Abstract
Aim:
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 Emax model with a fixed E0, which provided a common Emax and an approximate twofold difference in ED50 for Westerners and Asians. The PPD model was demonstrated to be stable and predictive.
Conclusion:
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.
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Acknowledgements
We thank Dr Ya-ning WANG (US FDA) for valuable discussions and advice. This study was supported by the National Science and Technology Supporting Projects of China (2008BAI51B03, 2009ZX09502-021), E-Institute of Shanghai High Education (E03008), the Leading Academic Discipline Project of the Shanghai Municipal Education Commission (J50303, 2008GSP19-5), and the Special Fund of Scientific Research for Selecting and Training Outstanding Young Teachers of Shanghai Municipal Education (SZY07027).
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Yang, J., Li, Lj., Wang, K. et al. Race differences: modeling the pharmacodynamics of rosuvastatin in Western and Asian hypercholesterolemia patients. Acta Pharmacol Sin 32, 116–125 (2011). https://doi.org/10.1038/aps.2010.169
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DOI: https://doi.org/10.1038/aps.2010.169
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