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© 1998 Oxford University Press
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An Evaluation of the Novel Selective Estrogen Receptor Modulator, Idoxifene, for Effects on Reproduction in Rats and Rabbits
Safety Assessment, SmithKlme Beecham Pharmaceuticals, King of Prussia Pennsylvania
Received July 18, 1997; accepted November 5, 1997
Idoxifene, a tissue-specific selective estrogen receptor modulator, was evaluated in male and female rats and female rabbits after oral administration for effects on fertility and/or embryo-fetal development. In all studies, adult toxicity was evident at doses 
0.03 mg/kg/day in rats and 0.1 mg/kg/day in rabbits as evidenced by decreased body weight and/or food consumption. In the male fertility study, rats were treated with 0.003,03, or 3.0 mg/kg/day for 64 to 68 days. Doses 0.3 mg/kg/day decreased seminal vesicle and prostate weights and impaired posttesticular sperm development, resulting in decreased epididymal sperm count and weight, but did not affect male fertility. In the female fertility study, rats were treated for 2 weeks prior to mating until insemination with 0.003, 0.03, or 3.0 mg/kg/day. Disrupted estrous cycles, impaired fertility, increased preimplantation loss, and increased vaginal fluid at necropsy were evident at 0.03 mg/kg/day. In the early embryonic development study, pregnant female rats were treated from days 0 to 6 postcoitus (pc) with 0.003, 0.03, or 3.0 mg/kg/day idoxifene. Partial or complete preimplantation loss was seen at 0.03 and 3.0 mg/kg/day, respectively. In the embryo-Jetal development study, pregnant rats were treated from days 6 to 17 pc with 0.003,0.03, or 3.0 mg/kg/day. At 3.0 mg/kg/day there was maternal lethality, excess vaginal fluid, embryofetal death, generalized fetal edema, and developmental delays. Excess vaginal fluid but no fetal effects were seen at 0.03 mg/kg/day. There were no treatment-related effects at 0.003 mg/kg/day in any rat reproduction study performed. In the rabbit embryo-fetal development study, pregnant New Zealand White rabbits were treated from days 6 to 20 pc with 0.01, 0.1, or 1.0 mg/kg/day idoxifene. At 1.0 mg/kg/day there was maternal lethality, vaginal or uterine bleeding, abortion/premature deliveries, and embryolethality. Vaginal or uterine bleeding was seen at 0.1 mg/kg/day. No treatment-related effects were observed at 0.01 mg/kg/day. Although systemic toxicity was evident in all the studies, the effects of idoxifene on rat and rabbit reproduction were considered to be due to the pharmacological activity of the compound.
Key Words: idoxifene; rat; rabbit; reproductive toxicity; developmental toxicity; selective estrogen receptor modulator (SERM).
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