Genentech, South San Francisco, California
Genentech, South San Francisco, California.
J Pharmacol Exp Ther. 2021 Aug;378(2):87-95. doi: 10.1124/jpet.121.000620. Epub 2021 May 28.
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 ( = 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 and AUC of ipatasertib by 2.3- and 5.5-fold, respectively, increased the half-life by 53%, and delayed the t by 1 hour. The C and AUC 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.
伊帕替膦酸盐是一种正在开发用于治疗癌症的泛 AKT 抑制剂。伊帕替膦酸盐在体内主要通过 CYP3A4 代谢为其主要代谢物 M1（G-037720），并且是 P-糖蛋白（P-gp）底物和有机阴离子转运多肽 1B1/1B3（OATP1B1/1B3）抑制剂。在健康受试者中进行了一项药物相互作用（DDI）研究（n=15），以评估酮康唑（200mg 溶液 QD，连续 4 天）作为一种强 CYP3A4 和 P-gp 抑制剂对伊帕替膦酸盐（100mg 单剂量）药代动力学的影响。酮康唑使伊帕替膦酸盐的 C 和 AUC 分别增加 2.3 倍和 5.5 倍，半衰期延长 53%，达峰时间延迟 1 小时。其代谢物 M1（G-037720）的 C 和 AUC 分别减少 91%和 68%。这项研究证实 CYP3A4 在伊帕替膦酸盐的清除中起主要作用。此外，在这项研究中还评估了伊帕替膦酸盐与内源性 OATP1B1/1B3 底物原卟啉 I（CP I）和原卟啉 III（CPIII）的相互作用。酮康唑存在时，CP I 和 CPIII 的血浆水平在 100mg 暴露水平和与酮康唑联合使用的更高暴露水平下均无变化。这表明伊帕替膦酸盐在体内对 OATP1B1/1B3 没有抑制作用。此外，体外研究表明 CPI 和 CPIII 不是 P-gp 底物，酮康唑对体内 CPI 和 CPIII 浓度没有影响。后者是一个重要的发现，因为这将简化未来使用 CPI/CPIII 作为 OATP1B1/1B3 生物标志物的药物相互作用研究的解释。 意义陈述：这项在健康志愿者中的药物相互作用研究表明，CYP3A4 在伊帕替膦酸盐的清除中起主要作用，并且伊帕替膦酸盐不是有机阴离子转运多肽 1B1/1B3 抑制剂。此外，研究还表明，酮康唑（一种 CYP3A4 和多种转运蛋白的抑制剂）不会影响体内 CPI/CPIII 水平。这增加了对这些内源性底物以及酮康唑在复杂药物相互作用研究中的理解和应用。
