Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2024 Aug 1:199:106809.
doi: 10.1016/j.ejps.2024.106809. Epub 2024 May 22.

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

Alicja Puszkiel  1 , Florence Dalenc  2 , Naïma Tafzi  3 , Pierre Marquet  3 , Marc Debled  4 , William Jacot  5 , Laurence Venat-Bouvet  6 , Catherine Ferrer  7 , Nadia Levasseur  8 , Rodolphe Paulon  9 , Jérôme Dauba  10 , Alexandre Evrard  11 , Vincent Mauriès  2 , Thomas Filleron  2 , Etienne Chatelut  12 , Fabienne Thomas  12 , Melanie White-Koning  13
Affiliations
Free article

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

Alicja Puszkiel et al. Eur J Pharm Sci. .
Free article

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.

Keywords: Adherence; CYP2A6; CYP3A4/5; Letrozole; Non-linear mixed-effects modelling; Pharmacokinetics.

PubMed Disclaimer

Conflict of interest statement

Declaration of competing interest The authors declare no competing interests to declare that are relevant to the content of this article.

MeSH terms

Associated data