作为一种口服激酶抑制剂，Ripretinib已被批准用于治疗晚期胃肠道间质瘤（GIST），且通常与其他药物联合使用以减缓疾病进展，因此潜在药物-药物相互作用（DDIs）和药物-疾病相互作用（DDZIs）引起了广泛关注。为了指导临床合理用药，本研究评估了联合应用药物和疾病对Ripretinib曝露的影响。使用Simcyp®模拟器开发了Ripretinib的生理药代动力学（PBPK）模型，并通过临床数据进行验证和优化。随后，我们使用已验证的模型检验了多种CYP3A4抑制剂和诱导剂以及不同疾病对Ripretinib曝露的影响。在DDI模拟中，中度CYP3A4抑制剂和诱导剂使Ripretinib的曝露度改变了1.25-2倍。在肝功能受损情况下（HI），模拟显示Ripretinib的AUC在Child-Pugh A，B和C分级时分别增加了32％，100％和152％，而Cmax则分别增加了2％，10％和15％。在肾功能受损（RI）情况下，模型模拟的中度和重度RI的AUC分别增加了27％和20％。总之，PBPK模型展示了Ripretinib在不同条件下药代动力学变化的定量预测，这可能有助于其合理使用。版权所有©2023 Elsevier B.V.。保留所有权利。

Ripretinib, as an oral kinase inhibitor, has been approved to treat advanced gastrointestinal stromal tumors (GIST) and is often used in combination with other drugs to slow disease progression, thus potential drug-drug Interactions (DDIs) and drug-disease interactions (DDZIs) have received much attention. To guide clinical rational drug use, this study assessed the effect of co-administered drugs and diseases on ripretinib exposure. Simcyp® Simulator was used to develop the physiologically-based pharmacokinetic (PBPK) model of ripretinib, which was validated and refined with clinical data. We then examined the impact of several CYP3A4 inhibitors and inducers as well as different diseases on ripretinib exposure using the validated model. In the DDI simulation, moderate CYP3A4 inhibitors and inducers changed the exposure of ripretinib by 1.25-2 fold. In hepatic impairment (HI), the simulation showed that ripretinib's AUC increased by 32%, 100%, and 152% for Child-Pugh A, B, and C classification while Cmax increased by 2%, 10%, and 15%, respectively. In renal impairment (RI), the model-simulated AUC in moderate and severe RIs increased by 27% and 20%. In conclusion, PBPK models demonstrated quantitative prediction of ripretinib's pharmacokinetic changes under varying conditions that might be useful for its rational use.Copyright © 2023 Elsevier B.V. All rights reserved.