👤 Ellen A Cannady

Evacetrapib, a potent and selective inhibitor of cholesteryl ester transfer protein (CETP), was under development for the treatment of cardiovascular (CV) disease. The purpose of this pre-postnatal study in rabbits was to evaluate the effects of evacetrapib on pregnancy, parturition, and lactation of the maternal animals and on the growth, viability, development, and reproductive performance of the first filial (F1) offspring. The rabbit is considered a relevant species for toxicity testing with evacetrapib as it demonstrates significant CETP expression, whereas mice and rats do not express significant levels of CETP. Evacetrapib was administered daily by oral gavage from gestation day (GD) 7 through lactation day (LD) 41 at dose levels of 0, 10, 30, and 100 mg/kg/day. There were no adverse effects on maternal survival, clinical signs, gestation length, parturition, and litter size. There were no effects on F1 clinical observations, body weight, sexual maturation, conditioned eye blink, functional observational battery, or pathology findings. Treatment-related decreases in F1 postnatal survival and equivocal reductions in F1 mating, fertility, and copulation/conception indices without changes in sperm parameters or pathology of reproductive organs were noted in F1 animals. The maternal no observed adverse effect level (NOAEL) after evacetrapib administration in female rabbits was 100 mg/kg/day. Based on the decreased F1 postnatal survival and equivocal changes in F1 fertility, the NOAEL for F1 neonatal developmental was 30 mg/kg/day. Birth Defects Research 109:486-496, 2017.© 2017 Wiley Periodicals, Inc. Show less

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. Show less