Reproductive toxicology studies supporting the safety of molindone, a dopamine receptor antagonist.

BACKGROUND: An extended-release molindone (a dopamine D2 and serotonin antagonist) is currently being developed as a novel treatment for impulsive aggression (IA) in patients optimally treated for ADHD. Oral Good Laboratory Practice reproductive toxicology studies (fertility and early embryonic [FEE], prenatal/postnatal [PPN], embryo-fetal development [EFD]) were conducted with molindone HCl using International Conference on Harmonisation (ICH) S5(R2)-compliant protocols. METHODS: In the FEE study, 0, 5, 15, or 30 mg kg-1 day-1 was administered to female (2 weeks premating through implantation) and male (4 weeks premating for 57 days) rats, and fertility parameters were evaluated. In the EFD studies, rats received 0, 5, 20, or 40 mg kg-1 day-1 on gestational days (GDs) 6-17; rabbits received 0, 5, 10, or 15 mg kg-1 day-1 on GDs 6-18. Ovarian/uterine and fetal parameters were evaluated at term. In the PPN study, F0 rats received 0, 5, 20, or 40 mg kg-1 day-1 (GD6-LD21); behavior and reproduction were evaluated in F1 offspring. RESULTS: Parental hypoactivity and reduced body weight gain occurred in all studies. In the FEE, prolonged estrous cycles and delayed mating occurred at ≥15 mg kg-1 day-1 , without effects on fertility or embryonic development. No developmental toxicity occurred in F1 fetuses. In F1 pups, reduced preweaning growth was observed at 40 mg kg-1 day-1 , but there were no effects on postweaning growth, behavior, or reproduction. CONCLUSIONS: Molindone was not developmentally toxic in rats or rabbits at 69X and 6X clinical exposures, confirming the reproductive safety of molindone. Changes in estrous cyclicity were related to species-specific pharmacological effects of molindone in rodents and are not considered relevant to human risk.

Reversibility of dopamine receptor antagonist-induced hyperprolactinemia and associated histological changes in Tg RasH2 wild-type mice.

The purpose of this study was to better understand the biological effects of increased prolactin levels induced in mice by dopamine D2 receptor antagonist molindone treatment. Toxicokinetics, prolactin levels, and reproductive tissue histology were evaluated in Tg rasH2 wild-type mice treated orally with molindone at 0, 5, 15, and 50mg/kg/day for 6 months, followed by a 2-month posttreatment recovery period. A greater than dose-proportional increase in molindone exposure ([AUC]0‒24) was observed on Day 180 for both sexes. Statistically significant (P<0.01) increases in prolactin levels were observed in most treatment groups compared with controls at 0.5h postdose on Days 1 and 180. Prolactin levels returned to baseline levels during the recovery period. Microscopic changes attributable to hyperprolactinemia, including corpora lutea enlargement and interstitial cell atrophy in the ovaries, and atrophy of the uterus and vagina were observed on Day 180. These changes were reversed during the recovery period in the 5- and 15-mg/kg/day treatment groups. Mice receiving molindone at 50mg/kg/day also showed signs of reversal on histologic examination.