Development of a Physiologically Based Pharmacokinetic Model for Losartan and Its Active Metabolite E3174 – Ethnic Differences in Pharmacokinetics between Caucasian and Asian Populations

Authors: Dong J, Fraczkiewicz G, Lukacova V, Bolger MB
Conference: ACoP
Keywords: genetic polymorphism, hepatic efflux, hypertension treatment, pharmacokinetics
Software: GastroPlus®
Division: PBPK

Objective

Losartan is a selective, competitive angiotensin 11 receptor type 1 (AT1) antagonist for hypertension treatment. Although losartan itself is pharmacologically active, its primary metabolite, E3174, produced by CYP2C9 and CYP3A4 enzymes, has 10- to 40-fold higher potency and a longer half-life. Ethnic differences in E3174 exposure have been observed between Caucasian and Asian subjects, which cannot be explained by genetic polymorphism of CYP2C9 alone. A validated losartan and E3174 model was developed to investigate the sources of ethnic differences in E317 4 pharmacokinetics.

Ninth American Conference on Pharmacometrics (ACoP) Annual Meeting, October 6-12, 2018, San Diego, CA

By Jin Dong, Grazyna Fraczkiewicz, Viera Lukacova, Michael B. Bolger