Evaluation of Ipatasertib Interactions with Itraconazole and Coproporphyrin I and III in a Single Drug Interaction Study in Healthy Subjects
Evaluation of Ipatasertib Interactions with Itraconazole and Coproporphyrin I and III in a Single Drug Interaction Study in Healthy Subjects
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DOI：
10.1124/jpet.121.000620
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发表时间：
2021-08-01
影响因子：
3.5
通讯作者：
Musib, Luna
中科院分区：
文献类型：
--
作者：
Sane, Rucha S.;Cheung, Kit Wun Kathy;Musib, Luna
Ipatasertib是一种正在开发中的泛AKT抑制剂，用于治疗癌症。Ipatasertib在体外被细胞色素P3A4代谢为其主要代谢物M1(G-037720)，是P-gp底物和OATP1B1/1B3抑制剂。为评价伊曲康唑(200 mg溶液，qd，4d)对伊帕司替布(100 mg单次给药)药代动力学的影响，对15例健康受试者进行了药物-药物相互作用(DDI)试验。伊曲康唑使ipatasertib的Cmax和AUC(0-无穷大)分别增加2.3倍和5.5倍，半衰期增加53%，t(Max)延长1小时。其代谢物M_1(G-037720)的Cmax和AUC(0-72h)分别降低了91%和68%。本研究证实了CYP3A4在ipatasertib清除中起主要作用。此外，本研究还研究了ipatasertib与OATP1B1/1B3的两种内源底物--同比例卟啉(CP)I和CPIII的相互作用。在ipatasertib存在的情况下，CPI和CPIII血浆水平没有变化，无论是100毫克的暴露还是与伊曲康唑联合的更高暴露。这表明ipatasertib在体内对OATP1B1/1B3没有抑制作用。此外，体外实验表明CPI和CPIII不是P-gp底物，而伊曲康唑在体内对CPI和CPIII浓度没有影响。后者是一个重要的发现，因为它将简化对未来使用CPI/CPIII作为OATP1B1/1B3生物标记物的DDI研究的解释。意义声明这项在健康志愿者中进行的药物-药物相互作用研究表明，CyP3A4在ipatasertib清除过程中起主要作用，ipatasertib不是一种有机阴离子转运多肽1b1/1B3抑制剂。此外，研究还表明，在体内，CYP3A4的抑制剂伊曲康唑和几种转运蛋白对CPI/CPIII水平没有影响。这增加了对这些内源性底物以及伊曲康唑在复杂药物相互作用研究中的理解和应用。
Ipatasertib is a pan-AKT inhibitor in development for the treatment of cancer. Ipatasertib was metabolized by CYP3A4 to its major metabolite, M1 (G-037720), and was a P-gp substrate and OATP1B1/1B3 inhibitor in vitro. A phase I drug-drug interaction (DDI) study (n = 15) was conducted in healthy subjects to evaluate the effect of itraconazole (200-mg solution QD, 4 days), a strong CYP3A4 and P-gp inhibitor, on pharmacokinetics of ipatasertib (100-mg single dose). Itraconazole increased the C-max and AUC(0-infinity) of ipatasertib by 2.3- and 5.5-fold, respectively, increased the half-life by 53%, and delayed the t(max) by 1 hour. The Cmax and AUC(0-72h) of its metabolite M1 (G-037720) reduced by 91% and 68%, respectively. This study confirmed that CYP3A4 plays a major role in ipatasertib clearance. Furthermore, the interaction of ipatasertib with coproporphyrin (CP) I and CPIII, the two endogenous substrates of OATP1B1/1B3, was evaluated in this study. CPI and CPIII plasma levels were unchanged in the presence of ipatasertib, both at exposures of 100 mg and at higher exposures in combination with itraconazole. This indicated no in vivo inhibition of OATP1B1/1B3 by ipatasertib. Additionally, it was shown that CPI and CPIII were not P-gp substrates in vitro, and itraconazole had no effect on CPI and CPIII concentrations in vivo. The latter is an important finding because it will simplify interpretation of future DDI studies using CPI/CPIII as OATP1B1/1B3 biomarkers.SIGNIFICANCE STATEMENTThis drug-drug interaction study in healthy volunteers demonstrated that CYP3A4 plays a major role in ipatasertib clearance, and that ipatasertib is not an organic anion transporting polypeptide 1B1/1B3 inhibitor. Furthermore, it was demonstrated that itraconazole, an inhibitor of CYP3A4 and several transporters, did not affect CPI/CPIII levels in vivo. This increases the understanding and application of these endogenous substrates as well as itraconazole in complex drug interaction studies.