Reproductive toxicity of exemestane, an antitumoral aromatase inactivator,in rats and rabbits

Exemestane is an orally active, irreversible inactivator of aromatase, stru cturally related to the natural substrate androstenedione, in clinical use at 25 mg daily for the treatment of advanced breast cancer in postmenopausa l women. The reproductive and developmental toxicity of exemestane was asse ssed in rats and rabbits with oral administration. Pivotal experiments incl uded a fertility study (Segment I), in which female rats received exemestan e doses of 4, 20, or 100 mg/kg/day from two weeks premating until GD 20 (ce sarean-sectioned dams), or until GD 15 and then from D 1 to D 21 postpartum (dams allowed to deliver), and developmental toxicity studies (Segment II) , in which rats and rabbits were treated from GD 6 through GD 17 (rats) or GD 18 (rabbits) at doses of 10, 50, 250, or 810 m,mg/kg/day and 30, 90, or 270 mg/kg/day, respectively. All rabbits and two-thirds of the rats were ce sarean sectioned toward the end of pregnancy to determine litter parameters and examine structural abnormalities in the fetuses; the remaining one-thi rd of the rats was allowed to litter and rear pups to weaning. No pivotal m ale fertility or peri- and postnatal studies were performed, taking into co nsideration the therapeutic use. Postnatal effects on the first generation offspring were assessed in both studies in rats, in the portion of dams all owed to deliver. Their F1 offspring were raised to adulthood, when they wer e evaluated for reproductive performance, and the F1 females were terminate d on GD 20. The dosing schedule for the Segment I study in rats, which incl uded a postnatal component, was established to exclude exposure before and during parturition (by withdrawing treatment from GD 16 until the end of pa rturition). This withdrawal of treatment was put in place because in a prel iminary study with treatment including the peripartum period, doses from 5 to 200 mg/kg/day prolonged gestation and interfered with parturition. Overa ll, studies in rats showed that female fertility was not affected up to 100 mg/kg/day, but doses higher than 4 mg/kg/day, which is approximately the p harmacologically active dose (ED50 = 3.7 m/kg), prolonged gestation and imp aired parturition, leading to maternal deaths in labor and perinatal deaths of offspring. Rats killed on GD 20 showed nondose-related increases in res orptions at doses higher than 10 mg/kg/day, a reduction in fetal body weigh ts at 20 and 100 mg/kg/day (fertility study) and 810 mg/kg/day (development al toxicity study), and an increase in placental weights at all doses. Fema le fetuses exposed in utero until GD 20 at 100 mg/kg/day showed an increase in the anogenital distance, very likely related to an increase of the pote nt androgen DHT as a consequence of aromatase inhibition. Morphologic exami nations in fetuses and born pups that were exposed in utero up to the end o f the organogenesis period, as well as postnatal investigations on offsprin g up to adulthood, showed no treatment-related effects. In a developmental toxicity study in rabbits, treatment at 270 mg/kg/day affected maternal foo d intake and body weight gain, caused abortion or total resorption in about 30% of pregnant females, and reduced body weight and numbers of live fetus es, but did not affect fetal morphology. It was concluded that exemestane d id not affect parturition in rats at 4 mg/kg/day or pregnancy in rabbits at 90 mg/kg/day (about 1.5 and 70 times the human dose, respectively, on a mg /m(2) basis) and was not teratogenic in rats and rabbits. Exemestane is marketed for use only in postmenopausal women. Its labeling i ncludes a contraindication to use in pregnant or lactating women. (C) 2001 Elsevier Science Inc. All rights reserved.