Embryo/fetal toxicity assessment of lasofoxifene, a selective estrogen receptor modulator (SERM), in rats and rabbits.
BACKGROUND
The purpose of this study was to evaluate the effects of lasofoxifene, a selective estrogen receptor modulator (SERM), on rat and rabbit fetal development.


METHODS
Lasofoxifene was administered orally to rats (1, 10, 100 mg/kg) between gestation days (GD) 6-17, and in rabbits (0.1, 1, 3 mg/kg) between GD 6-18. Maternal body weight and food consumption were monitored throughout pregnancy. Fetuses were delivered by Cesarean section on GD 21 in rats, and GD 28 in rabbits, to evaluate fetal viability, weight, and morphology. Drug concentrations in maternal plasma were measured in a separate cohort of animals at several time points commencing on GD 17 (rats) and 18 (rabbits). On GD 18 (rat) and GD 19 (rabbit) drug concentrations were measured in maternal plasma and in fetal tissue 2 hr post dosing to determine the fetal to maternal drug ratio.


RESULTS
In rats, there were dose-related declines in maternal weight gain and food consumption. Post implantation loss was significantly increased at dosages of 10 and 100 mg/kg, and the number of viable fetuses was decreased at 100 mg/kg. The placental weights increased, whereas fetal weights decreased in a dose-dependent manner. Lasofoxifene-related teratologic findings were noted at 10 and 100 mg/kg and included imperforate anus with hypoplastic tails, dilatation of the ureters and renal pelvis, misaligned sternebrae, hypoflexion of hindpaw, wavy ribs, and absent ossification of sternebrae. In rabbits, neither maternal weight gain nor food consumption were affected during treatment. Between GD 26-28, there was a dose-dependent increased incidence of red discharge beneath the cages. At 1 and 3 mg/kg, resorptions and post-implantation loss increased. There were no significant external or visceral effects, but 3 mg/kg there was an increased incidence of supernumerary ribs. Although the maternal plasma Cmax and AUC(0-24) were dose-dependent, the exposures in the rat were many orders of magnitude greater than in the rabbit even for the same 1 mg/kg dose. The single time point fetal/maternal drug ratio was higher in the rat (1.3-0.78) than in the rabbit (0.21-0.16).


CONCLUSIONS
In general, both maternal and fetal effects of lasofoxifene were similar to those reported with other SERMs. Although the incidence or severity of these effects was, in some instances, greater in the rat than in the rabbit, the doses and the resultant maternal and fetal exposures were many orders of magnitude higher in the rat, suggesting the rabbit to be more sensitive to the toxicological effects of lasofoxifene.
Department of Reproductive and Developmental Toxicity, Pfizer Global Research and Development, Safety Sciences, Groton, Eastern Point Road, Groton, Connecticut 06340, USA. terence_r_ozolins@groton.pfizer.com
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D000818:Animals; D001006:Anus, Imperforate / Q000139:chemically induced; D019540:Area Under Curve; D001835:Body Weight / Q000187:drug effects; D001842:Bone and Bones / Q000002:abnormalities; D004305:Dose-Response Relationship, Drug; D010064:Embryo Implantation / Q000187:drug effects; D004622:Embryo, Mammalian / Q000187:drug effects; D004967:Estrogens / Q000378:metabolism; D005247:Feeding Behavior / Q000187:drug effects; D005260:Female; D008297:Male; D018811:Maternal Exposure; D009929:Organ Size / Q000187:drug effects; D010388:Pelvis / Q000002:abnormalities; D010920:Placenta / Q000187:drug effects; D011759:Pyrrolidines / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000633:toxicity*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D012098:Reproduction / Q000187:drug effects; D020845:Selective Estrogen Receptor Modulators / Q000009:adverse effects / Q000633:toxicity*; D013045:Species Specificity; D013723:Teratogens; D013764:Tetrahydronaphthalenes / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000633:toxicity*; D013997:Time Factors; D014513:Ureter / Q000002:abnormalities
D004967:Estrogens; D011759:Pyrrolidines; D020845:Selective Estrogen Receptor Modulators; D013723:Teratogens; D013764:Tetrahydronaphthalenes; C111332:Lasofoxifene