title: Race differences: modeling the pharmacodynamics of rosuvastatin in Western and Asian hypercholesterolemia patients.
abstract: OBJECTIVE
  To evaluate race differences in the pharmacodynamics of rosuvastatin in Western and Asian hypercholesterolemia patients using a population pharmacodynamic (PPD) model generated and validated using published clinical efficacy trials.
  
  
  METHODS
  Published studies randomized trials with rosuvastatin treatment for at least 4 weeks in hypercholesterolemia patients were used for model building and validation. Population pharmacodynamic analyses were performed to describe the dose-response relationship with the mean values of LDL-C reduction (%) from dose-ranging trials using NONMEM software. Baseline LDL-C and race were analyzed as the potential covariates. Model robustness was evaluated using the bootstrap method and the data-splitting method, and Monte Carlo simulation was performed to assess the predictive performance of the PPD model with the mean effects from the one-dose trials.
  
  
  RESULTS
  Of the 36 eligible trials, 14 dose-ranging trials were used in model development and 22 one-dose trials were used for model prediction. The dose-response of rosuvastatin was successfully described by a simple E(max) model with a fixed E(0), which provided a common E(max) and an approximate twofold difference in ED(50) for Westerners and Asians. The PPD model was demonstrated to be stable and predictive.
  
  
  CONCLUSIONS
  The race differences in the pharmacodynamics of rosuvastatin are consistent with those observed in the pharmacokinetics of the drug, confirming that there is no significant difference in the exposure-response relationship for LDL-C reduction between Westerners and Asians. The study suggests that for a new compound with a mechanism of action similar to that of rosuvastatin, its efficacy in Western populations plus its pharmacokinetics in bridging studies in Asian populations may be used to support a registration of the new compound in Asian countries.
authors.affiliation: Laboratory of Pharmacometrics, Center for Drug Clinical Research, Shanghai University of Chinese Medicine, Shanghai 201203, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Yang
authors.forename: Lu-jin
authors.initials: LJ
authors.lastname: Li
authors.forename: Kun
authors.initials: K
authors.lastname: Wang
authors.forename: Ying-chun
authors.initials: YC
authors.lastname: He
authors.forename: Yu-cheng
authors.initials: YC
authors.lastname: Sheng
authors.forename: Ling
authors.initials: L
authors.lastname: Xu
authors.forename: Xiao-hui
authors.initials: XH
authors.lastname: Huang
authors.forename: Feng
authors.initials: F
authors.lastname: Guo
authors.forename: Qing-shan
authors.initials: QS
authors.lastname: Zheng
mesh_terms: D000924:Anticholesteremic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001208:Asia; D044466:Asian People; D008078:Cholesterol, LDL / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002986:Clinical Trials as Topic; D004305:Dose-Response Relationship, Drug; D020834:Ethnopharmacology; D005464:Fluorobenzenes / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006937:Hypercholesterolemia / Q000188:drug therapy* / Q000208:ethnology; D008954:Models, Biological; D011743:Pyrimidines / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000493:pharmacokinetics* / Q000627:therapeutic use; D044465:White People
chemical_list: D000924:Anticholesteremic Agents; D008078:Cholesterol, LDL; D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011743:Pyrimidines; D013449:Sulfonamides; D000068718:Rosuvastatin Calcium