Clinical Relevance of High Plasma Trough Levels of the Kinase Inhibitors Crizotinib, Alectinib, Osimertinib, Dabrafenib, and Trametinib in NSCLC Patients.

Autor:	Lin L; Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands., Barkman HJ; Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands., Smit EF; Department of Thoracic Oncology, Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam, The Netherlands.; Department of Pulmonology, Leiden University Medical Center, Leiden, The Netherlands., de Langen AJ; Department of Thoracic Oncology, Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam, The Netherlands., Steeghs N; Department of Medical Oncology, Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam, The Netherlands., Beijnen JH; Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.; Department of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands., Huitema ADR; Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.; Department of Pharmacology, Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands; and.; Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
Jazyk:	angličtina
Zdroj:	Therapeutic drug monitoring [Ther Drug Monit] 2024 Feb 01; Vol. 46 (1), pp. 73-79. Date of Electronic Publication: 2023 Jun 20.
DOI:	10.1097/FTD.0000000000001120
Abstrakt:	Background: the study aims to evaluate whether high plasma trough levels of the kinase inhibitors (K.I.s) crizotinib, alectinib, osimertinib, dabrafenib, and trametinib were associated with a higher risk of toxicity in non-small-cell lung cancer patients. Methods: In this retrospective cohort study, patients with non-small-cell lung cancer treated with the selected K.I.s were included if at least one plasma trough level at steady state (C min,ss ) was available. Data were extracted from electronic medical records and laboratory databases. The high group for each K.I. was defined as 10% of patients with the highest first C min,ss . The remaining patients were placed in the non-high group. The frequency of dose-limiting toxicities (DLTs), defined as adverse events leading to dose reduction, dose interruption, or permanent discontinuation, was compared between the 2 groups. Results: A total of 542 patients were included in the different K.I. groups. A high C min,ss of crizotinib (n = 96), alectinib (n = 105), osimertinib (n = 227), dabrafenib (n = 52), and trametinib (n = 62) correlated with a C min,ss ≥490, ≥870, ≥405, ≥150, and ≥25 ng/mL, respectively. DLTs were more common in the alectinib high group than in the alectinib non-high group (64% vs. 29%, P = 0.036). Liver toxicity was observed in 4 (36%) patients in the high group and 5 (5%) patients in the non-high group ( P = 0.007). For other K.I.s, no significant differences were observed in the frequency of DLTs between the high and non-high groups. Conclusions: For alectinib, high C min,ss was correlated with a higher risk of DLT. No differences in the frequency of DLTs were observed between the high and non-high groups for crizotinib, osimertinib, dabrafenib, and trametinib. Competing Interests: E. F. Smit reports consulting or advisory role (institution) for AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, Merck KGaA, MSD Oncology, Novartis, Roche/Genentech, Seattle Genetics, Takeda; and research funding (institution) from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Roche/Genentech, outside of the submitted work. A. J. de Langen reports grants from BMS, MSD, AstraZenica, and Boehringer, and nonfinancial support from Merck Serono and Roche, outside the submitted work. N. Steeghs provided consultation or attended advisory boards for Boehringer Ingelheim and Ellipses Pharma and received research grants for the institute from A.B. Science, Abbvie, Actuate Therapeutics, ADCtherapeutics, Amgen, Array, Ascendis Pharma, Astex, AstraZeneca, Bayer, Blueprint Medicines, Boehringer Ingelheim, BridgeBio, Bristol-Myers Squibb, Cantargia, Celgene, CellCentric, Cresecendo, Cytovation, Deciphera, Eli Lilly, Exelixis, Genentech, Genmab, Gilead, GlaxoSmithKline, Incyte, InteRNA, Janssen/Johnson&Johnson, Kinate, Merck, Merck Sharp & Dohme, Merus, Molecular Partners, Novartis, Numab, Pfizer, Pierre Fabre, Regeneron, Roche, Sanofi, Seattle Genetics, Servier, Taiho, Takeda, outside of the submitted work. J. H. Beijnen is a part-time employee and (indirect) shareholder of Modra Pharmaceuticals B.V. He is (partly) patent holder of oral taxane formulations which are clinically developed by Modra Pharmaceuticals B.V. (a spin-off company of the Netherlands Cancer Institute, not related to this work). L. Lin, H. J. Barkman, and A. D. R. Huitema declare no potential conflicts of interest. (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology.)
Databáze:	MEDLINE
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