Bridging in vitro buoyancy to clinical performance: A PBPK-driven analysis of once-daily Bepotastine gastro-retentive tablet in beagles and humans
Abstract
Bepotastine possesses a short half-life (~2 h) and a narrow absorption window limited to the upper small intestine, necessitating a gastro-retentive drug delivery system for once-daily administration. In this study, we developed a low-density gastro-retentive tablet designed for instantaneous floating (zero lag time) to prevent premature gastric emptying-a critical limitation of conventional floating systems. This was achieved through a rational engineering approach using AutoCAD-based geometric integration to precisely control the initial apparent density below 1.004 g/cm3. The synergistic combination of low viscosity hypromellose (15 cP) and magnesium aluminometasilicate facilitated immediate buoyancy and sustained it for over 4 h through wicking-induced air entrapment and robust gel layer formation. In beagle dogs, the gastro-retentive tablet achieved 95.7% systemic exposure relative to a twice-daily reference, whereas non-floating sustained-release formulations reached only 64.5-88.6%, highlighting the necessity of gastric retention. Notably, a randomized clinical study in 28 healthy subjects confirmed that the scaled-up gastro-retentive formulation was bioequivalent to the reference product. Produced via standard manufacturing processes, the 100,000-tablet batch also demonstrated no clinically significant food effect. Species-specific physiologically based pharmacokinetic modeling mechanistically estimated gastric residence times of approximately 180 min in beagles and…
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