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Bioequivalence Comparison of Pediatric Dasatinib Formulations and Elucidation of Absorption Mechanisms Through Integrated PBPK Modeling
Authors:Shruthi Vaidhyanathan  Xiaoning Wang  John Crison  Sailesh Varia  Julia Z.H. Gao  Ajay Saxena  David Good
Affiliation:1. Drug Product Science and Technology, Bristol-Myers Squibb, New Brunswick, New Jersey 08901;2. Clinical Pharmacology and Pharmacometrics, Bristol-Myers Squibb, Lawrenceville, New Jersey 08648;3. Biopharmaceutics R&D, Bristol-Myers Squibb, New Brunswick, New Jersey 08901;4. Biopharmaceutics, Biocon Bristol-Myers Squibb R&D Centre (BBRC), Bangalore, India
Abstract:SPRYCEL® (Dasatinib) is a Biopharmaceutical Classification System II weakly basic drug that exhibits strong pH-dependent solubility. Dasatinib is currently presented in 2 drug product formulations as an adult immediate release tablet and a pediatric powder for oral suspension. A bioequivalence study comparing the formulations in adult healthy subjects found that overall exposure (AUC0-24) from suspension treatments was ~9% to 13% lower, Cmax was similar, and median Tmax from powder for oral suspension was ~30 min earlier. To understand the mechanism contributing to this behavior, a combination of biorelevant dissolution studies and physiologically based pharmacokinetic modeling was used to simulate in vivo performance. In vitro biorelevant dissolution confirmed that the rate and extent of release was similar between tablet and suspension formulations (>90% release within first 15 min). Physiologically based pharmacokinetic parameter sensitivity analysis demonstrated particular sensitivity to dosage form gastric residence time. A 12% higher AUC0-24 was simulated for tablet dosage forms with 10 to 15 min longer gastric transit relative to solutions or suspensions of small particulates (rapid gastric emptying). The corresponding narrow simulated Cmax range also agreed with observed tablet and suspension bioequivalence data. The unique physicochemical properties, absorption characteristics, and inherent differences in dosage form transit behavior are attributed to influence the dasatinib bioequivalence.
Keywords:absorption  physiologically based pharmacokinetic (PBPK) modeling  bioequivalence  formulation  gastroPlus modeling  special populations  intestinal absorption  biopharmaceutical characterization
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