Identification of non-adherence to adjuvant letrozole using a population pharmacokinetics approach in hormone receptor-positive breast cancer patients.

Autor: Puszkiel A; Cancer Research Center of Toulouse (CRCT), Inserm U1037, Université Paul Sabatier - Toulouse III, 2 Avenue Hubert Curien, Toulouse 31100, France., Dalenc F; Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse - Oncopole, Toulouse, France., Tafzi N; Department of Pharmacology, Toxicology and Pharmacovigilance, CHU Limoges, Limoges, France., Marquet P; Department of Pharmacology, Toxicology and Pharmacovigilance, CHU Limoges, Limoges, France., Debled M; Department of Medical Oncology, Institut Bergonié, Bordeaux, France., Jacot W; Institut du Cancer de Montpellier, ICM, Université de Montpellier, IRCM, Inserm U1194, Montpellier, France., Venat-Bouvet L; Department of Medical Oncology, CHU Limoges, Limoges, France., Ferrer C; Department of Medical Oncology, CHU Nîmes-Carémeau, Nîmes, France., Levasseur N; Department of Medical Oncology, CH Cahors, Cahors, France., Paulon R; Department of Medical Oncology, Centre Hospitalier Intercommunal Castres-Mazamet, Castres, France., Dauba J; Department of Medical Oncology, CH Mont de Marsan, Mont-de-Marsan, France., Evrard A; Institut du Cancer de Montpellier, ICM, Université de Montpellier, IRCM, Inserm U1194, Montpellier, France; Laboratoire de Biochimie et Biologie Moléculaire, CHU Nîmes-Carémeau, Nîmes, France., Mauriès V; Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse - Oncopole, Toulouse, France., Filleron T; Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse - Oncopole, Toulouse, France., Chatelut E; Cancer Research Center of Toulouse (CRCT), Inserm U1037, Université Paul Sabatier - Toulouse III, 2 Avenue Hubert Curien, Toulouse 31100, France; Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse - Oncopole, Toulouse, France., Thomas F; Cancer Research Center of Toulouse (CRCT), Inserm U1037, Université Paul Sabatier - Toulouse III, 2 Avenue Hubert Curien, Toulouse 31100, France; Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse - Oncopole, Toulouse, France., White-Koning M; Cancer Research Center of Toulouse (CRCT), Inserm U1037, Université Paul Sabatier - Toulouse III, 2 Avenue Hubert Curien, Toulouse 31100, France. Electronic address: melanie.white-koning@univ-tlse3.fr.
Jazyk: angličtina
Zdroj: European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences [Eur J Pharm Sci] 2024 Aug 01; Vol. 199, pp. 106809. Date of Electronic Publication: 2024 May 22.
DOI: 10.1016/j.ejps.2024.106809
Abstrakt: Background: Letrozole, an aromatase inhibitor metabolised via CYP2A6 and CYP3A4/5 enzymes, is used as adjuvant therapy for women with hormone receptor (HR)-positive early breast cancer. The objective of this study was to quantify the impact of CYP2A6 genotype on letrozole pharmacokinetics (PK), to identify non-adherent patients using a population approach and explore the possibility of a relationship between non-adherence and early relapse.
Methods: Breast cancer patients enrolled in the prospective PHACS study (ClinicalTrials.gov NCT01127295) and treated with adjuvant letrozole 2.5 mg/day were included. Trough letrozole concentrations (C ss,trough ) were measured every 6 months for 3 years by a validated LC-MS/MS method. Concentration-time data were analysed using non-linear mixed effects modelling. Three methods were evaluated for identification of non-adherent subjects using the base PK model.
Results: 617 patients contributing 2534 plasma concentrations were included and led to a one-compartment PK model with linear absorption and elimination. Model-based methods identified 28 % of patients as non-adherent based on high fluctuations of their C ss,trough compared to 3 % based on patient declarations. The covariate analysis performed in adherent subjects revealed that CYP2A6 intermediate (IM) and slow metabolisers (SM) had 21 % (CI95 % = 12 - 30 %) and 46 % (CI95 % = 41 - 51 %) lower apparent clearance, respectively, compared to normal and ultrarapid metabolisers (NM+UM). Early relapse (19 patients) was not associated with model-estimated, concentration-based or declared adherence in the total population (p = 0.41, p = 0.37 and p = 0.45, respectively).
Conclusions: These findings will help future investigations focusing on the exposure-efficacy relationship for letrozole in adjuvant setting.
Competing Interests: Declaration of competing interest The authors declare no competing interests to declare that are relevant to the content of this article.
(Copyright © 2024. Published by Elsevier B.V.)
Databáze: MEDLINE
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