Reproductive toxicity of exemestane, an antitumoral aromatase inactivator, in rats and rabbits.
Exemestane is an orally active, irreversible inactivator of aromatase, structurally related to the natural substrate androstenedione, in clinical use at 25 mg daily for the treatment of advanced breast cancer in postmenopausal women. The reproductive and developmental toxicity of exemestane was assessed in rats and rabbits with oral administration. Pivotal experiments included a fertility study (Segment I), in which female rats received exemestane doses of 4, 20, or 100 mg/kg/day from two weeks premating until GD 20 (cesarean-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 mg/kg/day and 30, 90, or 270 mg/kg/day, respectively. All rabbits and two-thirds of the rats were cesarean sectioned toward the end of pregnancy to determine litter parameters and examine structural abnormalities in the fetuses; the remaining one-third of the rats was allowed to litter and rear pups to weaning. No pivotal male fertility or peri- and postnatal studies were performed, taking into consideration the therapeutic use. Postnatal effects on the first generation offspring were assessed in both studies in rats, in the portion of dams allowed to deliver. Their F1 offspring were raised to adulthood, when they were evaluated for reproductive performance, and the F1 females were terminated on GD 20. The dosing schedule for the Segment I study in rats, which included a postnatal component, was established to exclude exposure before and during parturition (by withdrawing treatment from GD 16 until the end of parturition). This withdrawal of treatment was put in place because in a preliminary study with treatment including the peripartum period, doses from 5 to 200 mg/kg/day prolonged gestation and interfered with parturition.Overall, 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 pharmacologically active dose (ED50 = 3.7 mg/kg), prolonged gestation and impaired parturition, leading to maternal deaths in labor and perinatal deaths of offspring. Rats killed on GD 20 showed nondose-related increases in resorptions at doses higher than 10 mg/kg/day, a reduction in fetal body weights at 20 and 100 mg/kg/day (fertility study) and 810 mg/kg/day (developmental toxicity study), and an increase in placental weights at all doses. Female 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 potent androgen DHT as a consequence of aromatase inhibition. Morphologic examinations in fetuses and born pups that were exposed in utero up to the end of the organogenesis period, as well as postnatal investigations on offspring up to adulthood, showed no treatment-related effects. In a developmental toxicity study in rabbits, treatment at 270 mg/kg/day affected maternal food intake and body weight gain, caused abortion or total resorption in about 30% of pregnant females, and reduced body weight and numbers of live fetuses, but did not affect fetal morphology. It was concluded that exemestane did 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/m2 basis) and was not teratogenic in rats and rabbits. Exemestane is marketed for use only in postmenopausal women. Its labeling includes a contraindication to use in pregnant or lactating women.
Beltrame
D
D
Pharmacia & Upjohn, Worldwide Toxicology, 20014, Nerviano, Italy. diana.beltrame@eu.pnu.com
di Salle
E
E
Giavini
E
E
Gunnarsson
K
K
Brughera
M
M
D000014:Abnormalities, Drug-Induced; D000284:Administration, Oral; D000730:Androstadienes / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D000831:Animals, Newborn; D047072:Aromatase Inhibitors; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000633:toxicity*; D005260:Female; D005298:Fertility / Q000187:drug effects; D008098:Litter Size / Q000187:drug effects; D008297:Male; D018811:Maternal Exposure; D009929:Organ Size / Q000187:drug effects; D018812:Paternal Exposure; D011247:Pregnancy; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D012098:Reproduction / Q000187:drug effects*; D013045:Species Specificity; D013737:Testis / Q000187:drug effects / Q000473:pathology
D000730:Androstadienes; D047072:Aromatase Inhibitors; D004791:Enzyme Inhibitors; C056516:exemestane