Lack of ethnic differences in the pharmacokinetics and pharmacodynamics of evolocumab between Caucasian and Asian populations

Aims To evaluate the potential ethnic differences in the pharmacokinetics (PK) and pharmacodynamics (PD) of evolocumab in Caucasian and Asian populations using population PK/PD modelling analysis. Methods Data from different ethnic groups in 5 Phase I clinical trials, including two American studies, one Japanese study and two Chinese studies, were chosen for model building and evaluation. A target-mediated drug disposition model together with an indirect response model best captured evolocumab binding and the removal of unbound proprotein convertase subtilisin/kexin type 9 (PCSK9) as well as a reduction in circulating low-density lipoprotein cholesterol (LDL-C). Ethnicity and other related factors (body weight, target expression level etc.) were analysed as potential covariates. Results The estimated linear clearance and volume of evolocumab were 0.24 l day(-1) and 2.75 l, respectively, which was consistent with the previous modelling results from the American trials. The time course of the LDL-C reduction was described by an indirect response model with the elimination rate of LDL-C being modulated by unbound PCSK9. The concentration of unbound PCSK9 associated with the half-maximal inhibition of LDL-C elimination was 1.28 nmol l(-1). Both the PK and PD characteristics were consistent between the Caucasian and Asian populations. Conclusion The target-mediated drug disposition model successfully described the PK and PD characteristics of evolocumab, and this analysis found no significant differences in the PK/PD relationship for its LDL-C lowering effects between Caucasians and Asians.