved dosing (100\u00a0mg daily). Plasma was collected from all patients, and cerebrospinal fluid (CSF) was collected at baseline and during the study from 5 patients with suspected or confirmed leptomeningeal carcinomatosis or carcinomatous meningitis. For those 5 patients, lorlatinib concentrations ranged from 2.64 to 125\u00a0ng\/mL in the CSF and from 12.7 to 457\u00a0ng\/mL in the plasma; free plasma concentrations ranged from 4.318 to 155.385\u00a0ng\/mL. The CSF\/free plasma ratio was 0.77 (R<jats:sup>2<\/jats:sup>\u00a0=\u00a00.96 and <jats:italic>P\u00a0<\/jats:italic>&lt;\u00a0.001). Using a post\u2010hoc population pharmacokinetic model, the average steady\u2010state unbound plasma concentration of lorlatinib was derived and the CSF concentration was estimated for all patients. Known minimum efficacy concentrations (C<jats:sub>eff<\/jats:sub>) for wild\u2010type and mutated (L1196M and G1202R) <jats:italic>ALK<\/jats:italic> were used to derive central nervous system (CNS) C<jats:sub>eff<\/jats:sub>. Estimated CNS concentrations exceeded the derived CNS C<jats:sub>eff<\/jats:sub> values in all patients for wild\u2010type <jats:italic>ALK<\/jats:italic> and the <jats:italic>ALK<\/jats:italic> L1196M mutation, and in 35.8% of patients for the <jats:italic>ALK<\/jats:italic> G1202R mutation. Projected lorlatinib CNS concentrations were consistent with the high intracranial response rates reported in clinical trials and provide further evidence of the potent CNS penetration of lorlatinib.<\/jats:p>","DOI":"10.1002\/jcph.2056","type":"journal-article","created":{"date-parts":[[2022,4,4]],"date-time":"2022-04-04T08:58:05Z","timestamp":1649062685000},"page":"1170-1176","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Evaluation of Lorlatinib Cerebrospinal Fluid Concentrations in Relation to Target Concentrations for Anaplastic Lymphoma Kinase (ALK) Inhibition"],"prefix":"10.1002","volume":"62","author":[{"given":"Steven","family":"Sun","sequence":"first","affiliation":[{"name":"Skaggs School of Pharmacy and Pharmaceutical Sciences (SSPPS) University of California, San Diego (UCSD)  La Jolla California USA"},{"name":"Clinical Pharmacology, Oncology Business Unit Pfizer Inc.  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