Evaluation of Ipatasertib Interactions with Itraconazole and Coproporphyrin I and III in a Single Drug Interaction Study in Healthy Subjects

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 subje...

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Vydané v:The Journal of pharmacology and experimental therapeutics Ročník 378; číslo 2; s. 87
Hlavní autori: Sane, Rucha S, Cheung, Kit Wun Kathy, Cho, Eunpi, Liederer, Bianca M, Hanover, Justin, Malhi, Vikram, Plise, Emile, Wong, Susan, Musib, Luna
Médium: Journal Article
Jazyk:English
Vydavateľské údaje: United States 01.08.2021
Predmet:
Adult
Coproporphyrins - metabolism
Cytochrome P-450 CYP3A - metabolism
Drug Interactions
Female
Healthy Volunteers
Humans
Itraconazole - pharmacology
Male
Middle Aged
Piperazines
Pyrimidines - pharmacokinetics
Pyrimidines - pharmacology
Young Adult
ISSN:1521-0103, 1521-0103
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Shrnutí: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.
Bibliografia:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:1521-0103
1521-0103
DOI:10.1124/jpet.121.000620