Supernus Pharmaceuticals, Inc., Rockville, Maryland.
Eurofins Advinus Ltd., Bengaluru, India.
Birth Defects Res. 2018 Oct 2;110(16):1250-1262. doi: 10.1002/bdr2.1381. Epub 2018 Sep 19.
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.
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.
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.
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.
一种延胡索酸莫林酮（一种多巴胺 D 和 5-羟色胺拮抗剂）目前正在被开发为一种治疗 ADHD 患者冲动性攻击（IA）的新型药物。使用符合国际协调会议（ICH）S5（R2）标准的方案进行了盐酸莫林酮的口服良好实验室规范生殖毒理学研究（生育和早期胚胎[FEE]、产前/产后[PPN]、胚胎-胎儿发育[EFD]）。
在 FEE 研究中，0、5、15 或 30mg/kg/天的剂量给予雌性（交配前 2 周至着床）和雄性（交配前 4 周，共 57 天）大鼠，并评估生育参数。在 EFD 研究中，大鼠在妊娠第 6-17 天接受 0、5、20 或 40mg/kg/天的剂量；兔子在妊娠第 6-18 天接受 0、5、10 或 15mg/kg/天的剂量。在足月时评估卵巢/子宫和胎儿参数。在 PPN 研究中，F 代大鼠接受 0、5、20 或 40mg/kg/天（GD6-LD21）；在 F 代后代中评估行为和繁殖。
在所有研究中，亲代出现活动减少和体重增加减少。在 FEE 中，≥15mg/kg/天导致发情周期延长和交配延迟，但对生育力或胚胎发育没有影响。F 代胎儿无发育毒性。在 F 代幼仔中，在 40mg/kg/天观察到断奶前生长减少，但对断奶后生长、行为或繁殖没有影响。
在 69X 和 6X 临床暴露下，莫林酮在大鼠或兔子中没有发育毒性，证实了莫林酮的生殖安全性。发情周期的变化与莫林酮在啮齿动物中的种属特异性药理学作用有关，与人类风险无关。
