Abstract

Purpose: The objective of this study was to improve the predictive performance of cytochrome P450 (CYP) 2C19 substrates in Japanese subjects using physiologically based pharmacokinetic (PBPK) modeling.
Materials and methods: Esomeprazole, a CYP2C19 substrate, was selected as a test compound, and the Simcyp simulator was used for pharmacokinetic prediction. The compound file of esomeprazole model developed in healthy Caucasian subjects was applied directly. The population file “Sim-Japanese” in Simcyp was adopted to predict esomeprazole pharmacokinetics in Japanese, while CYP2C19 enzyme abundances in the liver and the gastrointestinal tract for homozygous extensive metabolizers (homo EMs), heterozygous extensive metabolizers (hetero EMs), and poor metabolizers (PMs) were adjusted to be the same as in Caucasians.
Results: The PBPK model predicted esomeprazole exposure after 10-, 20-, and 40-mg doses in Japanese subjects within 1.5-fold of observed values in all three ­CYP2C19 phenotypes. The reported concentration-time profiles were mostly well-captured within the 95% prediction intervals.
Conclusion: By adjusting CYP2C19 enzyme abundances levels in the Japanese population, the systemic exposure of esomeprazole in Japanese subjects can be reasonably extrapolated using a PBPK model developed in Caucasian subjects. This analysis serves as a case application for assessing the predictive performance of CYP2C19 substrate in Japanese subjects by using PBPK modeling approach.

Author Details

Authors

• Mitsuo Higashimori¹
• Hitoshi Shimada¹
• Katsuomi Ichikawa¹
• Diansong Zhou²

Departments

• ¹ Science & Data Technology Division, Research & Development, AstraZeneca K.K., Osaka, Japan, and
• ² Research & Development, AstraZeneca, Waltham, MA, USA

Address

Mitsuo Higashimori, PhD

Science & Data Technology Division
Research & Development, AstraZeneca K.K.
3-1, Ofuka-cho, Kita-ku, Osaka 530-0011, Japan
Email: [email protected]

Citation