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

Autor: Wang EQ; Clinical Pharmacology & Bioanalytics, Pfizer Inc., New York, New York, USA., Kaila N; Clinical Pharmacology & Bioanalytics, Pfizer Inc., Groton, Connecticut, USA., Plowchalk D; Clinical Pharmacology & Bioanalytics, Pfizer Inc., Groton, Connecticut, USA., Gibiansky L; QuantPharm LLC, North, Maryland, USA., Yunis C; Global Product Development, Pfizer Inc., Florida, USA., Sweeney K; Clinical Pharmacology & Bioanalytics, Pfizer Inc., Groton, Connecticut, USA.
Jazyk: angličtina
Zdroj: CPT: pharmacometrics & systems pharmacology [CPT Pharmacometrics Syst Pharmacol] 2023 Dec; Vol. 12 (12), pp. 2013-2026. Date of Electronic Publication: 2023 Nov 22.
DOI: 10.1002/psp4.13050
Abstrakt: 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.
(© 2023 Pfizer Inc. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)
Databáze: MEDLINE
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