The potential reproductive toxicity of Elmiron (sodium pentosan polysulfate) in Sprague-Dawley rats was evaluated using the Reproductive Assessment by Continuous Breeding (RACB) protocol. Elmiron has been given orphan drug status in the United States for the compassionate treatment of interstitial cystitis. This study was designed to produce some publicly-accessible data on the potential of Elmiron to produce reproductive toxicity in rats. Dose levels for the continuous breeding phase for this study were set at 111, 333, and 1000 mg/kg based on the information obtained from a previous 90-day gavage study with Elmiron.
F0 female and male body weights were unchanged. Body weights of the F1 1000 mg/kg males and females were significantly decreased as early as Postnatal Day (PND) 4 and continued to be lower than the control group throughout the majority of Task 4. F0 and F1 male and female feed consumption values were unchanged.
Exposure to Elmiron by gavage (20 rats/sex/group) did not affect the reproductive performance of F0 rats (Task 2) or F1 rats (Task 4). No breeding, fertility, or necropsy endpoint related to reproduction was altered by Elmiron exposure. No differences were noted in the F0 or F1 epididymal sperm morphology, epididymal sperm density, sperm motion parameters, testicular spermatid head counts, percent normal sperm, or F1 estrous cyclicity.
Dose-related differences were noted in the hematology of the F0 animals and in hematology and clinical chemistry of the F1 animals. These changes, consistent with hypochromic anemia, were primarily observed in the 1000 mg/kg Task 2 males and Task 4 males and females. In Task 2, there was a 26% increase in platelets in the 1000 mg/kg males and an 8-17% increase in mean platelet volume (MPV) in all treated males. In Task 4, there was a 23% and 13% increase in platelets and MPV in the 1000 mg/kg males, respectively, and a 12% increase in MPV in the 1000 mg/kg females. These increases are generally associated with platelet activation which normally occurs after platelet stimulation by thrombin. Hyperproteinemia was noted in the Task 4 males, as evidenced by an increase of 15-26% in globulin in all treated males, and an increase of 7% in total protein and a decrease of 22% in A/G ratio in both the 333 and 1000 mg/kg males.
At necropsy, treatment-related increases were noted in absolute and/or relative kidney, liver, and spleen weights of the F0 and F1 animals. In the 333 and 1000 mg/kg F0 male absolute and relative liver, kidneys, and spleen weights, there was an increase of 12-53%, while the 111 mg/kg F0 male absolute kidneys and spleen weights were increased by 10-15%. The 1000 mg/kg F0 female absolute/relative liver, kidneys (absolute only), and spleen weights were increased by 7-32%. In the 111 mg/kg F1 male absolute and relative kidneys weight, there was a decrease of 13-16%, while in the 1000 mg/kg F1 male relative liver and spleen weights, there was an increase of 15-22%. The 1000 mg/kg F1 female relative kidneys and absolute and relative liver weights were increased by 7-22%.
No treatment-related gross pathology findings were noted in the F0 generation but in the F1 generation there was a treatment-related increase in renal pelvis dilatation in the males and females and an increase in uterine dilatation in the females. Treatment-related microscopic findings noted primarily in the 1000 mg/kg males and females, but also in the 111 mg/kg and 333 mg/kg males and females included hepatocytic cytoplasmic vacuolization, bile duct hyperplasia, renal tubule cytoplasmic vacuolization, and renal tubule degeneration and dilatation.
A no-observable-adverse-effect level (NOAEL) in this study was not reached because some organ weights, microscopic changes, and/or hematology values were slightly affected at 111 mg/kg in both males and/or females. A maximum tolerated dose (MTD) was reached in both generations based on increased organ weights and microscopic changes. No reproductive toxicity was noted in either generation at dose levels up to 1000 mg/kg/day.
REPRODUCTIVE TOXICANT:
Male - No.
Female - No.
NTIS # PB97-182604