title: Developmental toxicity study of lersivirine in mice.
abstract: Lersivirine is a second-generation nonnucleoside reverse transcriptase inhibitor undergoing clinical development for the treatment of HIV-1. An embryo-fetal developmental toxicity study was performed to evaluate the maternal and developmental toxicity of lersivirine in pregnant mice. Mated Crl:CD1(ICR) mice were administered 0, 150, 350, and 500 mg/kg lersivirine once daily by oral gavage on gestation days 6 to 17, followed by cesarean section on gestation day 18. The first 2 days of dosing for the high-dose group were done at 250 mg/kg to allow induction of hepatic metabolizing enzymes, after which the dose was increased to 500 mg/kg/day. This dosing paradigm allowed for maintenance of exposure in the high-dose group despite the considerable autoinduction that occurs in rodents following lersivirine treatment. Lersivirine did not cause an increase in external, visceral, or skeletal malformations. Intrauterine growth retardation, demonstrated by reduced fetal body weights and increased variations associated with delayed skeletal ossification, was noted at 350 and 500 mg/kg/day. The results of these studies indicate that lersivirine is not teratogenic in mice.
authors.affiliation: Drug Safety Research and Development, Pfizer Worldwide Research & Development, Groton, CT 06340, USA. Gregg.d.cappon@pfizer.com
authors.forename: Gregg D
authors.initials: GD
authors.lastname: Cappon
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Bowman
authors.forename: Sarah N
authors.initials: SN
authors.lastname: Campion
authors.forename: Gary
authors.initials: G
authors.lastname: Chmielewski
authors.forename: Mark E
authors.initials: ME
authors.lastname: Hurtt
authors.forename: Gregory L
authors.initials: GL
authors.lastname: Finch
authors.forename: Elise M
authors.initials: EM
authors.lastname: Lewis
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001842:Bone and Bones / Q000002:abnormalities / Q000187:drug effects / Q000196:embryology / Q000503:physiopathology; D002585:Cesarean Section; D004622:Embryo, Mammalian / Q000187:drug effects* / Q000196:embryology; D047108:Embryonic Development / Q000187:drug effects*; D005247:Feeding Behavior / Q000187:drug effects; D005260:Female; D005333:Fetus / Q000002:abnormalities / Q000187:drug effects / Q000473:pathology; D018811:Maternal Exposure; D051379:Mice; D009570:Nitriles / Q000633:toxicity*; D010012:Osteogenesis / Q000187:drug effects; D011247:Pregnancy; D011720:Pyrazoles / Q000633:toxicity*; D018675:Toxicity Tests
chemical_list: D009570:Nitriles; D011720:Pyrazoles; C531151:UK 453,061