PII-099 - PBPK MODELING TO PREDICT THE EFFECT OF GASTRIC PH ON BIOEQUIVALENCE OF PALBOCICLIB TABLETS

R. Jamil¹, A. Babiskin¹, L. Zhang¹, L. Fang², F. Wu²; ¹FDA, White Oak, MD, United States, ²U.S. Food and Drug Administration, Silver Spring, MD, USA.

Background: Palbociclib is a BCS Class II weak base drug that shows pH-dependent solubility. IBRANCE tablets (palbociclib immediate release (IR) tablets, NDA 212436), the reference listed drug (RLD), contain a pH modifier to help minimize the pH-effect in the presence of acid-reducing agents (ARAs). There is a potential of having different pH impact caused by the co-administration of an ARA due to formulation differences. Therefore, the current FDA product-specific guidance (PSG) for palbociclib IR tablets recommends conducting an additional fasting BE study in the presence of an ARA. This research aims to develop a PBPK model of palbociclib IR tablets to identify biopredictive dissolution and assess the impact of co-administration of ARAs on BE for palbociclib IR tablets.

Methods: GastroPlus® (version 9.9.0002) was used to develop a PBPK model under fasting conditions using two different approaches for incorporating dissolution data: (1) fitting a Z-factor to dissolution data and (2) directly using dissolution data. The developed PBPK models were validated using submission datasets and virtual bioequivalence (VBE) simulations for approved generic palbociclib tablets. The validated PBPK model was then used to predict PK and BE of generic palbociclib tablets in subjects administered with an ARA.

Results: During model development, both approaches for incorporating dissolution into PBPK modeling successfully predicted RLD Cmax and AUCinf (i.e., percent prediction error within 20%) under fasted conditions. During model validation, the direct dissolution incorporation approach appears better than the Z-factor approach in predicting Cmax and AUCinf of RLD. The model prediction using direct dissolution incorporation approach passed BE criteria for all approved ANDA datasets. The direct dissolution incorporation approach also predicted BE of an approved generic palbociclib IR product under fasted conditions with the co-administration of an ARA using available pH 4.5 dissolution data (Figure 1).

Conclusion: A fasted PBPK model with the direct dissolution incorporation method can be used to predict BE of generic palbociclib IR tablet products with and without the co-administration of ARAs. The presented models may be used to identify biopredictive dissolution and assess the impact of co-administration of ARAs on BE for generic palbociclib IR tablets.