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Physiologically Based Biopharmaceutics Model of Apixaban for Biopharmaceutics Risk Assessment.

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Physiologically Based Biopharmaceutics Modeling (PBBM) accurately predicts apixaban bioavailability and bioequivalence. Smaller particle sizes below 120 µm ensure bioequivalence and support biowaiver criteria for drug development.

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Critical Biopharmaceutics AttributesPhysiologically Based Biopharmaceutics Modelingapixabanmodel-informed drug development

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Area of Science:

  • Pharmacokinetics and Biopharmaceutics
  • Computational Drug Development
  • Formulation Science

Background:

  • Apixaban, a borderline BCS Class III/IV drug, presents challenges in predicting bioavailability (BA) and bioequivalence (BE).
  • Understanding formulation impacts on apixaban's in vivo performance is crucial for drug development.
  • Physiologically Based Biopharmaceutics Modeling (PBBM) offers a predictive framework for complex drugs.

Purpose of the Study:

  • To develop and validate a PBBM framework for predicting apixaban BA and BE.
  • To investigate the influence of formulation factors (particle size, granulation) on apixaban's absorption.
  • To identify formulation characteristics ensuring bioequivalence and supporting regulatory decisions.

Main Methods:

  • Integrated physicochemical, formulation, and drug parameters into a PBBM framework.
  • Utilized the Noyes-Whitney equation to model dissolution influenced by particle size and granulation.
  • Employed a middle-out strategy combining in silico, in vitro, and in vivo data for simulation.

Main Results:

  • Validated PBBM predictions against observed pharmacokinetic profiles for apixaban across various doses and formulations.
  • Demonstrated acceptable prediction accuracy for BA and BE under diverse conditions.
  • Identified a 'dissolution safe space' providing insights into acceptable formulation attributes.

Conclusions:

  • PBBM effectively predicts apixaban BA and BE, streamlining drug development and reducing clinical trials.
  • Particle sizes <120 µm ensure bioequivalence with reference formulations.
  • Faster dissolution rates, linked to smaller particle sizes, align with BCS biowaiver criteria, optimizing drug quality.