Complex DDI by Fenebrutinib and the Use of Transporter Endogenous Biomarkers to Elucidate the Mechanism of DDI
Complex DDI by Fenebrutinib and the Use of Transporter Endogenous Biomarkers to Elucidate the Mechanism of DDI
复制标题
DOI：
10.1002/cpt.1599
复制
发表时间：
2019-09-16
影响因子：
6.7
通讯作者：
Chinn, Leslie W.
中科院分区：
文献类型：
--
作者：
Jones, Nicholas S.;Yoshida, Kenta;Chinn, Leslie W.
对可能涉及多种消除途径的复杂临床药物相互作用（DDI）的机制理解一直具有挑战性，特别是考虑到普遍缺乏转运蛋白的特异性探针底物。在这里，我们进行了一项临床 DDI 研究，以评估芬布替尼使用咪达唑仑（MDZ；CYP3A）、辛伐他汀（CYP3A 和 OATP1B）和瑞舒伐他汀（BCRP 和 OATP1B）作为探针底物的相互作用潜力。 Fenebrutinib (200 mg) 使这些探针底物的曲线下面积 (AUC) 增加了两倍至三倍。为了评估观察到的 DDI 的机制，我们测量了 OATP1B 的内源生物标志物粪卟啉 I (CP-I) 和粪卟啉 III (CP-III) 的浓度。 fenebrutinib 的 CP-I 或 CP-III 水平没有变化，这表明观察到的 DDI 是由 CYP3A 和 BCRP 的抑制而不是 OATP1B 引起的，可能是由于生物利用度增加。这是第一个发表的文章，使用内源性转运蛋白生物标志物来了解涉及多种消除途径的复杂 DDI 的机制。
Mechanistic understanding of complex clinical drug-drug interactions (DDIs) with potential involvement of multiple elimination pathways has been challenging, especially given the general lack of specific probe substrates for transporters. Here, we conducted a clinical DDI study to evaluate the interaction potential of fenebrutinib using midazolam (MDZ; CYP3A), simvastatin (CYP3A and OATP1B), and rosuvastatin (BCRP and OATP1B) as probe substrates. Fenebrutinib (200 mg) increased the area under the curve (AUC) of these probe substrates twofold to threefold. To evaluate the mechanism of the observed DDIs, we measured the concentration of coproporphyrin I (CP-I) and coproporphyrin III (CP-III), endogenous biomarkers of OATP1B. There was no change in CP-I or CP-III levels with fenebrutinib, suggesting that the observed DDIs were caused by inhibition of CYP3A and BCRP rather than OATP1B, likely due to increased bioavailability. This is the first published account using an endogenous transporter biomarker to understand the mechanism of complex DDIs involving multiple elimination pathways.