Key result
The population pharmacokinetic/pharmacodynamic model successfully described the relationship between alirocumab concentrations and LDL-C levels, identifying 10 covariates that explained between-subject variability without a clinically meaningful impact on LDL-C reduction.
This population pharmacokinetic/pharmacodynamic model successfully predicts individual LDL-C lowering responses to alirocumab based on patient covariates, supporting its biologic license application.
Model enables alirocumab exposure-response simulations; leaves open prospective validation before guiding individualized dosing.
BACKGROUND: Alirocumab, a human monoclonal antibody against proprotein convertase subtilisin/kexin type 9 (PCSK9), significantly lowers low-density lipoprotein cholesterol levels. OBJECTIVE: This analysis aimed to develop and qualify a population pharmacokinetic/pharmacodynamic model for alirocumab based on pooled data obtained from 13 phase I/II/III clinical trials. METHODS: From a dataset of 2799 individuals (14,346 low-density lipoprotein-cholesterol values), individual pharmacokinetic parameters from the population pharmacokinetic model presented in Part I of this series were used to estimate alirocumab concentrations. As a second step, we then developed the current population pharmacokinetic/pharmacodynamic model using an indirect response model with a Hill coefficient, parameterized with increasing low-density lipoprotein cholesterol elimination, to relate alirocumab concentrations to low-density lipoprotein cholesterol values. RESULTS: The population pharmacokinetic/pharmacodynamic model allowed the characterization of the pharmacokinetic/pharmacodynamic properties of alirocumab in the target population and estimation of individual low-density lipoprotein cholesterol levels and derived pharmacodynamic parameters (the maximum decrease in low-density lipoprotein cholesterol values from baseline and the difference between baseline low-density lipoprotein cholesterol and the pre-dose value before the next alirocumab dose). Significant parameter-covariate relationships were retained in the model, with a total of ten covariates (sex, age, weight, free baseline PCSK9, total time-varying PCSK9, concomitant statin administration, total baseline PCSK9, co-administration of high-dose statins, disease status) included in the final population pharmacokinetic/pharmacodynamic model to explain between-subject variability. Nevertheless, the high number of covariates included in the model did not have a clinically meaningful impact on model-derived pharmacodynamic parameters. CONCLUSIONS: This model successfully allowed the characterization of the population pharmacokinetic/pharmacodynamic properties of alirocumab in its target population and the estimation of individual low-density lipoprotein cholesterol levels.
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Nicolas et al. (2018) studied Hypercholesterolemia (n=2,799). Alirocumab was evaluated on Low-density lipoprotein cholesterol (LDL-C) lowering (model-derived pharmacodynamic parameters). The population pharmacokinetic/pharmacodynamic model successfully described the relationship between alirocumab concentrations and LDL-C levels, identifying 10 covariates that explained between-subject variability without a clinically meaningful impact on LDL-C reduction.
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