Track: Formulation and Delivery - Chemical - Formulation - Oral - Immediate Release
Category: Late Breaking Poster Abstract
Development of Bioequivalent Pazopanib Tablets Using Quality by Design Approach and Comparative Pharmacokinetics in Beagle Dogs
Purpose: Pazopanib is a multi-targeted receptor tyrosine kinase inhibitor that has been approved worldwide for the treatment of kidney and renal pelvis carcinoma. The aqueous solubility of pazopanib is very low and varies significantly with pH. With low solubility at pH above 4.0 and limited absorption in the gastrointestinal tract, orally administered pazopanib exhibits limited bioavailability of 13-21% with large variations. For the development of a bioequivalent tablet formulation, several process variables need optimization, including the density of granules and the hardness of tablets. In this study, the design space for manufacturing process of pazopanib tablet formulation was secured through a quality by design (QbD) approach, andbioequivalence of the optimized formulation was confirmed by assessing the pharmacokinetics (PK) in beagle dogs. Methods: The optimal pazopanib tablet product was obtained through Design of Experiment (DoE). The experimental design and data analysis were performed using Minitab. The statistical analysis for the correlation between factors and responses was conducted using Minitab’s Pareto chart. The dissolution test was carried out using USP apparatus 2. The PK profile of pazopanib tablet was evaluated in beagle dogs. Tablets of 400 mg pazopanib, as the reference (original product) and tablet formulation, were prepared and orally administered to the dogs. Blood samples were collected for 48 hours, and the drug concentration in plasma was determined with LC/MS/MS system. Results: Minitab software proposed the design space disintegrant ratio and tablet hardness for equivalence with the reference formulation. The optimized formulation exhibited equivalent dissolution profiles in various pH media. The PK study in beagle dogs showed that AUClast and Cmax of the optimized formulation were 107.3% and 102.8% of those of the reference formulation respectively, indicating its bioequivalence. Conclusion: By implementing the design of experiment (DOE) and statistical evaluations, the optimized pazopanib formulation and its design space for bioequivalence with the original product were secured.