title: Fertility and Embryo-Fetal Development Assessment in Rats and Rabbits with Evacetrapib: A Cholesteryl Ester Transfer Protein Inhibitor.
abstract: The purpose of these studies was to evaluate the effects of evacetrapib on male and female fertility and on embryo-fetal development (EFD).
  
  
  
  Evacetrapib, a potent and selective inhibitor of cholesteryl ester transfer protein (CETP), was administered daily by oral gavage starting 2 weeks (for female) or 4 weeks (for male) before mating, during cohabitation, and until necropsy in the male rat fertility study or through gestation day (GD) 17 in the female rat combined fertility/EFD study. For rabbit EFD studies, animals were dosed from GDs 7 to 19 or from 1 week before mating through GD 19. Dose levels of evacetrapib ranged from 60 to 600 mg/kg for rats and from 1 to 100 mg/kg/day for rabbits.
  
  
  
  Parental findings in rats included decreased body weight and food consumption and moribund euthanasia in animals given 600 mg/kg/day and decreased food consumption at 300 mg/kg/day. There were no adverse effects on estrus cycling, fertility indices, sperm parameters, maternal reproductive parameters, male reproductive tissue, or fetal viability, growth, or external/visceral morphology. An increase in the incidence of 14th rudimentary ribs, a minor, transient variation considered nonadverse, was the only significant developmental finding in rats given 600 mg/kg/day. Slight decreases in body weight and food consumption at 100 mg/kg/day were the only maternal effects observed in rabbits with no adverse developmental effects noted.
  
  
  
  No adverse effects on fertility or EFD were observed in rats at doses up to 600 mg/kg/day and no adverse effects on EFD were noted in rabbits at doses up to 100 mg/kg/day. Birth Defects Research 109:513-527, 2017. © 2017 Wiley Periodicals, Inc.
authors.affiliation: Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana.
authors.forename: William J
authors.identifier: 0000-0003-0139-9693
authors.initials: WJ
authors.lastname: Breslin
authors.affiliation: Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana.
authors.forename: Kim G
authors.initials: KG
authors.lastname: Hilbish
authors.affiliation: Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana.
authors.forename: Ellen A
authors.initials: EA
authors.lastname: Cannady
authors.affiliation: Charles River Laboratories, Ashland, Ohio.
authors.forename: Tammy L
authors.initials: TL
authors.lastname: Edwards
mesh_terms: D000818:Animals; D001569:Benzodiazepines / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity*; D001835:Body Weight / Q000187:drug effects; D053480:Cholesterol Ester Transfer Proteins; D004305:Dose-Response Relationship, Drug; D005260:Female; D005298:Fertility / Q000187:drug effects; D047109:Fetal Development / Q000187:drug effects*; D008297:Male; D009929:Organ Size / Q000187:drug effects; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D012098:Reproduction / Q000187:drug effects; D013094:Spermatozoa / Q000187:drug effects
chemical_list: D053480:Cholesterol Ester Transfer Proteins; D001569:Benzodiazepines; C568301:evacetrapib
keywords: cholesteryl ester transfer protein (CETP) inhibitor; developmental toxicity; embryofetal development; evacetrapib; fertility; reproductive toxicity