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Integrating In Vitro, Modeling, and In Vivo Approaches to Investigate Warfarin Bioequivalence
1Office of Generic Drugs, US Food and Drug Administration, Silver Spring, Maryland, USA.
CPT: Pharmacometrics & Systems Pharmacology
|April 6, 2017
Summary
Physiologically based pharmacokinetic modeling and simulation investigated bioequivalence concerns for generic warfarin. Warfarin pharmacokinetics were not sensitive to acidic dissolution but were affected by dissolution at pH 6.8, confirming virtual bioequivalence study results.
Area of Science:
- Pharmacokinetics and Pharmaceutical Sciences
- Drug Development and Bioequivalence Studies
- Computational Modeling in Pharmacology
Background:
- Generic warfarin products have raised bioequivalence (BE) concerns.
- Investigating the impact of formulation factors on drug absorption is crucial for generic drug approval.
- Understanding the influence of dissolution profiles on warfarin pharmacokinetics is essential for ensuring therapeutic equivalence.
Purpose of the Study:
- To investigate bioequivalence concerns associated with generic warfarin products using modeling and simulation.
- To test the hypothesis that loss of isopropyl alcohol and slow dissolution in acidic pH significantly impact warfarin sodium tablet pharmacokinetics.
- To compare in silico predictions with in vivo bioequivalence study results.
Main Methods:
- Physiologically based pharmacokinetic (PBPK) absorption modeling and simulation were employed.
- Formulation factors and in vitro dissolution profiles were used as input parameters for PBPK models.
- Sensitivity analyses were performed, followed by virtual bioequivalence studies and a human clinical bioequivalence study.
Main Results:
- Warfarin pharmacokinetics showed no sensitivity to solubility, particle size, density, or dissolution rate at pH 4.5.
- Dissolution rate at pH 6.8 and product potency significantly affected warfarin pharmacokinetics.
- Virtual BE studies predicted bioequivalence for stressed tablets (slow dissolution at pH 4.5, similar at pH 6.8) compared to unstressed tablets.
- A human clinical bioequivalence study confirmed the simulation findings.
Conclusions:
- Physiologically based pharmacokinetic modeling and simulation are valuable tools for assessing bioequivalence concerns.
- Dissolution rate at neutral/alkaline pH (6.8) is a critical factor for warfarin sodium tablet bioequivalence, more so than acidic dissolution.
- The study confirmed that certain in vitro dissolution profiles can predict in vivo bioequivalence for generic warfarin products.
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