Model‐Based Quantification of Impact of Genetic Polymorphisms and Co‐Medications on Pharmacokinetics of Tamoxifen and Six Metabolites in Breast Cancer
| Autor: | Laurence Venat-Bouvet, Melanie White-Koning, William Jacot, Alicja Puszkiel, Jacques Robert, Etienne Chatelut, Hortense Laharie-Mineur, Thomas Filleron, Valérie Le Morvan, N. Dohollou, Marc Debled, Florence Dalenc, Chantal Bernard-Marty, Alexandre Evrard, Caroline Delmas, Fabienne Thomas, Henri Roché, Jean-Christophe Boyer, Cécile Arellano, Christelle Vachoux |
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| Rok vydání: | 2020 |
| Předmět: |
Adult
medicine.medical_specialty CYP2D6 Antineoplastic Agents Hormonal Pharmacogenomic Variants Population Breast Neoplasms CYP2C19 Models Biological 030226 pharmacology & pharmacy Gastroenterology 03 medical and health sciences 0302 clinical medicine Breast cancer Pharmacokinetics Internal medicine medicine Humans Pharmacology (medical) Longitudinal Studies skin and connective tissue diseases education Active metabolite Aged Aged 80 and over Pharmacology education.field_of_study Polymorphism Genetic CYP3A4 business.industry Middle Aged medicine.disease Tamoxifen Cytochrome P-450 CYP2D6 030220 oncology & carcinogenesis Female business medicine.drug |
| Zdroj: | Clinical Pharmacology & Therapeutics. 109:1244-1255 |
| ISSN: | 1532-6535 0009-9236 |
| DOI: | 10.1002/cpt.2077 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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