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Drug transporters are critical in drug absorption, distribution, and excretion processes. They should be included in physiological-based pharmacokinetic (PBPK) models, which help predict human drug disposition. However, predicting this is challenging during drug development, especially when liver transport is involved. However, with a realistic representation of body transport processes, an accurate model may be possible.
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Drug clearance is a critical pharmacokinetic process involving the irreversible removal of drugs from the body through various organs over a specified time period. Physiological models are indispensable in determining organ-specific clearance, defined by the proportion of the drug eliminated per unit of time from the organ's blood volume.
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The three-compartment open model is a pharmacokinetic model used to describe the distribution and elimination of drugs following extravascular administration. It comprises a central compartment representing the plasma and two peripheral compartments. The highly perfused peripheral compartment represents organs and tissues with a rich blood supply, such as the liver, kidneys, and lungs. The scarcely perfused peripheral compartment represents tissues with lower blood supply, such as adipose...
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Introducing the Dynamic Well-Stirred Model for Predicting Hepatic Clearance and Extraction Ratio.

Zhengyin Yan1, Li Ma1, Pasquale Carione1

  • 1Department of Drug Metabolism and Pharmacokinetics, Genentech Inc., South San Francisco, CA, 94080, USA.

Journal of Pharmaceutical Sciences
|January 14, 2024
PubMed
Summary
This summary is machine-generated.

The dynamic well-stirred model (dWSM) using dynamic free fraction (fD) improves hepatic clearance prediction over the traditional model (WSM) with unbound fraction (fu). The dWSM accurately accounts for drug binding kinetics, enhancing predictions for diverse drugs.

Keywords:
Clearance predictionDynamic free fractionDynamic well-stirred modelIn vitro in vivo extrapolationWell-stirred model

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Area of Science:

  • Pharmacokinetics
  • Drug Metabolism
  • Biopharmaceutical Sciences

Background:

  • The traditional well-stirred model (WSM) uses unbound drug fraction (fu) to predict hepatic clearance, assuming instantaneous drug-protein binding equilibrium.
  • This assumption may lead to inaccuracies, particularly for highly bound drugs, potentially underestimating free drug concentrations.

Purpose of the Study:

  • To introduce and validate a dynamic well-stirred model (dWSM) that incorporates dynamic free fraction (fD) to better account for drug-protein binding kinetics.
  • To compare the predictive accuracy of dWSM against WSM for hepatic clearance and liver extraction ratio across a diverse range of drugs.

Main Methods:

  • Theoretical analysis comparing the impact of fu and fD on intrinsic clearance.
  • In vitro experiments using recombinant CYP3A4 with highly bound midazolam and highly free verapamil.
  • Validation of dWSM using in vitro microsomal clearance data from 36 diverse drugs.

Main Results:

  • Dynamic free fraction (fD) accurately corrects albumin binding effects on intrinsic clearance for both highly bound and highly free drugs.
  • The traditional unbound fraction (fu) over-corrects for highly bound drugs like midazolam.
  • dWSM significantly improved the prediction accuracy of human hepatic clearance and liver extraction ratio compared to WSM.

Conclusions:

  • The dWSM, utilizing fD, provides a more broadly applicable and accurate method for predicting hepatic clearance, especially for drugs with varying protein binding characteristics.
  • Drug plasma protein binding kinetics are crucial for accurate hepatic clearance prediction, and dWSM addresses limitations of the traditional WSM.