| Added by | ircm doc |
|---|---|
| Group name | EquipeCTCS |
| Item Type | Journal Article |
| Title | Identification of non-adherence to adjuvant letrozole using a population pharmacokinetics approach in hormone receptor-positive breast cancer patients |
| Creator | Puszkiel et al. |
| Author | Alicja Puszkiel |
| Author | Florence Dalenc |
| Author | Naïma Tafzi |
| Author | Pierre Marquet |
| Author | Marc Debled |
| Author | William Jacot |
| Author | Laurence Venat-Bouvet |
| Author | Catherine Ferrer |
| Author | Nadia Levasseur |
| Author | Rodolphe Paulon |
| Author | Jérôme Dauba |
| Author | Alexandre Evrard |
| Author | Vincent Mauriès |
| Author | Thomas Filleron |
| Author | Etienne Chatelut |
| Author | Fabienne Thomas |
| Author | Melanie White-Koning |
| Abstract | 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 (Css,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 Css,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. |
| Publication | European Journal of Pharmaceutical Sciences: Official Journal of the European Federation for Pharmaceutical Sciences |
| Volume | 199 |
| Pages | 106809 |
| Date | 2024-08-01 |
| Journal Abbr | Eur J Pharm Sci |
| Language | eng |
| DOI | 10.1016/j.ejps.2024.106809 |
| ISSN | 1879-0720 |
| Library Catalog | PubMed |
| Extra | PMID: 38788907 |
| Tags | Adherence, Adult, Aged, Aged, 80 and over, Antineoplastic Agents, Breast Neoplasms, Chemotherapy, Adjuvant, clinic, CYP2A6, CYP3A4/5, Female, Humans, Medication Adherence, Middle Aged, Models, Biological, Non-linear mixed-effects modelling, Prospective Studies, Receptors, Estrogen |
| Date Added | 2025/01/16 - 12:09:06 |
| Date Modified | 2025/01/16 - 12:09:28 |
| Notes and Attachments | PubMed entry (Attachment) |
Institut de Recherche en Cancérologie de
