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

CPT Pharmacometrics Syst Pharmacol. 2023 Dec;12(12):2013-2026. doi: 10.1002/psp4.13050. Epub 2023 Nov 22.

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.

Trial registration: ClinicalTrials.gov NCT00991159 NCT01163851 NCT01435382 NCT01243151 NCT02043301 NCT02458209 NCT01342211 NCT01350141 NCT01592240 NCT02055976 NCT01968954 NCT01968967 NCT01968980 NCT02100514 NCT02135029.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Monoclonal, Humanized / pharmacology
  • Antibodies, Monoclonal, Humanized / therapeutic use
  • Cholesterol, LDL / therapeutic use
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors* / therapeutic use
  • Hypercholesterolemia* / drug therapy
  • Male
  • Proprotein Convertase 9

Substances

  • bococizumab
  • Cholesterol, LDL
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • PCSK9 protein, human
  • Proprotein Convertase 9
  • Antibodies, Monoclonal, Humanized

Associated data

  • ClinicalTrials.gov/NCT00991159
  • ClinicalTrials.gov/NCT01163851
  • ClinicalTrials.gov/NCT01435382
  • ClinicalTrials.gov/NCT01243151
  • ClinicalTrials.gov/NCT02043301
  • ClinicalTrials.gov/NCT02458209
  • ClinicalTrials.gov/NCT01342211
  • ClinicalTrials.gov/NCT01350141
  • ClinicalTrials.gov/NCT01592240
  • ClinicalTrials.gov/NCT02055976
  • ClinicalTrials.gov/NCT01968954
  • ClinicalTrials.gov/NCT01968967
  • ClinicalTrials.gov/NCT01968980
  • ClinicalTrials.gov/NCT02100514
  • ClinicalTrials.gov/NCT02135029