Establishment of the population pharmacokinetics model of sibutramine in Chinese healthy volunteers

Key words: 
• sibutramine /
• population pharmacokinetics /
• nonlinear mixed effects model

Abstract: objective To develop the population pharmacokinetics model of sibutramine (SIB) in Chinese healthy volunteers.Methods Twenty male healthy volunteers were enrolled into the study.13 blood sampling were drawn after administration of 10 mg SIB within 24h.Theplasma samplesfor SIB concentration were analyzed using validated HPLC/MS method.The population pharmacokinetics was characterized by non-linear mixed effects model (NONMEM).Visual predictive check (VPC) and normalized predictive distribution error (NPDE) were used to evaluate the predictive ability of the model.The reliability and stability of the population pharmacokinetic model developed was further assessed by a nonparametric bootstrap procedure,Results A two-compartment pharmacokinetic model with first-order absorption and elimination was used to describe the concentration-time data.The weight and age had no significant impact on the model parameters.The population typical values (inter-individual variability) of Vl,V2,CL,Q,Ka and Tlag were 7.85 (42.8%) L,2.03 (48.2%)L,1.08 (38.5%)L/h,0.289 (27.1%)L/h,1.95 (56.8%)h～and 0.187 (17.8%)h respectively.Most of parameter estimates from non-parametric bootstrap procedure were comparable and within 10% of the estimates from NONMEM.The stability and the predictive performance were accepted by Bootstrapping,the goodness-of-fit,VPC and NPDE.Conclusion The final population pharmacokinetics model of SIB in Chinese healthy was established by NONMEM,The modcl was steady and reliable.