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A physiological-based pharmacokinetic model embedded with a target-mediated drug disposition mechanism can characterize single dose warfarin pharmacokinetic profiles in subjects with various CYP2C9 genotypes under different co-treatments

Shen Cheng, Darcy R Flora, Allan E. Rettie, Richard C. Brundage and Timothy S. Tracy
Drug Metabolism and Disposition November 15, 2022, DMD-AR-2022-001048; DOI: https://doi.org/10.1124/dmd.122.001048
Shen Cheng
1present affiliation: Metrum Research Group, United States
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Darcy R Flora
2Present Affiliation: GRYT Health Inc., United States
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Allan E. Rettie
3Dept. of Medicinal Chemistry, University of Washington, United States
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Richard C. Brundage
4Experimental and Clinical Pharmacology, University of Minnesota, United States
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  • For correspondence: brund001@umn.edu
Timothy S. Tracy
5Tracy Consultants, United States
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Abstract

Warfarin, a commonly prescribed oral anticoagulant medication, is highly effective in treating deep vein thrombosis and pulmonary embolism. However, the clinical dosing of warfarin is complicated by high inter-individual variability in drug exposure and response and its narrow therapeutic index. CYP2C9 genetic polymorphism and drug-drug interactions (DDIs) are substantial contributors to this high variability of warfarin pharmacokinetics (PK), among numerous factors. Building a physiological-based pharmacokinetic (PBPK) model for warfarin is not only critical for a mechanistic characterization of warfarin PK, but also useful for investigating the complicated dose-exposure relationship of warfarin. Thus, the objective of this study was to develop a PBPK model for warfarin which integrates information regarding CYP2C9 genetic polymorphisms and their impact on DDIs. Generic PBPK models for both S- and R-warfarin, the two enantiomers of warfarin, were constructed in R with the mrgsolve package. As expected, a generic PBPK model structure did not adequately characterize the warfarin PK profile collected up to 15 days following the administration of single oral dose of warfarin, especially for S-warfarin. However, following the integration of an empirical target-mediated drug disposition (TMDD) component, the PBPK-TMDD model well characterized the PK profiles collected for both S- and R-warfarin in subjects with different CYP2C9 genotypes. Following the integration of enzyme inhibition and induction effects, the PBPK-TMDD model also characterized the PK profiles of both S- and R-warfarin in various DDI settings. The developed mathematic framework may be useful in building algorithms to better inform the clinical dosing of warfarin.

Significance Statement The present study found a traditional physiology-based pharmacokinetic (PBPK) model cannot sufficiently characterize the pharmacokinetic profiles of warfarin enantiomers when warfarin is administered as a single dose, but a PBPK model with a target-mediated drug disposition mechanism can. After incorporating CYP2C9 genotypes and drug-drug interaction information, the developed model is anticipated to facilitate the understanding of warfarin disposition in subjects with different CYP2C9 genotypes in the absence and presence of both cytochrome P450 inhibitors and cytochrome P450 inducers.

  • drug-drug interactions
  • human pharmacokinetics
  • pharmacogenetics/pharmacogenomics
  • physiologically-based pharmacokinetic modeling/PBPK
  • Copyright © 2020 American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 51 (10)
Drug Metabolism and Disposition
Vol. 51, Issue 10
1 Oct 2023
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Warfarin PBPK model with TMDD mechanism

Shen Cheng, Darcy R Flora, Allan E. Rettie, Richard C. Brundage and Timothy S. Tracy
Drug Metabolism and Disposition November 15, 2022, DMD-AR-2022-001048; DOI: https://doi.org/10.1124/dmd.122.001048

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OtherArticle

Warfarin PBPK model with TMDD mechanism

Shen Cheng, Darcy R Flora, Allan E. Rettie, Richard C. Brundage and Timothy S. Tracy
Drug Metabolism and Disposition November 15, 2022, DMD-AR-2022-001048; DOI: https://doi.org/10.1124/dmd.122.001048
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