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

Abstract

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.

Keywords: biopharmaceutics; cardiovascular; modelling and simulation; monoclonal antibodies; pharmacokinetic-pharmacodynamic.

Figure 1

Schematic of target‐mediated drug disposition model. I_max, maximal inhibition; IC₅₀, PCSK9 concentration associated with 50% I_max; k_a, absorption rate constant; k_el, elimination rate constant; k_syn, PCSK9 production rate constant; k_deg, PCSK9 elimination rate constant; K_D, dissociation constant; k_int, evolocumab‐PCSK9 complex elimination rate constant; k_in, LDL‐C production rate constant; k_out, LDL‐C elimination rate constant; PCSK9, proprotein convertase subtilisin/kexin type 9; LDL‐C, low‐density lipoprotein cholesterol

Figure 2

Goodness‐of‐fit plots of model predictions (A) unbound evolocumab, population predicted value vs. observed value. (B) unbound evolocumab, individual predicted value vs. observed value. (C) Proprotein convertase subtilisin/kexin type 9 (PCSK9), population predicted value vs. observed value. (D) PCSK9, individual predicted value vs. observed value. (E) Low‐density lipoprotein cholesterol (LDL‐C), population predicted value vs. observed value. (F) LDL‐C, individual predicted value vs. observed value. The black line and red line represent the line of identity and regression line, respectively. Points are all observations. (Red point: Caucasian population; blue point: Asian population)

Figure 3

Visual prediction assessment of 140 mg SC (upper) and 420 mg SC (lower), median ± 90% prediction interval of simulated pharmacokinetics and pharmacodynamics (solid blue line and blue‐shaded region, respectively, after 1000 times simulation) and observed data (black point), red line for observed median

Figure 4

Jack‐knife validation. Bar charts of the typical parameter values obtained from the final model using the leave‐one‐out method. The abscissa represents the study number dropped from the full data. The red bar represents parameters obtained when no study was excluded. k_a, absorption rate constant; CL, clearance; VC, volume of distribution in central compartment; IC₅₀, concentration associated with half‐maximal inhibition

Figure 5

The relationship between ethnicity and the main pharmacokinetic/pharmacodynamic parameters. k_a, absorption rate constant; IC₅₀, concentration associated with half‐maximal inhibition

Figure 6

Relationship between low‐density lipoprotein cholesterol (LDL‐C) lowering of evolocumab by ethnicity [Asian (blue) and Caucasian (red) and simulation line (green)]

Figure 7

The relationship between bodyweight and the main pharmacokinetic/pharmacodynamic parameters. k_a, absorption rate constant; IC₅₀, concentration associated with half‐maximal inhibition

Figure 8

Model simulation, comparison of the pharmacokinetic/pharmacodynamic relationships between different proprotein convertase subtilisin/kexin type 9 (PCSK9) expression levels (Caucasian healthy volunteers = 5.82 nmol l^–1, Caucasian hypercholesterolaemic subjects = 3.72 nmol l^–1) using two labelling dosages (left: 140 mg every 2 weeks subcutaneously; right: 420 mg every month subcutaneously). LDL‐C, low‐density lipoprotein cholesterol

Figure 9

Model simulation, time–concentration curve and time–efficacy curve for doses of 70 mg and 420 mg administered subcutaneously. LDL‐C, low‐density lipoprotein cholesterol

Figure 10

Model prediction for low‐density lipoprotein cholesterol (LDL‐C) lowering based on the Asian PCSK9 level at baseline for doses of 140 mg every 2 weeks (Q2W; red line) and 420 mg every month (QM; brown line). The solid points are the mean changes in LDL‐C from the Japanese Phase 2 and Phase 3 studies