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.

Toxicity assessment of molindone hydrochloride, a dopamine D2/D5 receptor antagonist in juvenile and adult rats.

Neuroleptic drug molindone hydrochloride is a dopamine D2/D5 receptor antagonist and it is in late stage development for the treatment of impulsive aggression in children and adolescents who have attention deficient/hyperactivity disorder (ADHD). This new indication for this drug would expand the target population to include younger patients, and therefore, toxicity assessments in juvenile animals were undertaken in order to determine susceptibility differences, if any, between this age group and the adult rats. Adult rats were administered molindone by oral gavage for 13 weeks at dose levels of 0, 5, 20, or 60 mg/kg-bw/day. Juvenile rats were dosed for 8 weeks by oral gavage at dose levels of 0, 5, 25, 50, or 75 mg/kg-bw/day. Standard toxicological assessments were made using relevant study designs in consultation with FDA. Treatment-related elevation in serum cholesterol and triglycerides and decreases in glucose levels were observed in both the age groups. Organ weight changes included increases in liver, adrenal gland and seminal vesicles/prostate weights. Decreases in uterine weights were also observed in adult females exposed to the top two doses with sufficient exposure. In juveniles, sexual maturity parameters secondary to decreased body weights were observed, but, were reversed. In conclusion, the adverse effects noted in reproductive tissues of adults were attributed to hyperprolactinemia and these changes were not considered to be relevant to humans due to species differences in hormonal regulation of reproduction. On the whole, there were no remarkable differences in the toxicity profile of the drug between the two age groups.

In vitro and in vivo genotoxicity assessment of the dopamine receptor antagonist molindone hydrochloride.

Molindone hydrochloride is a dihydroindolone neuroleptic with dopamine D2 and D5 receptor antagonist activity. As an integral component of its preclinical safety evaluation, molindone hydrochloride was evaluated in a series of in vitro and in vivo genetic toxicology assays. In the bacterial reverse gene mutation assays employing four Salmonella tester strains (TA98, TA100, TA1535, and TA1537) and the E. coli tester strain WP2uvrA, molindone hydrochloride was negative in all strains, except TA100, in which it induced a positive response (up to 3-fold) in the presence of rat liver S9. With human S9, a small (2-fold), but nonreproducible, increase in revertants was observed in TA100 at the highest concentration of molindone tested (5,000 µg/plate). The mutagenicity was completely abrogated by the addition of glutathione and UDP-glucuronic acid to rat liver S9, suggesting detoxification of the mutagenic metabolite(s) by Phase II conjugation reactions, pathways commonly operational in humans. Molindone hydrochloride did not induce chromosomal aberrations in human lymphocyte cultures, did not elicit a positive response in a rat bone marrow micronucleus test for clastogencity/aneugenicity, and did not give a positive response in the rat liver comet assay for DNA damage. Collectively, the weight of evidence from these studies, combined with a large margin of safety and efficient detoxification through Phase II conjugation supports the interpretation that molindone hydrochloride does not pose a genotoxic risk to humans at the anticipated clinical dose levels.

Molindone compared to haloperidol in a guinea-pig model of tardive dyskinesia.

Molindone was compared with haloperidol in animal models of tardive dyskinesia. Treatment with molindone for 14 days at 3, 6, 20 and 40 mg/kg, enhanced the stereotyped behavioral response induced by apomorphine and increased the numbered of D-2 dopamine receptors in the striatum (Bmax) labelled by high affinity (Kd = 40 pmol) binding or [3H] spiroperidol in the guinea-pig. Molindone at 1 mg/kg, caused no behavioral supersensitivity or change in the binding of dopamine receptors. Chronic administration of haloperidol (0.1, 0.5 and 5.0 mg/kg) also increased both the behavioral response to apomorphine and the number of dopamine receptors. Haloperidol, at 0.02 and 0.004 mg/kg, had no effect. Molindone potentiated dopaminergic activity in animal models in a similar way to other neuroleptics, suggesting that its use may also result in tardive dyskinesia.

Effect of alpha-methyl-p-tyrosine on neuroleptic-induced catalepsy in rat.

Pretreatment with alpha-methyl-p-tyrosine, a tyrosine hydroxylase inhibitor, was found to increase the intensity of catalepsy induced by haloperidol, chlorpromazine and molindone. The drug probably decreases the synthesis of dopamine and makes less dopamine available for release and to compete with the neuroleptic for the postsynaptic striatal dopamine receptor sites with resultant potentiation of the neuroleptic-induced catalepsy.