| Title |
Exploiting Pharmacokinetic Models of Tamoxifen and Endoxifen to Identify Factors Causing Subtherapeutic Concentrations in Breast Cancer Patients
|
|---|---|
| Published in |
Clinical Pharmacokinetics, May 2017
|
| DOI | 10.1007/s40262-017-0555-z |
| Pubmed ID | |
| Authors |
Lena Klopp-Schulze, Markus Joerger, Sebastian G. Wicha, Rob ter Heine, Chantal Csajka, Zinnia P. Parra-Guillen, Charlotte Kloft |
| Abstract |
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. |
X Demographics
The data shown below were collected from the profiles of 3 X users who shared this research output. Click here to find out more about how the information was compiled.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| Spain | 3 | 100% |
Demographic breakdown
| Type | Count | As % |
|---|---|---|
| Members of the public | 3 | 100% |
Mendeley readers
The data shown below were compiled from readership statistics for 39 Mendeley readers of this research output. Click here to see the associated Mendeley record.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| Unknown | 39 | 100% |
Demographic breakdown
| Readers by professional status | Count | As % |
|---|---|---|
| Student > Ph. D. Student | 5 | 13% |
| Student > Master | 4 | 10% |
| Student > Doctoral Student | 4 | 10% |
| Researcher | 3 | 8% |
| Student > Postgraduate | 3 | 8% |
| Other | 7 | 18% |
| Unknown | 13 | 33% |
| Readers by discipline | Count | As % |
|---|---|---|
| Pharmacology, Toxicology and Pharmaceutical Science | 11 | 28% |
| Medicine and Dentistry | 7 | 18% |
| Biochemistry, Genetics and Molecular Biology | 3 | 8% |
| Unspecified | 1 | 3% |
| Computer Science | 1 | 3% |
| Other | 3 | 8% |
| Unknown | 13 | 33% |
Attention Score in Context
This research output has an Altmetric Attention Score of 2. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 14 February 2018.
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#14,349,470
of 22,977,819 outputs
Outputs from Clinical Pharmacokinetics
#1,141
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#175,337
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Outputs of similar age from Clinical Pharmacokinetics
#18
of 28 outputs
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