Journal article
Exploiting Pharmacokinetic Models of Tamoxifen and Endoxifen to Identify Factors Causing Subtherapeutic Concentrations in Breast Cancer Patients.
- Klopp-Schulze L Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, Kelchstr. 31, 12169, Berlin, Germany.
- Joerger M Department of Medical Oncology and Haematology, Cantonal Hospital, St. Gallen, Switzerland.
- Wicha SG Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, Kelchstr. 31, 12169, Berlin, Germany.
- Ter Heine R Department of Pharmacy, Radboud University Medical Centre, Nijmegen, The Netherlands.
- Csajka C Division of Clinical Pharmacology and Toxicology, Service of Biomedicine, University Hospital Center and University of Lausanne, Lausanne, Switzerland.
- Parra-Guillen ZP Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, Kelchstr. 31, 12169, Berlin, Germany.
- Kloft C Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, Kelchstr. 31, 12169, Berlin, Germany. charlotte.kloft@fu-berlin.de.
- 2017-05-26
Published in:
- Clinical pharmacokinetics. - 2018
Adult
Aged
Antineoplastic Agents, Hormonal
Biological Availability
Breast Neoplasms
Computer Simulation
Cytochrome P-450 CYP2D6
Cytochrome P-450 CYP3A
Dose-Response Relationship, Drug
Drug Monitoring
Female
Genotype
Humans
Medication Adherence
Middle Aged
Models, Biological
Phenotype
Tamoxifen
Young Adult
English
BACKGROUND AND OBJECTIVES
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.
METHODS
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.
RESULTS
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.
CONCLUSIONS
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.
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.
METHODS
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.
RESULTS
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.
CONCLUSIONS
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.
- Language
-
- English
- Open access status
- closed
- Identifiers
-
- DOI 10.1007/s40262-017-0555-z
- PMID 28540639
- Persistent URL
- https://sonar.ch/global/documents/20237
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