Pharmacometric analyses to characterize the effect of CSL112 on apolipoprotein A-I and cholesterol efflux capacity in acute myocardial infarction patients.
Br J Clin Pharmacol
; 87(6): 2558-2571, 2021 06.
Article
em En
| MEDLINE
| ID: mdl-33217027
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.Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Apolipoproteína A-I
/
Infarto do Miocárdio
Tipo de estudo:
Clinical_trials
/
Prognostic_studies
Limite:
Female
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Humans
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Male
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article