title: Developmental toxicity of lersivirine in rabbits when administered throughout organogenesis and when limited to sensitive windows of axial skeletal development.
abstract: BACKGROUND
  Lersivirine is a second-generation nonnucleoside reverse transcriptase inhibitor undergoing clinical development for the treatment of human immunodeficiency virus-1. An embryo-fetal development study was performed to evaluate the potential for maternal and developmental toxicity of lersivirine.
  
  
  METHODS
  Pregnant New Zealand White rabbits were administered 0, 100, 250, and 500 mg/kg lersivirine by oral gavage once daily on gestation days (GDs) 7 to 19, followed by cesarean section on GD 29 and fetal evaluation.
  
  
  RESULTS
  Maternal toxicity was noted at all dose levels (decreased food consumption and body weight gain), with fetal toxicity at 500 mg/kg (decreased fetal weights, increased postimplantation loss). Equivocal findings for axial skeletal malformations were observed in three fetuses at 500 mg/kg. To better understand if these malformations were related to treatment with lersivirine, a follow-up rabbit embryo-fetal development study was performed with 1000 mg/kg/day lersivirine (500 mg/kg BID, 12-hr interdose interval) for two different 3-day windows, GDs 8 to 10 or GDs 11 to 13, which represent the sensitive windows of axial skeletal development in rabbits. Control rabbits were administered vehicle following the same dosing regimen from GDs 8 to 13. Cesarean sections were performed on GD 29, and fetal skeletons were examined for the potential of lersivirine to cause skeletal malformations in rabbits. At maternal exposure levels higher than the initial study, lersivirine did not induce fetal skeletal malformations when administered in the sensitive windows of axial skeletal development.
  
  
  CONCLUSIONS
  The results of these studies indicate that lersivirine did not exhibit any evidence of teratogenicity in rabbits.
authors.affiliation: Drug Safety Research and Development, Pfizer Worldwide Research & Development, Groton, CT 06340, USA. sarah.campion@pfizer.com
authors.forename: Sarah N
authors.initials: SN
authors.lastname: Campion
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Bowman
authors.forename: Gregg D
authors.initials: GD
authors.lastname: Cappon
authors.forename: Anthony
authors.initials: A
authors.lastname: Harrison
authors.forename: Gregory L
authors.initials: GL
authors.lastname: Finch
authors.forename: Mark E
authors.initials: ME
authors.lastname: Hurtt
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001846:Bone Development / Q000187:drug effects*; D001842:Bone and Bones / Q000002:abnormalities / Q000187:drug effects / Q000196:embryology / Q000473:pathology; D002585:Cesarean Section; D004305:Dose-Response Relationship, Drug; D047108:Embryonic Development / Q000187:drug effects*; D005247:Feeding Behavior / Q000187:drug effects; D005260:Female; D005333:Fetus / Q000002:abnormalities / Q000187:drug effects / Q000473:pathology; D006801:Humans; D018811:Maternal Exposure; D009570:Nitriles / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity*; D038081:Organogenesis / Q000187:drug effects*; D011247:Pregnancy; D011720:Pyrazoles / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity*; D011817:Rabbits; D016019:Survival Analysis; D018675:Toxicity Tests; D014781:Viscera / Q000002:abnormalities / Q000187:drug effects / Q000196:embryology
chemical_list: D009570:Nitriles; D011720:Pyrazoles; C531151:UK 453,061