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

@entity1 @entity1297 @entity47681
BACKGROUND AND OBJECTIVES: We propose a strategy for studying ethnopharmacology by conducting sequential @entity1297 ( @entity1297 ) prediction (a 'bottom-up' approach) and population pharmacokinetic (popPK) confirmation (a 'top-down' approach), or in reverse order, depending on whether the purpose is ethnic effect assessment for a new molecular entity under development or a tool for ethnic sensitivity prediction for a given pathway. The strategy is exemplified with @entity47681 . METHODS: A @entity1297 model was built using Simcyp(  ) to simulate the pharmacokinetics of @entity47681 and to predict the ethnic sensitivity in clearance, given pharmacokinetic data in just one ethnicity. Subsequently, a popPK model was built using NONMEM(  ) to assess the effect of ethnicity on clearance, using @entity1 data from multiple ethnic groups. A comparison was made to confirm the @entity1297 -based ethnic sensitivity prediction, using the results of the popPK analysis. RESULTS: @entity1297 modelling predicted that the @entity47681 geometric mean clearance values after 20  mg oral administration in Caucasians would be 1.32-fold and 1.27-fold higher than the values in Chinese and Japanese, respectively. The ratios of typical clearance in Caucasians to the values in Chinese and Japanese estimated by popPK analysis were 1.20 and 1.17, respectively. The popPK analysis results were similar to the @entity1297 modelling results. CONCLUSION: As a general framework, we propose that @entity1297 modelling should be considered to predict ethnic sensitivity of pharmacokinetics prior to any @entity1 data and/or with data in only one ethnicity. In some cases, this will be sufficient to guide initial dose selection in different ethnicities. After clinical trials in different ethnicities, popPK analysis can be used to confirm ethnic differences and to support dose justification and labelling. @entity1297 modelling prediction and popPK analysis confirmation can complement each other to assess ethnic differences in pharmacokinetics at different drug development stages.
