Population PK/PD modeling of low‐density lipoprotein cholesterol response in hypercholesterolemic participants following administration of bococizumab, a potent anti‐PCSK9 monoclonal antibody

Abstract

Abstract We sought to characterize the population pharmacokinetic/pharmacodynamic (PK/PD) relationship of bococizumab (RN316/PF‐04950615), a humanized IgG2Δa monoclonal antibody that binds to secreted human proprotein convertase subtilisin kexin type 9 (PCSK9), using data derived from 16 phase I, II, and III clinical studies (36,066 bococizumab observations, 46,790 low‐density lipoprotein cholesterol [LDL‐C] measurements, 3499 participants). A two‐compartment disposition model with parallel linear and Michaelis–Menten elimination and an indirect response model was used to characterize the population PK and LDL‐C response of bococizumab. Potential model parameters and covariate relationships were explored, and visual predictive checks were used for model assessment and validation. Key covariates included the effect of anti‐drug antibodies (ADAs) on exposure through impact on clearance and bioavailability; impact of statins on bococizumab elimination (maximal rate of metabolism); and impact of statins, Asian race, and male sex on LDL‐C efficacy (maximum effect). ADAs and neutralizing ADAs did not have additional effects on LDL‐C beyond the influence on bococizumab exposure. In conclusion, the population PK/PD model adequately describes bococizumab concentration and LDL‐C efficacy. The covariate effects are consistent with the presumed mechanism of action of PCSK9 inhibitors. With increasing availability of antibody‐based therapeutics, improved understanding of the effect of ADAs and statins on bococizumab PK/PD adds to the literature and enhances our pharmacological understanding of how immunogenicity and concomitant medications may impact the PK/PD of biotherapeutics.