Background: The prevalence of diabetes mellitus (DM) dramatically increased over the past decades.Dipeptidyl peptidase Ⅳ (DPP-4) inhibitors are a relatively new group of anti-diabetic agents.CPRC3 is a novel DPP-4 inhibitor under clinical development with the characteristic of nonlinear pharmacokinetics.Aims: To characterize the nonlinear pharmacokinetics of CPRC3 in Chinese healthy volunteers and T2DM patients and test the hypothesis that concentration-dependent binding to its target, DPP-4, is responsible for its nonlinear behavior.Methods: CPRC3 plasma concentrations and DPP-4 activities were obtained from two studies (a phase 1a and a phase 1 b).Non-linear mixed-effects modelling techniques was carried out using NONMEM software.The first-order conditional estimation method and the ADVAN6 subroutine were used to estimate parameters and variability.Covariate effects on parameters were investigated using stepwise forward inclusion and backward elimination.Results: The pharmacokinetic analysis included 756 and 368 measurements of plasma CPRC3 concentrations from Chinese healthy volunteers and T2DM patients respectively.Besides, the pharmacokinetic/pharmacodynamic (PK/PD) analysis also included 882 and 420 measurements of plasma DPP-4 activity from Chinese healthy volunteers and T2DM patients respectively.A target-mediated drug disposition (TMDD) model which was based on quasi-equilibrium conditions accounting for capacity-limited of CPRC3 to DPP-4 in plasma and tissues had good predictive performance.T2DM was the covariate parameters of clearance (CL) and sex was the covariate parameters of absorption rate constant (KA1) in the model.The target binding had a major impact on CPRC3 pharmacokinetics.Except for KA1 (110.5%), the inter-individual and inter-occasion variability of PK parameters was low to moderate (11.3%-77.3%).The inter-individual variability of Emax was low (16.9%).Conclusions: A population PK/PD analysis showed that the nonlinear pharmacokinetics of CPRC3 in humans is attributable to a concentration-dependent binding to its target protein, DPP-4.The TMDD model show that TD2M and sex might affect the CL and KA1 respectively.The TMDD showed that TD2M and sex might alter the CL and KA1, but there is no need for CPRC3 dose adjustment for different sex by the reason of the exposure had no significant difference.