Combined Semi-mechanistic Target-Mediated Drug Disposition and Pharmacokinetic–Pharmacodynamic Models of Alirocumab, PCSK9, and Low-Density Lipoprotein Cholesterol in a Pooled Analysis of Randomized Phase I/II/III Studies

Alirocumab is a cholesterol-lowering monoclonal antibody targeting proprotein convertase subtilisin kexin type 9 (PCSK9) indicated in the prevention of cardiovascular risk and exhibiting target-mediated drug disposition (TMDD). The aim of this work was to develop an integrated pharmacokinetic–pharmacodynamic model to describe the interaction of alirocumab with PCSK9 and its impact on the evolution of low-density lipoprotein cholesterol (LDL-C) levels and explore labeling specification for subpopulations. Using data collected from nine phase I/II/III clinical studies (n = 527, subcutaneous or intravenous administration), a TMDD model considering the quasi-steady-state approximation was developed to characterize the interaction dynamics of alirocumab and PCSK9, combined with an indirect pharmacodynamic model describing the inhibition of LDL-C by PCSK9 in a one-step approach using nonlinear-mixed effects modeling. A “full fixed effects modeling” strategy was implemented to quantify parameter–covariate relationships. The model captures the interaction between alirocumab and its target PCSK9 and how this mechanism drives LDL-C depletion, with an estimation of the associated between-subject variability of model parameters and the quantification of clinically relevant parameter–covariate relationships. Co-administration of statins was found to increase the central volume of distribution of alirocumab by 1.75-fold (5.6 L versus 3.2 L) and allow for a 14