title: Impact of Target-Mediated Elimination on the Dose and Regimen of Evolocumab, a Human Monoclonal Antibody Against Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9).
abstract: Understanding the pharmacokinetic (PK) and pharmacodynamic (PD) relationship of a therapeutic monoclonal antibody against proprotein convertase subtilisin/kexin type 9 (PCSK9) exhibiting target-mediated drug disposition (TMDD) is critical for selecting optimal dosing regimens. We describe the PK/PD relationship of evolocumab using a mathematical model that captures evolocumab binding and removal of unbound PCSK9 as well as reduction in circulating low-density lipoprotein cholesterol (LDL-C). Data were pooled from 2 clinical studies: a single-dose escalation study in healthy subjects (7-420 mg SC; n = 44) and a multiple-dose escalation study in statin-treated hypercholesterolemic patients (14 mg weekly to 420 mg monthly [QM] SC; n = 57). A TMDD model described the time course of unbound evolocumab concentrations and removal of unbound PCSK9. The estimated linear clearance and volume of evolocumab were 0.256 L/day and 2.66 L, respectively, consistent with other monoclonal antibodies. The time course of LDL-C reduction was described by an indirect response model with the elimination rate of LDL-C being modulated by unbound PCSK9. The concentration of unbound PCSK9 associated with half-maximal inhibition (IC50) of LDL-C elimination was 1.46 nM. Based on simulations, 140 mg every 2 weeks (Q2W) and 420 mg QM were predicted to achieve a similar time-averaged effect of 69% reduction in LDL-C in patients on statin therapy, suggesting that an approximate 3-fold dose increase is required for a 2-fold extension in the dosing interval. Evolocumab dosing regimens of 140 mg Q2W or 420 mg QM were predicted to result in comparable reductions in LDL-C over a monthly period, consistent with results from recently completed phase 3 studies.
authors.affiliation: Amgen Inc, Thousand Oaks, CA, USA.|Current affiliation: AbbVie, North Chicago, IL, USA.
authors.forename: John P
authors.initials: JP
authors.lastname: Gibbs
authors.affiliation: Amgen Inc, Thousand Oaks, CA, USA.
authors.forename: Sameer
authors.initials: S
authors.lastname: Doshi
authors.affiliation: Amgen Inc, Thousand Oaks, CA, USA.
authors.forename: Mita
authors.initials: M
authors.lastname: Kuchimanchi
authors.affiliation: Amgen Inc, Thousand Oaks, CA, USA.|Current affiliation: BioMarin Pharmaceuticals, Novato, CA, USA.
authors.forename: Anita
authors.initials: A
authors.lastname: Grover
authors.affiliation: Amgen Inc, Thousand Oaks, CA, USA.
authors.forename: Maurice G
authors.initials: MG
authors.lastname: Emery
authors.affiliation: Amgen Inc, Thousand Oaks, CA, USA.|Current affiliation: Quantitative Solutions, a Certara Company, Seattle, WA, USA.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Dodds
authors.affiliation: Amgen Inc, Thousand Oaks, CA, USA.|Current affiliation: BioMarin Pharmaceuticals, Novato, CA, USA.
authors.forename: Megan A
authors.initials: MA
authors.lastname: Gibbs
authors.affiliation: Amgen Inc, Thousand Oaks, CA, USA.
authors.forename: Ransi
authors.initials: R
authors.lastname: Somaratne
authors.affiliation: Amgen Inc, Thousand Oaks, CA, USA.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Wasserman
authors.affiliation: Division of Lipidology, Department of Medicine, University of Cape Town, Cape Town,  South Africa.
authors.forename: Dirk
authors.initials: D
authors.lastname: Blom
mesh_terms: D000911:Antibodies, Monoclonal / Q000097:blood / Q000493:pharmacokinetics*; D061067:Antibodies, Monoclonal, Humanized / Q000097:blood / Q000493:pharmacokinetics*; D001682:Biological Availability; D008078:Cholesterol, LDL / Q000097:blood; D005260:Female; D006801:Humans; D006937:Hypercholesterolemia / Q000097:blood; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D000091362:PCSK9 Inhibitors
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D008078:Cholesterol, LDL; D000091362:PCSK9 Inhibitors; C577155:evolocumab
keywords: LDL-C; PCSK9; monoclonal antibody; pharmacokinetic/pharmacodynamic; pharmacokinetics; target-mediated drug disposition