TY - JOUR T1 - <strong>Evaluation of Ipatasertib Interactions with Itraconazole and Coproporphyrin I and III in a Single Drug Interaction Study in Healthy Subjects </strong> JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.121.000620 SP - JPET-AR-2021-000620 AU - Rucha Sane AU - Kit Wun Kathy Cheung AU - Eunpi Cho AU - Bianca M Liederer AU - Justin Hanover AU - Vikram Malhi AU - Emile Plise AU - Susan Wong AU - Luna Musib Y1 - 2021/01/01 UR - http://jpet.aspetjournals.org/content/early/2021/05/28/jpet.121.000620.abstract N2 - 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-Ꝏ 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 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 In this drug-drug interaction study in healthy volunteers, we demonstrated that CYP3A4 plays a major role in ipatasertib clearance, and that ipatasertib is not an OATP1B1/1B3 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. ER -