{Reference Type}: Journal Article
{Title}: Integrating Dynamic in vitro Systems and Mechanistic Absorption Modeling: Case Study of Pralsetinib.
{Author}: Dolton MJ;Bowman C;Ma F;Cheeti S;Kuruvilla D;Kassir N;Chen Y;Liu J;Chiang PC;
{Journal}: J Pharm Sci
{Volume}: 0
{Issue}: 0
{Year}: 2024 Jul 26
{Factor}: 3.784
{DOI}: 10.1016/j.xphs.2024.07.006
{Abstract}: Dynamic in vitro absorption systems and mechanistic absorption modeling via PBPK have both shown promise in predicting human oral absorption, although these efforts have been largely separate; this work aimed to integrate knowledge from these approaches to investigate the oral absorption of a RET inhibitor, pralsetinib, with BCS Class II properties. Tiny-TIM (TIM B.V., Weteringbrug​, The Netherlands) is a dynamic in vitro model with close simulation of the successive physiological conditions of the human stomach and small intestine. Tiny-TIM runs with pralsetinib were performed at doses of 200 mg and 400 mg under fasting conditions. Mechanistic modeling of absorption was performed in Simcyp V21 (Certara, Manchester, UK). Pralsetinib fasted bioaccessibility in the Tiny-TIM system was 63% at 200 mg and 53% at 400 mg; a 16% reduction at 400 mg was observed under elevated gastric pH. Maximum pralsetinib solubility from the small intestinal compartment in Tiny-TIM directly informed the supersaturation/precipitation model parameters. The PBPK model predicted a similar fraction absorbed at 200 mg and 400 mg, consistent with the dose proportional increases in observed pralsetinib exposure. Integrating dynamic in vitro systems with mechanistic absorption modeling provides a promising approach for understanding and predicting human absorption with challenging low solubility compounds.