Please use this identifier to cite or link to this item: doi:10.22028/D291-38624
Title: Prediction of Drug–Drug–Gene Interaction Scenarios of (E)-Clomiphene and Its Metabolites Using Physiologically Based Pharmacokinetic Modeling
Author(s): Kovar, Christina
Kovar, Lukas
Rüdesheim, Simeon
Selzer, Dominik
Ganchev, Boian
Kröner, Patrick
Igel, Svitlana
Kerb, Reinhold
Schaeffeler, Elke
Mürdter, Thomas E.
Schwab, Matthias
Lehr, Thorsten
Language: English
Title: Pharmaceutics
Volume: 14
Issue: 12
Publisher/Platform: MDPI
Year of Publication: 2022
Free key words: clomiphene
cytochrome P450 2D6 (CYP2D6) polymorphisms
drug–drug interactions (DDIs)
drug–drug–gene interactions (DDGIs)
drug–gene interactions (DGIs)
physiologically based pharmacokinetic (PBPK) modeling
DDC notations: 500 Science
Publikation type: Journal Article
Abstract: Clomiphene, a selective estrogen receptor modulator (SERM), has been used for the treatment of anovulation for more than 50 years. However, since (E)-clomiphene ((E)-Clom) and its metabolites are eliminated primarily via Cytochrome P450 (CYP) 2D6 and CYP3A4, exposure can be affected by CYP2D6 polymorphisms and concomitant use with CYP inhibitors. Thus, clomiphene therapy may be susceptible to drug–gene interactions (DGIs), drug–drug interactions (DDIs) and drug–drug–gene interactions (DDGIs). Physiologically based pharmacokinetic (PBPK) modeling is a tool to quantify such DGI and DD(G)I scenarios. This study aimed to develop a whole-body PBPK model of (E)-Clom including three important metabolites to describe and predict DGI and DD(G)I effects. Model performance was evaluated both graphically and by calculating quantitative measures. Here, 90% of predicted Cmax and 80% of AUClast values were within two-fold of the corresponding observed value for DGIs and DD(G)Is with clarithromycin and paroxetine. The model also revealed quantitative contributions of different CYP enzymes to the involved metabolic pathways of (E)-Clom and its metabolites. The developed PBPK model can be employed to assess the exposure of (E)-Clom and its active metabolites in as-yet unexplored DD(G)I scenarios in future studies.
DOI of the first publication: 10.3390/pharmaceutics14122604
Link to this record: urn:nbn:de:bsz:291--ds-386245
ISSN: 1999-4923
Date of registration: 23-Dec-2022
Description of the related object: Supplementary Materials
Related object:
Faculty: NT - Naturwissenschaftlich- Technische Fakultät
Department: NT - Pharmazie
Professorship: NT - Prof. Dr. Thorsten Lehr
Collections:SciDok - Der Wissenschaftsserver der Universität des Saarlandes

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