Exploiting Pharmacokinetic Models of Tamoxifen and Endoxifen to Identify Factors Causing Subtherapeutic Concentrations in Breast Cancer Patients.

Détails

ID Serval
serval:BIB_A8448D11AA3D
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Exploiting Pharmacokinetic Models of Tamoxifen and Endoxifen to Identify Factors Causing Subtherapeutic Concentrations in Breast Cancer Patients.
Périodique
Clinical pharmacokinetics
Auteur(s)
Klopp-Schulze L., Joerger M., Wicha S.G., Ter Heine R., Csajka C., Parra-Guillen Z.P., Kloft C.
ISSN
1179-1926 (Electronic)
ISSN-L
0312-5963
Statut éditorial
Publié
Date de publication
02/2018
Peer-reviewed
Oui
Volume
57
Numéro
2
Pages
229-242
Langue
anglais
Notes
Publication types: Comparative Study ; Journal Article
Publication Status: ppublish
Résumé
A better understanding of the highly variable pharmacokinetics (PK) of tamoxifen and its active metabolite endoxifen in breast cancer patients is crucial to support individualised treatment. This study used a modelling and simulation approach to quantitatively assess the influence of cytochrome P450 (CYP) 2D6 activity and other relevant factors on tamoxifen and endoxifen PK to identify subgroups at risk for subtherapeutic endoxifen concentrations.
Simulations were performed using two previously published PK models jointly describing tamoxifen and endoxifen with CYP2D6 and CYP3A4/5 enzyme activities implemented as covariates. Steady-state predictions were compared between models and with the literature values. Factors potentially causing between-model discrepancies were explored. A previously published threshold (6 ng/mL) was used to identify patients with subtherapeutic endoxifen concentrations and to perform a dose adaptation study.
Steady-state predictions of tamoxifen and endoxifen were considerably different between the models. The factors, differences in sampling time, adherence and bioavailability, were not able to fully capture between-model variability. Endoxifen steady-state fluctuations within a dosing interval were minimal (<6%). Poor (97%) and intermediate (54%) CYP2D6 metabolisers failed to achieve therapeutic endoxifen concentrations, suggesting adapted doses of tamoxifen 80 and 40 mg, respectively, achieving therapeutic endoxifen concentrations in 89.7% of patients (standard dosing 45.2%). However, interindividual variability remained.
To achieve therapeutic endoxifen concentrations early in treatment, it is advisable to initiate treatment by CYP2D6 genotype/phenotype-guided dosing, followed by therapeutic drug monitoring at steady-state. We strongly advocate to adequately measure, report and prospectively investigate influential factors (i.e. adherence, bioavailability, time to PK steady-state) in clinical trials.
Mots-clé
Adult, Aged, Antineoplastic Agents, Hormonal/administration & dosage, Antineoplastic Agents, Hormonal/pharmacokinetics, Biological Availability, Breast Neoplasms/drug therapy, Computer Simulation, Cytochrome P-450 CYP2D6/genetics, Cytochrome P-450 CYP2D6/metabolism, Cytochrome P-450 CYP3A/metabolism, Dose-Response Relationship, Drug, Drug Monitoring/methods, Female, Genotype, Humans, Medication Adherence/statistics & numerical data, Middle Aged, Models, Biological, Phenotype, Tamoxifen/administration & dosage, Tamoxifen/analogs & derivatives, Tamoxifen/pharmacokinetics, Young Adult
Pubmed
Web of science
Création de la notice
06/06/2017 21:50
Dernière modification de la notice
20/08/2019 16:12
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