title: Combining 'Bottom-Up' and 'Top-Down' Methods to Assess Ethnic Difference in Clearance: Bitopertin as an Example.
abstract: We propose a strategy for studying ethnopharmacology by conducting sequential physiologically based pharmacokinetic (PBPK) 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 bitopertin.
  
  
  
  A PBPK model was built using Simcyp(®) to simulate the pharmacokinetics of bitopertin 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 human data from multiple ethnic groups. A comparison was made to confirm the PBPK-based ethnic sensitivity prediction, using the results of the popPK analysis.
  
  
  
  PBPK modelling predicted that the bitopertin 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 PBPK modelling results.
  
  
  
  As a general framework, we propose that PBPK modelling should be considered to predict ethnic sensitivity of pharmacokinetics prior to any human 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. PBPK modelling prediction and popPK analysis confirmation can complement each other to assess ethnic differences in pharmacokinetics at different drug development stages.
authors.affiliation: Roche Pharma Research and Early Development, Roche Innovation Center Shanghai, Building 6, Lane 917, Ha Lei Road, Pudong, Shanghai, China.
authors.forename: Sheng
authors.initials: S
authors.lastname: Feng
authors.affiliation: Roche Pharma Research and Early Development, Roche Innovation Center Shanghai, Building 6, Lane 917, Ha Lei Road, Pudong, Shanghai, China. jun.shi.js1@roche.com.
authors.forename: Jun
authors.initials: J
authors.lastname: Shi
authors.affiliation: Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland.
authors.forename: Neil
authors.initials: N
authors.lastname: Parrott
authors.affiliation: Peking Union Medical College Hospital, Beijing, China.
authors.forename: Pei
authors.initials: P
authors.lastname: Hu
authors.affiliation: Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Weber
authors.affiliation: Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland.
authors.forename: Meret
authors.initials: M
authors.lastname: Martin-Facklam
authors.affiliation: Chugai Pharmaceutical Co., Ltd, Tokyo, Japan.
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Saito
authors.affiliation: Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland.
authors.forename: Richard
authors.initials: R
authors.lastname: Peck
mesh_terms: D000293:Adolescent; D000328:Adult; D044466:Asian People; D015992:Body Mass Index; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D010879:Piperazines / Q000493:pharmacokinetics*; D013450:Sulfones / Q000493:pharmacokinetics*; D044465:White People; D055815:Young Adult
chemical_list: C550631:(4-(3-fluoro-5-trifluoromethylpyridin-2-yl)piperazin-1-yl)(5-methanesulfonyl-2-(2,2,2-trifluoro-1-methylethoxy)phenyl)methanone; D010879:Piperazines; D013450:Sulfones