Combining 'Bottom-Up' and 'Top-Down' Methods to Assess Ethnic Difference in Clearance: Bitopertin as an Example

Area of Science:

• Pharmacokinetics
• Drug Development
• Pharmacogenomics

Background:

• Ethnopharmacology requires robust methods to assess ethnic variations in drug behavior.
• Physiologically based pharmacokinetic (PBPK) and population pharmacokinetic (popPK) modeling offer complementary approaches.

Purpose of the Study:

• To propose and exemplify a sequential PBPK and popPK modeling strategy for studying ethnopharmacology.
• To assess ethnic sensitivity in drug clearance using bitopertin as a case study.

Main Methods:

• A "bottom-up" PBPK model was developed to predict bitopertin pharmacokinetics and ethnic sensitivity in clearance.
• A "top-down" popPK model was built to confirm ethnic effects on clearance using human data.
• PBPK predictions were compared with popPK analysis results.

Main Results:

• PBPK modeling predicted higher bitopertin clearance in Caucasians compared to Chinese and Japanese populations.
• PopPK analysis confirmed similar ethnic differences in clearance, with results aligning with PBPK predictions.

Conclusions:

• A combined PBPK and popPK approach provides a comprehensive framework for assessing ethnic pharmacokinetic differences.
• PBPK modeling can predict ethnic sensitivity early in drug development, while popPK confirms findings later.
• This integrated strategy supports informed dose selection and labeling across diverse ethnic groups.