title: Decreased maternal and fetal cholesterol following maternal bococizumab (anti-PCSK9 monoclonal antibody) administration does not affect rat embryo-fetal development.
abstract: Bococizumab is a humanized monoclonal IgG2Δa antibody against proprotein convertase subtilisin/kexin type 9 (PCSK9) for the treatment of hyperlipidemia. The evaluation of potential effects on embryo-fetal development was conducted in the rat. In a pharmacokinetic/pharmacodynamic study bococizumab was administered intravenously to pregnant Sprague-Dawley (SD) rats (n = 8/group) at 0, 10, 30, and 100 mg/kg during organogenesis. Maternal and fetal bococizumab, total cholesterol and HDL concentrations were determined. Bococizumab was well tolerated and there were no effects on ovarian or uterine parameters. Maternal and fetal bococizumab exposure increased with increasing dose, with a corresponding dose-dependent decrease in fetal cholesterol levels. Maternal cholesterol levels were decreased significantly, with reductions that were of a similar magnitude regardless of dose. In the definitive embryo-fetal development study bococizumab was administered to pregnant SD rats (n = 20/group) at 0, 10, 30, and 100 mg/kg and no adverse maternal or developmental effects were observed up to 100 mg/kg. These studies have provided an appropriate and relevant safety assessment of bococizumab in pregnant rats to inform human risk assessment, demonstrating no adverse effects on embryo-fetal development at magnitudes greater than anticipated clinical exposure and in the presence of maximal reductions in maternal cholesterol and dose-dependent reductions in fetal cholesterol.
authors.affiliation: Drug Safety Research and Development, Pfizer Worldwide Research & Development, Groton, CT, USA.
authors.forename: Sarah N
authors.initials: SN
authors.lastname: Campion
authors.affiliation: Drug Safety Research and Development, Pfizer Worldwide Research & Development, La Jolla, CA, USA.
authors.forename: Bora
authors.initials: B
authors.lastname: Han
authors.affiliation: Drug Safety Research and Development, Pfizer Worldwide Research & Development, Groton, CT, USA.
authors.forename: Gregg D
authors.initials: GD
authors.lastname: Cappon
authors.affiliation: Charles River Laboratories, Preclinical Services Pennsylvania, Horsham, PA, USA.
authors.forename: Elise M
authors.initials: EM
authors.lastname: Lewis
authors.affiliation: Pharmacokinetics Dynamics and Metabolism, Pfizer Worldwide Research & Development, La Jolla, CA, USA.
authors.forename: Eugenia
authors.initials: E
authors.lastname: Kraynov
authors.affiliation: Rinat, Pfizer Worldwide Research & Development, South San Francisco, CA, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Liang
authors.affiliation: Drug Safety Research and Development, Pfizer Worldwide Research & Development, Groton, CT, USA. Electronic address: christopher.j.bowman@pfizer.com.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Bowman
mesh_terms: D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000097:blood*; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000633:toxicity; D002784:Cholesterol / Q000097:blood*; D004305:Dose-Response Relationship, Drug; D005260:Female; D047109:Fetal Development / Q000187:drug effects / Q000502:physiology*; D008431:Maternal-Fetal Exchange / Q000187:drug effects / Q000502:physiology*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000097:blood / Q000139:chemically induced; D000071449:Proprotein Convertase 9; D051381:Rats; D017207:Rats, Sprague-Dawley; D012697:Serine Endopeptidases / Q000097:blood*
chemical_list: D000888:Antibodies, Anti-Idiotypic; D061067:Antibodies, Monoclonal, Humanized; C000598888:bococizumab; D002784:Cholesterol; C510804:PCSK9 protein, rat; D000071449:Proprotein Convertase 9; D012697:Serine Endopeptidases
keywords: Bococizumab; Cholesterol; Embryo-fetal development; Monoclonal antibody