Sistema de Salut de Catalunya
Institut Català de la Salut
[Chen J] Pfzer, New York, NY, USA. Genentech, South San Francisco, CA, USA. [Bearz A] National Cancer Institute, Aviano, Italy. [Kim DW] Seoul National University College of Medicine and Seoul National University Hospital, Seoul, Republic of Korea. [Mamdani H] Department of Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA. [Bauman J] Fox Chase Cancer Center, Philadelphia, PA, USA. [Chiari R] Medical Oncology, AULSS6 Veneto, Padua, Italy. [Felip E] Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain
Vall d'Hebron Barcelona Hospital Campus
2024-02-13T10:46:23Z
2024-02-13T10:46:23Z
2024-02
Lorlatinib; Glycoprotein; Advanced non-small cell lung cancer
Lorlatinib; Glicoproteïna; Càncer de pulmó de cèl·lules no petites
Lorlatinib; Glicoproteína; Cáncer de pulmón de células no pequeñas
Background and Objective Lorlatinib is a tyrosine kinase inhibitor approved for the treatment of advanced anaplastic lymphoma kinase–positive non-small cell lung cancer. This study assessed the effect of steady-state lorlatinib on the metabolic enzymes cytochrome P450 (CYP) 2B6, CYP2C9, and uridine 5′-diphospho-glucuronosyltransferase (UGT) and the P-glycoprotein (P-gp) transporter. Methods Thirty-two patients received a single oral dose of a probe drug on Day − 2 to determine the pharmacokinetics of the probe drug alone. Starting on Day 1, patients received 100 mg oral lorlatinib daily. On Day 15, a single oral dose of the probe drug was administered concurrently with lorlatinib. Pharmacokinetic parameters for these probe substrates were assessed. Results Plasma exposures of all probe substrates were reduced by lorlatinib compared with the probe alone. The greatest reduction in area under the plasma concentration–time curve from time zero to infinity (AUC∞) and maximum (peak) plasma drug concentration (Cmax) (67% and 63% decrease, respectively) was observed with the P-gp probe substrate fexofenadine. Lorlatinib coadministration also decreased the AUC∞ and Cmax of bupropion (CYP2B6 probe substrate) by 25% and 27%, tolbutamide (CYP2C9 probe substrate) by 43% and 15%, and acetaminophen (UGT probe substrate) by 45% and 28%, respectively. Conclusions Lorlatinib is a net moderate inducer of P-gp and a weak inducer of CYP2B6, CYP2C9, and UGT after steady state is achieved with daily dosing. Medications that are P-gp substrates with a narrow therapeutic window should be avoided in patients taking lorlatinib; no dose modifications are needed with substrates of CYP2B6, CYP2C9, or UGT. ClinicalTrials.gov: NCT01970865.
This study was sponsored by Pfizer.
Artículo
Versión publicada
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Proteïnes quinases - Inhibidors - Ús terapèutic; Pulmons - Càncer - Tractament; Glicoproteïnes; DISEASES::Neoplasms::Neoplasms by Site::Thoracic Neoplasms::Respiratory Tract Neoplasms::Lung Neoplasms::Bronchial Neoplasms::Carcinoma, Bronchogenic::Carcinoma, Non-Small-Cell Lung; CHEMICALS AND DRUGS::Amino Acids, Peptides, and Proteins::Proteins::Glycoproteins; CHEMICALS AND DRUGS::Chemical Actions and Uses::Pharmacologic Actions::Molecular Mechanisms of Pharmacological Action::Enzyme Inhibitors::Protein Kinase Inhibitors; ENFERMEDADES::neoplasias::neoplasias por localización::neoplasias torácicas::neoplasias del tracto respiratorio::neoplasias pulmonares::neoplasias de los bronquios::carcinoma broncogénico::carcinoma de pulmón de células no pequeñas; COMPUESTOS QUÍMICOS Y DROGAS::aminoácidos, péptidos y proteínas::proteínas::glicoproteínas; COMPUESTOS QUÍMICOS Y DROGAS::acciones y usos químicos::acciones farmacológicas::mecanismos moleculares de acción farmacológica::inhibidores enzimáticos::inhibidores de proteínas cinasas
Springer
Clinical Pharmacokinetics;63
https://doi.org/10.1007/s40262-023-01309-4
Attribution-NonCommercial 4.0 International
http://creativecommons.org/licenses/by-nc/4.0/
