Ipatasertib是一种用于治疗癌症的泛AKT抑制剂。Ipatasertib被CYP3A4代谢为其主要代谢产物,M1(G-037720),在体外是P-gp底物和OATP1B1/1B3抑制剂。在健康受试者中进行了I期药物-药物相互作用(DDI)研究(n=15),以评估伊曲康唑(200-mg溶液QD,4天),一种强效CYP3A4和P-gp抑制剂,关于ipatasertib(100-mg单剂量)的药代动力学。伊曲康唑使伊帕他替布的Cmax和AUC0-∞分别增加2.3倍和5.5倍,分别,半衰期增加了53%,并将tmax延迟1小时。其代谢物M1(G-037720)的Cmax和AUC0-72h分别降低了91%和68%,分别。这项研究证实CYP3A4在ipatasertib清除中起主要作用。此外,ipatasertib与卟啉(CP)I和CPIII的相互作用,在这项研究中评估了OATP1B1/1B3的两种内源性底物。在ipatasertib存在的情况下,CPI和CPIII血浆水平没有变化,在100mg的暴露量和与伊曲康唑组合的较高暴露量。这表明ipatasertib对OATP1B1/1B3没有体内抑制作用。此外,结果表明,CPI和CPIII在体外不是P-gp底物,伊曲康唑对体内CPI和CPIII浓度无影响。后者是一个重要的发现,因为它将简化使用CPI/CPIII作为OATP1B1/1B3生物标志物的未来DDI研究的解释。重要声明: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清除中起主要作用,并且ipatasertib不是有机阴离子转运多肽1B1/1B3抑制剂。此外,证明伊曲康唑,CYP3A4和几种转运蛋白的抑制剂,不影响体内CPI/CPIII水平。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 Cmax and AUC0 -∞ of ipatasertib by 2.3- and 5.5-fold, respectively, increased the half-life by 53%, and delayed the tmax by 1 hour. The Cmax and AUC0-72h 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 STATEMENT: This 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.