Background: An extended-release molindone (a dopamine D 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 day 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 day on gestational days (GDs) 6-17; rabbits received 0, 5, 10, or 15 mg kg day on GDs 6-18. Ovarian/uterine and fetal parameters were evaluated at term. In the PPN study, F rats received 0, 5, 20, or 40 mg kg day (GD6-LD21); behavior and reproduction were evaluated in F 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 day , without effects on fertility or embryonic development. No developmental toxicity occurred in F fetuses. In F pups, reduced preweaning growth was observed at 40 mg kg day , 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.
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