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Virtual Bioequivalence Assessment of Ritlecitinib Capsules with Incorporation of Observed Clinical Variability Using
Anas Saadeddin1, Vivek Purohit2, Yeamin Huh2
1Pharmaceutical Science, Pfizer Worldwide Research and Development, Madrid, Spain.
The AAPS Journal
|January 24, 2024
Summary
Ritlecitinib dissolution differences between capsule strengths were evaluated using a physiologically based pharmacokinetic (PBPK) model. The PBPK model successfully predicted bioequivalence for ritlecitinib 50-mg capsules, supporting a biowaiver.
Area of Science:
- Pharmacokinetics
- Drug Development
- Alopecia Areata Treatment
Background:
- Ritlecitinib, a JAK3 and tyrosine kinase inhibitor, is developed for alopecia areata.
- High solubility is expected, but in vitro dissolution varied between 100-mg and 50-mg capsules.
- A biowaiver based on dissolution similarity was not feasible.
Purpose of the Study:
- To evaluate the in vivo relevance of observed in vitro dissolution differences.
- To develop and apply a physiologically based pharmacokinetic (PBPK) model for ritlecitinib.
- To assess bioequivalence between ritlecitinib capsule formulations using virtual bioequivalence (VBE) trials.
Main Methods:
- Development and verification of a ritlecitinib PBPK model.
- Conducting virtual bioequivalence (VBE) trials using the Simcyp VBE module.
- Incorporating clinically observed intra-subject coefficient of variation (ICV) into VBE assessments.
Main Results:
- The PBPK model translated in vitro dissolution to in vivo pharmacokinetic profiles.
- Initial VBE trials predicted lower ICV than observed clinically.
- VBE trials incorporating clinical ICV demonstrated bioequivalence between 50-mg and 100-mg ritlecitinib capsules (>90% probability of success).
Conclusions:
- A PBPK model-based biowaiver for a clinical bioequivalence study was demonstrated.
- A novel method integrating clinically observed ICV into PBPK-driven VBE trials was introduced.
- This approach supports regulatory decision-making for drug product variations.
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