Evaluation of apomorphine HCl effects on reproductive endpoints: Studies in male rats and dogs

Apomorphine HCl is currently in phase III clinical trials for the treatment of erectile dysfunction. The potential for reproductive toxicity in males was assessed based on a 13-week rat study-a fertility study in male rats-an d a 6-month study in dogs. The subcutaneous (sc) route was selected to simu late the sublingual route in humans. Dosages of apomorphine were 0.0 (vehic le), 0.8, 2, and 8 mg/kg/day in the 13-week study in rats (20/group), with 8 mg/kg/day used for only 9 weeks. In the fertility study, 24 males/group w ere cohabited with females, and doses were 0.0, 0.2, 0.8, and 2 mg/kg/day. Males were treated for 4 weeks prior to cohabitation and for 5 weeks throug hout cohabitation. Organ weights, including testis and left epididymis, spe rm count and morphology in the epididymis, and sperm motility in the vas de ferens were evaluated. Male fertility index, and in females, the numbers of fetuses, implantation sites, and corpora lutea were counted. Male dogs (fi ve/group) were dosed with 0.04, 0.1, or 0.4 mg/kg/day for 6 months. Epididy mal and prostate weight, and testicular and epididymal histology were evalu ated. Daily morbidity/mortality, weekly clinical observations, body weight, and food consumption were evaluated in all studies. No adverse effect was observed in any of the reproductive parameters in the studies. The NOEL for reproductive toxicity was congruent to 0.4 mg/kg/day in dogs and greater t han or equal to 2 mg/kg/day in rats. These doses in rats and dogs correlate d with plasma levels of approximate to 240 and 130 ng/mL, and AUCs of 200 a nd 100 ng.h/mL, respectively. These levels suggest a safety margin for the evaluated male reproductive endpoints of at least 104 times based on the Cm ax, and 44 times based on AUC of the clinical dose.