Population Pharmacokinetic/Pharmacodynamic Analysis of Alirocumab in Healthy Volunteers or Hypercholesterolemic Subjects Using an Indirect Response Model to Predict Low-Density Lipoprotein Cholesterol Lowering: Support for a Biologics License Application Submission: Part II

• Published in: Clinical pharmacokinetics Vol. 58; no. 1; pp. 115 - 130
• Main Authors: Nicolas, Xavier, Djebli, Nassim, Rauch, Clémence, Brunet, Aurélie, Hurbin, Fabrice, Martinez, Jean-Marie, Fabre, David
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.01.2019; Springer Nature B.V
• Subjects: Adult; Aged; Antibodies, Monoclonal, Humanized - pharmacokinetics; Antibodies, Monoclonal, Humanized - pharmacology; Anticholesteremic Agents - pharmacokinetics; Anticholesteremic Agents - pharmacology; Biological Products - pharmacokinetics; Biological Products - pharmacology; Cardiovascular disease; Cholesterol; Cholesterol, LDL - blood; Clinical trials; Drug dosages; FDA approval; Female; Gender differences; Health risk assessment; Healthy Volunteers; Humans; Hypercholesterolemia - blood; Hypercholesterolemia - metabolism; Internal Medicine; Lipids; Low density lipoprotein; Male; Medicine; Medicine & Public Health; Middle Aged; Models, Biological; Monoclonal antibodies; Original; Original Research Article; Pharmacodynamics; Pharmacokinetics; Pharmacology/Toxicology; Pharmacotherapy; Physiology; Statins; Studies; United States > US
• ISSN: 0312-5963; 1179-1926
• DOI: 10.1007/s40262-018-0670-5

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.