Pharmacometric analyses to characterize the effect of CSL112 on apolipoprotein A-I and cholesterol efflux capacity in acute myocardial infarction patients

Abstract

Aims: To characterize relationships between apolipoprotein A-I (apoA-I) exposure and cholesterol efflux capacity (CEC) and covariate effects following CSL112 (apoA-I [human]) administration in an integrated population including acute myocardial infarction (AMI) patients.

Methods: A pharmacometric analysis utilized data from seven clinical trials, including patients with AMI, subjects with renal impairment and healthy subjects. A population pharmacokinetic (PK) analysis was performed to relate CSL112 doses to changes in apoA-I plasma concentrations. Covariate analysis was conducted to identify sources of variability in apoA-I exposure. Exposure-response modeling was conducted to describe the relationship between apoA-I exposure and total or ATP binding cassette transporter A1-(ABCA1)-dependent CEC and to identify clinical predictors of CEC.

Results: A two-compartment model described apoA-I PK. ApoA-I clearance was slightly lower in subjects with AMI, whereas baseline apoA-I was marginally higher in female and Japanese subjects. Covariate effects on apoA-I exposure were in the order of 10% and thus not clinically relevant. The relationships between apoA-I exposure and CECs were described by nonlinear models. Simulations showed CEC elevation resulting from apoA-I exposure increment was comparable in AMI and non-AMI subjects; no covariate had clinically meaningful effects on CEC. Simulations also demonstrated that CEC in patients with AMI post 6 g CSL112 dosing was substantially elevated compared to placebo and lower dose levels.

Conclusions: The model-based exposure-response analysis demonstrated, irrespective of body weight, sex and race, that fixed 6 g CSL112 dosing causes a desired CEC elevation, which may benefit AMI patients by potentially reducing early recurrent cardiovascular event risk.

Trial registration: ClinicalTrials.gov NCT01129661 NCT01281774 NCT02427035 NCT01499420 NCT02742103 NCT02108262.

Keywords: atherosclerosis; clinical trials; modelling and simulation; pharmacokinetics-pharmacodynamics; pharmacometrics.

Conflict of interest statement

B.Z., D.D., P.T., B.K., S.W., A.G. and M.T. are employees of CSL Behring. H.K. and M.P. are employees of Certara.

© 2020 CSL Behring. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

Figures

FIGURE 1

Prediction‐corrected visual predictive check (VPC) obtained through n = 1000 simulations from the final population PK model by regimen: placebo, single doses and multiple doses (QW × 4) of CSL112, and by all subjects, healthy subjects and patients. The blue circles represent the prediction‐corrected observed apoA‐I concentrations. The solid and dashed red lines represent the observed median and 10th‐90th percentile range, respectively. The pink and purple bands represent the 95% confidence interval (CI) of the median prediction, and the 10th and 90th prediction interval, respectively. ApoA‐I, apolipoprotein A‐I; QW × 4, weekly dose for 4 weeks

FIGURE 2

Box plots of model‐estimated individual apoA‐I exposures (AUC0‐48) following the fourth infusion by dose and race in healthy subjects (A) and by dose and sex in post‐AMI subjects (B), and the median value of AUC0‐48 from each group of post‐AMI subjects (B). Circles denote outlying data. AMI, acute myocardial infarction; AUC0‐48, area under the curve from 0 to 48 hours; Jp, Japanese; M, male; F, female

FIGURE 3

Scatter plots of observed apoA‐I concentrations vs observed total and ABCA1‐dependent CEC by race (Japanese and non‐Japanese) (A, B), AMI status (C, D), sex (E, F) and weight (G, H). ApoA‐I, apolipoprotein A‐I; ABCA1, ATP‐binding cassette transporter‐1; AMI, acute myocardial infarction; CEC, cholesterol efflux capacity

FIGURE 4

Prediction‐corrected visual predictive check (VPC) of the exposure‐response models for total CEC (A) and ABCA1‐dependent CEC (B). The blue circles represent the prediction‐corrected observed CECs. The solid and dashed red lines represent the observed median and 10th‐90th percentile range, respectively. The pink and purple bands represent the 95% confidence intervals of the 90th, median and 10th percentiles of the simulated data. ABCA1, ATP‐binding cassette transporter 1; CEC, cholesterol efflux capacity

FIGURE 5

Forest plots of the model‐predicted covariate (AMI, sex and body weight) effects on total (A)‐(D) and ABCA1‐dependent CEC (E)‐(H) in response to different increment in apoA‐I concentration. Typical subjects were defined as non‐Japanese, healthy males with apoA‐I baseline concentration of 121.9 mg dL−1. Baseline‐corrected CECs in response to increment in apoA‐I concentration, which is equal to 50% (A, E), 75% (B, F), 100% (C, G) and 125% (D, H) of a typical subject's baseline, respectively, were simulated and summarized. The covariate effects were displayed as fold change from median predicted CEC in typical subject. For each covariate value, the horizontal line represents the 90% prediction interval for the respective ratio. The vertical dashed lines indicate the predefined clinical relevance criteria (0.80‐1.25, bioequivalence range). ApoA‐I, apolipoprotein A‐I; AMI, acute myocardial infarction; ABCA1, ATP‐binding cassette transporter‐1; CEC, cholesterol efflux capacity

FIGURE 6

Model‐predicted individual time‐averaged total (A) and ABCA1‐dependent (B) CEC (AUC0‐48/48 h) vs baseline‐corrected apoA‐I exposure (AUC0‐48). The black lines and yellow shaded area represent median and 90% prediction interval, respectively, of power‐model predictions for 1000 virtual subjects. Blue, green and red circles represent individual model estimations for subjects assigned to placebo, 2 g and 6 g, respectively, in the AEGIS‐I and CSL112_1002 studies. Blue horizontal dash lines indicate the efflux capacity threshold, which is the median of predicted CEC in the placebo group. Horizontal bars and black star represent 90% CI and median of individual apoA‐I exposures for placebo and the CSL112 2 g and 6 g doses for subjects in both the AEGIS‐I and CSL112_1002 studies. ApoA‐I, apolipoprotein A‐I; ABCA1, ATP‐binding cassette transporter‐1; AUC0‐48, area under the curve from 0‐48 hours; CEC, cholesterol efflux capacity