Published November 10, 2020
| Version v1
Journal article
Model‐Based Quantification of Impact of Genetic Polymorphisms and Co‐Medications on Pharmacokinetics of Tamoxifen and Six Metabolites in Breast Cancer
Creators
- Puszkiel, Alicja
- Arellano, Cécile
- Vachoux, Christelle
- Evrard, Alexandre
- Morvan, Valérie Le
- Boyer, Jean-Christophe
- Robert, Jacques
- Delmas, Caroline
- Dalenc, Florence
- Debled, Marc
- Venat Bouvet, Laurence
- Jacot, William
- Dohollou, Nadine
- Bernard-Marty, Chantal
- Laharie-Mineur, Hortense
- Filleron, Thomas
- Roché, Henri
- Chatelut, Étienne
- Thomas, Fabienne
- White-Koning, Mélanie
Contributors
Others:
- Centre de Recherches en Cancérologie de Toulouse (CRCT) ; Université Toulouse III - Paul Sabatier (UT3) ; Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
- Laboratoire de Biochimie [CHRU Nîmes] ; Centre Hospitalier Universitaire de Nîmes (CHU Nîmes)
- Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM) ; CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)
- Institut Bergonié [Bordeaux] ; UNICANCER
- Laboratoire de pharmacologie des agents anticancéreux (LPAA) ; Institut Bergonié [Bordeaux] ; UNICANCER-UNICANCER-Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS)
- Institut Claudius Regaud (ICR)
- Service d'Oncologie médicale [CHU Limoges] ; CHU Limoges
- Polyclinique Bordeaux Nord Aquitaine (PBNA)
- Clinique Pasteur [Toulouse]
- Clinique Tivoli Ducos [Bordeaux]
- Centre de recherche en épidémiologie et santé des populations (CESP) ; Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay
- Oncostat (U1018 (Équipe 2)) ; Institut Gustave Roussy (IGR)-Centre de recherche en épidémiologie et santé des populations (CESP) ; Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay
- Université Paris-Saclay
Description
Variations in clinical response to tamoxifen (TAM) may be related to polymorphic cytochromes P450 (CYPs) involved in forming its active metabolite endoxifen (ENDO). We developed a population pharmacokinetic (PopPK) model for tamoxifen and six metabolites to determine clinically relevant factors of ENDO exposure. Concentration‐time data for TAM and 6 metabolites come from a prospective, multicenter, 3‐year follow‐up study of adjuvant TAM (20 mg/day) in patients with breast cancer, with plasma samples drawn every 6 months, and genotypes for 63 genetic polymorphisms (PHACS study, NCT01127295). Concentration data for TAM and 6 metabolites from 928 patients ( n = 27,433 concentrations) were analyzed simultaneously with a 7‐compartment PopPK model. CYP2D6 phenotype (poor metabolizer (PM), intermediate metabolizer (IM), normal metabolizer (NM), and ultra‐rapid metabolizer (UM)), CYP3A4*22 , CYP2C19*2 , and CYP2B6*6 genotypes, concomitant CYP2D6 inhibitors, age, and body weight had a significant impact on TAM metabolism. Formation of ENDO from N‐desmethyltamoxifen was decreased by 84% (relative standard error (RSE) = 14%) in PM patients and by 47% (RSE = 9%) in IM patients and increased in UM patients by 27% (RSE = 12%) compared with NM patients. Dose‐adjustment simulations support an increase from 20 mg/day to 40 and 80 mg/day in IM patients and PM patients, respectively, to reach ENDO levels similar to those in NM patients. However, when considering Antiestrogenic Activity Score (AAS), a dose increase to 60 mg/day in PM patients seems sufficient. This PopPK model can be used as a tool to predict ENDO levels or AAS according to the patient's CYP2D6 phenotype for TAM dose adaptation.
Abstract
International audienceAdditional details
Identifiers
- URL
- https://hal.science/hal-04938406
- URN
- urn:oai:HAL:hal-04938406v1
Origin repository
- Origin repository
- UNICA