Please use this identifier to cite or link to this item: doi:10.22028/D291-36579
Title: Physiologically-based pharmacokinetic modeling of dextromethorphan to investigate interindividual variability within CYP2D6 activity score groups
Author(s): Rüdesheim, Simeon
Selzer, Dominik
Fuhr, Uwe
Schwab, Matthias
Lehr, Thorsten
Language: English
Title: CPT: Pharmacometrics & Systems Pharmacology
Volume: 11
Issue: 4
Pages: 494–511
Publisher/Platform: Wiley
Year of Publication: 2022
DDC notations: 500 Science
Publikation type: Journal Article
Abstract: This study provides a whole-body physiologically-based pharmacokinetic (PBPK) model of dextromethorphan and its metabolites dextrorphan and dextrorphan O-glucuronide for predicting the effects of cytochrome P450 2D6 (CYP2D6) drug-gene interactions (DGIs) on dextromethorphan pharmacokinetics (PK). Moreover, the effect of interindividual variability (IIV) within CYP2D6 activity score groups on the PK of dextromethorphan and its metabolites was investigated. A parent-metabolite-metabolite PBPK model of dextromethorphan, dextrorphan, and dextrorphan O-glucuronide was developed in PK-Sim and MoBi. Drug-dependent parameters were obtained from the literature or optimized. Plasma concentration-time profiles of all three analytes were gathered from published studies and used for model development and model evaluation. The model was evaluated comparing simulated plasma concentration-time profiles, area under the concentration-time curve from the time of the first measurement to the time of the last measurement (AUClast) and maximum concentration (Cmax) values to observed study data. The final PBPK model accurately describes 28 population plasma concentration-time profiles and plasma concentration-time profiles of 72 individuals from four cocktail studies. Moreover, the model predicts CYP2D6 DGI scenarios with six of seven DGI AUClast and seven of seven DGI Cmax ratios within the acceptance criteria. The high IIV in plasma concentrations was analyzed by characterizing the distribution of individually optimized CYP2D6 kcat values stratified by activity score group. Population simulations with sampling from the resulting distributions with calculated log-normal dispersion and mean parameters could explain a large extent of the observed IIV. The model is publicly available alongside comprehensive documentation of model building and model evaluation.
DOI of the first publication: 10.1002/psp4.12776
URL of the first publication: https://ascpt.onlinelibrary.wiley.com/doi/10.1002/psp4.12776
Link to this record: urn:nbn:de:bsz:291--ds-365790
hdl:20.500.11880/33229
http://dx.doi.org/10.22028/D291-36579
ISSN: 2163-8306
Date of registration: 24-Jun-2022
Description of the related object: Supporting Information
Related object: https://ascpt.onlinelibrary.wiley.com/action/downloadSupplement?doi=10.1002%2Fpsp4.12776&file=psp412776-sup-0003-SupInfo.zip
https://ascpt.onlinelibrary.wiley.com/action/downloadSupplement?doi=10.1002%2Fpsp4.12776&file=psp412776-sup-0002-SupInfo.zip
https://ascpt.onlinelibrary.wiley.com/action/downloadSupplement?doi=10.1002%2Fpsp4.12776&file=psp412776-sup-0001-SupInfo.pdf
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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