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.
摘要：
动态体外吸收系统和通过PBPK的机械吸收模型在预测人类口服吸收方面都显示出希望。尽管这些努力在很大程度上是分开的；这项工作旨在整合这些方法的知识来研究RET抑制剂的口服吸收，普雷替尼,具有BCSII类属性。Tiny-TIM(TIMB.V.,Weteringbrug,荷兰）是一种动态的体外模型，可以密切模拟人体胃和小肠的连续生理状况。在禁食条件下以200mg和400mg的剂量与普雷替尼一起进行Tiny-TIM运行。在SimcypV21(Certara，曼彻斯特,英国）。在Tiny-TIM系统中，Pralsetinib的禁食生物可及性在200mg时为63％，在400mg时为53％；在升高的胃pH下，观察到400mg时降低了16％。Tiny-TIM中小肠区室的最大普雷替尼溶解度直接告知过饱和/沉淀模型参数。PBPK模型预测了在200mg和400mg时吸收的相似分数，与观察到的普雷替尼暴露的剂量成比例增加一致。将动态体外系统与机械吸收模型相结合，为理解和预测具有挑战性的低溶解度化合物的人体吸收提供了一种有前途的方法。
