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Establishment of Biopredictive Dissolution and Bioequivalence Safe Space Using the Physiologically Based
Fulin Bi1, Tong Yuan1, Baohong Zhang2
1Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, 210009, China.
AAPS Pharmscitech
|December 17, 2024
Summary
Developing accurate in vitro dissolution methods is crucial for generic tacrolimus extended-release (ER) capsules, which have a narrow therapeutic index (NTI). Physiologically based biopharmaceutics modeling (PBBM) and biorelevant media can predict bioequivalence (BE) and establish safe spaces for NTI drugs.
Area of Science:
- Pharmaceutical Sciences
- Drug Development
- Biopharmaceutics
Background:
- Tacrolimus extended-release (ER) capsules have a narrow therapeutic index (NTI), making them sensitive to variations in in vivo exposure.
- Stricter bioequivalence (BE) standards for generic drugs necessitate precise assessment of drug release kinetics.
- An in vitro dissolution method with high in vivo predictive power is essential for generic NTI drug development.
Purpose of the Study:
- To develop and validate a physiologically based biopharmaceutics modeling (PBBM) approach for 5 mg tacrolimus ER capsules.
- To establish a biopredictive dissolution method using the Flow-Through Cell apparatus (USP IV) and biorelevant media.
- To propose bioequivalence (BE) safe spaces for tacrolimus ER capsules using PBBM and virtual bioequivalence trials.
Main Methods:
- Physiologically based biopharmaceutics modeling (PBBM) was developed and validated for tacrolimus ER capsules.
- The Flow-Through Cell apparatus (USP IV) with biorelevant media was used to assess reference and non-BE test formulations.
- Virtual bioequivalence trials were conducted using PBBM to define a BE safe space.
Main Results:
- A biopredictive dissolution method was successfully established for tacrolimus ER capsules.
- PBBM enabled the identification of formulations that might pass internal quality control but fail bioequivalence.
- The study proposed criteria to define a bioequivalence (BE) safe space for NTI drugs.
Conclusions:
- Biopredictive dissolution methods based on biorelevant dissolution offer significant advantages for generic drug development.
- Integrating PBBM with biopredictive dissolution methods provides a practical approach for the bioequivalence evaluation of NTI drugs.
- This combined approach serves as a valuable tool for developing new tacrolimus ER formulations.
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