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, Lukacova V, Bolger MB, Fraczkiewicz G
Conference: ISSX
Keywords: ethnic differences in pharmacokinetics, losartan, metabolism, PBPK modeling, transporter kinetics
Software: GastroPlus®
Division: PBPK

Objective

Losartan is a selective, competitive angiotensin II 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 nexplained by genetic polymorphism of CYP2C9 alone. A validated losartan and E3174 model was developed to investigate the sources of ethnic differences in E3174 pharmacokinetics.

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

12th International ISSX Meeting, July 28-31, 2019, Portland, Oregon