Toxicological Sciences, Vol 51, 273-279, Copyright © 1999 by Society of Toxicology
AF Youssef, FL Fort, B Ronsen, R Schroeder, K Williams and C Auletta
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--and a 6-month study in dogs. The subcutaneous (s.c.) route was
selected to simulate the sublingual route in humans. Dosages of apomorphine
were 0.0 (vehicle), 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 were 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 throughout cohabitation. Organ weights, including testis and
left epididymis, sperm count and morphology in the epididymis, and sperm
motility in the vas deferens were evaluated. Male fertility index, and in
females, the numbers of fetuses, implantation sites, and corpora lutea were
counted. Male dogs (five/group) were dosed with 0.04, 0.1, or 0.4 mg/kg/day
for 6 months. Epididymal and prostate weight, and testicular and epididymal
histology were evaluated. 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
approximately equal to 0.4 mg/kg/day in dogs and > or = 2 mg/kg/day in
rats. These doses in rats and dogs correlated with plasma levels of
approximately 240 and 130 ng/mL, and AUCs of 200 and 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 Cmax, and 44
times based on AUC of the clinical dose.
ARTICLES
Evaluation of apomorphine HCl effects on reproductive endpoints: studies in male rats and dogs
TAP Holdings, Inc., Deerfield, Illinois 60015, USA. ashraf.youssef@tappharma.com
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