Background and objectives: Bitopertin (RG1678, RO4917838) is a glycine reuptake inhibitor that is postulated to improve NMDA receptor hypofunction by increasing the synaptic concentration of glycine, an obligatory co-agonist at the NMDA receptor.In vitro and in vivo studies have shown that CYP3A4 is the major enzyme responsible for metabolism of bitopertin.We used physiologically-based pharmacokinetic (PBPK) modeling (Bottom-up approach) and population pharmacokinetic (Pop PK) analysis (Top-down approach) sequential to assess the ethnic difference in clearance of bitopertin.Methods: A PBPK model was built using SimCYP(a)to simulate the pharmacokinetics (PK) of bitopertin in Caucasian, Chinese, and Japanese populations and to predict the ethnic sensitivity in clearance given PK data in just one ethnicity.Subsequently, a Pop PK model was built using NONMEM to assess the effect of ethnicity on the 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 Pop PK analysis.Results: PBPK modeling predicted that the bitopertin geometric mean clearance after 20 mg oral administration in Caucasians was 1.32-fold and 1.27-fold higher than the values in Chinese and Japanese, respectively.The PK of bitopertin was best described by a two compartment model incorporating a saturable Michaelis-Menten kinetic absorption process and dose-adjusted Fa.The ratios of typical clearance in Caucasians to the values in Chinese and Japanese estimated by Pop PK analysis were 1.20 and 1.17, respectively.Pop PK analysis results were similar to the PBPK modeling results.Conclusions:PBPK modeling accurately predicted bitopertin clearances in Caucasians, Chinese and Japanese and the 1.2-fold differences in the clearance of bitopertin between Caucasians and Asians, which was confirmed by Pop PK analysis.PBPK modeling and Pop PK analysis can complement each other to assess the ethnic differences in PK at different drug development stages.