SILODOSIN (Page 4 of 5)
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility
In a 2-year oral carcinogenicity study in rats administered doses up to 150 mg/kg/day [about 8 times the exposure at the MRHD based on AUC of silodosin], an increase in thyroid follicular cell tumor incidence was seen in male rats receiving doses of150 mg/kg/day. Silodosin induced stimulation of thyroid stimulating hormone (TSH) secretion in the male rat as a result of increased metabolism and decreased circulating levels of thyroxine (T4 ). These changes are believed to produce specific morphological and functional changes in the rat thyroid including hypertrophy, hyperplasia, and neoplasia. Silodosin did not alter TSH or T4 levels in clinical trials and no effects based on thyroid examinations were noted. The relevance to human risk of these thyroid tumors in rats is not known.
In a 2-year oral carcinogenicity study in mice administered doses up to 100 mg/kg/day in males (about 9 times the exposure at the MRHD based on AUC of silodosin) and 400 mg/kg/day in females (about 72 times the exposure at the MRHD based on AUC), there were no significant tumor findings in male mice. Female mice treated for 2 years with doses of 150 mg/kg/day (about 29 times the exposure at the MRHD based on AUC) or greater had statistically significant increases in the incidence of mammary gland adenoacanthomas and adenocarcinomas. The increased incidence of mammary gland neoplasms in female mice was considered secondary to silodosin-induced hyperprolactinemia measured in the treated mice. Elevated prolactin levels were not observed in clinical trials. The relevance to human risk of prolactin-mediated endocrine tumors in mice is not known. Rats and mice do not produce glucuronidated silodosin, which is present in human serum at approximately four times the level of circulating silodosin and which has similar pharmacological activity to silodosin.
Silodosin produced no evidence of mutagenic or genotoxic potential in the in vitro Ames assay, mouse lymphoma assay, unscheduled DNA synthesis assay and the in vivo mouse micronucleus assay. A weakly positive response was obtained in two in vitro Chinese Hamster Lung (CHL) tests for chromosomal aberration assays at high, cytotoxic concentrations.
Treatment of male rats with silodosin for 15 days resulted in decreased fertility at the high dose of 20 mg/kg/day (about 2 times the exposure at the MRHD based on AUC) which was reversible following a two-week recovery period. No effect was observed at 6 mg/kg/day. The clinical relevance of this finding is not known.
In a fertility study in female rats, the high dose of 20 mg/kg/day (about 1 to 4 times the exposure at the MRHD based on AUC) resulted in estrus cycle changes, but no effect on fertility. No effect on the estrus cycle was observed at 6 mg/kg/day.
In a male rat fertility study, sperm viability and count were significantly lower after administration of 600 mg/kg/day (about 65 times the exposure at the MRHD based on AUC) for one month. Histopathological examination of infertile males revealed changes in the testes and epididymides at 200 mg/kg/day (about 30 times the exposure at the MRHD based on AUC).
14 CLINICAL STUDIES
14.1 Benign Prostatic Hyperplasia
Two 12-week, randomized, double-blind, placebo-controlled, multicenter studies were conducted with 8 mg daily of silodosin. In these two studies, 923 patients [mean age 64.6 years; Caucasian (89.3%), Hispanic (4.9%), Black (3.9%), Asian (1.2%), Other (0.8%)] were randomized and 466 patients received silodosin 8 mg daily. The two studies were identical in design except for the inclusion of pharmacokinetic sampling in Study 1. The primary efficacy assessment was the International Prostate Symptom Score (IPSS) which evaluated irritative (frequency, urgency, and nocturia), and obstructive (hesitancy, incomplete emptying, intermittency, and weak stream) symptoms. Maximum urine flow rate (Qmax) was a secondary efficacy measure.
Mean changes from baseline to last assessment (Week 12) in total IPSS score were statistically significantly greater for groups treated with silodosin than those treated with placebo in both studies (Table 4 and Figures 2 and 3). Table 4 Mean Change (SD) from Baseline to Week 12 in International Prostate Symptom Score in Two Randomized, Controlled, Double-Blind Studies
| Study 1 | Study 2 | |||||
| Total Symptom Score | Silodosin 8 mg (n=233) | Placebo (n=228) | p-value | Silodosin 8 mg (n=233) | Placebo (n=228) | p-value |
| Baseline | 21.5 (5.38) | 21.4 (4.91) | 21.2 (4.88) | 21.2 (4.92) | ||
| Week 12 / LOCF Change from baseline | -6.5 (6.73) | -3.6 (5.85) | < 0.0001 | -6.3 (6.54) | -3.4 (5.83) | < 0.0001 |
| LOCF – Last observation carried forward for those not completing 12 weeks of treatment. | ||||||
Figure 2 Mean Change from Baseline in IPSS Total Score by Treatment Group and Visit in Study 1
B – Baseline determination taken Day 1 of the study before the initial dose. Subsequent values are observed cases except for LOCF values.
LOCF – Last observation carried forward for those not completing 12 weeks of treatment.
Figure 3 Mean Change from Baseline in IPSS Total Score by Treatment Group and Visit in Study 2
B – Baseline determination taken Day 1 of the study before the initial dose. Subsequent values are observed cases except for LOCF values.
LOCF – Last observation carried forward for those not completing 12 weeks of treatment.
Mean IPSS total score for silodosin once daily groups showed a decrease starting at the first scheduled observation and remained decreased through the 12 weeks of treatment in both studies. Silodosin produced statistically significant increases in maximum urinary flow rates from baseline to last assessment (Week 12) versus placebo in both studies (Table 5 and Figures 4 and 5). Mean peak flow rate increased starting at the first scheduled observation at Day 1 and remained greater than the baseline flow rate through the 12 weeks of treatment for both studies.
Table 5 Mean Change (SD) from Baseline in Maximum Urinary Flow Rate (mL/sec) in Two Randomized, Controlled, Double-Blind Studies
| Study 1 | Study 2 | |||||
| Mean Maximum Flow rate (mL/sec) | Silodosin 8 mg (n = 233) | Placebo (n = 228) | p-value | Silodosin 8 mg (n = 233) | Placebo (n = 229) | p-value |
| Baseline | 9.0 (2.60) | 9.0 (2.85) | 8.4 (2.48) | 8.7 (2.67) | ||
| Week 12 / LOCF Change from Baseline | 2.2 (4.31) | 1.2 (3.81) | 0.0060 | 2.9 (4.53) | 1.9 (4.82) | 0.0431 |
| LOCF – Last observation carried forward for those not completing 12 weeks of treatment. | ||||||
Figure 4 Mean Change from Baseline in Qmax (mL/sec) by Treatment Group and Visit in Study 1
B – Baseline determination taken Day 1 of the study before the initial dose. Subsequent values are observed cases except for LOCF values.
LOCF – Last observation carried forward for those not completing 12 weeks of treatment.
Note – The first Qmax assessments at Day 1 were taken 2 to 6 hours after patients received the first dose of double-blind medication.
Note – Measurements at each visit were scheduled 2 to 6 hours after dosing (approximate peak plasma silodosin concentration). Figure 5 Mean Change from Baseline in Qmax (mL/sec) by Treatment Group and Visit in Study 2
B – Baseline determination taken Day 1 of the study before the initial dose. Subsequent values are observed cases except for LOCF values.
LOCF – Last observation carried forward for those not completing 12 weeks of treatment.
Note – The first Qmax assessments at Day 1 were taken 2 to 6 hours after patients received the first dose of double-blind medication.
Note – Measurements at each visit were scheduled 2 to 6 hours after dosing (approximate peak plasma silodosin concentration).
All MedLibrary.org resources are included in as near-original form as possible, meaning that the information from the original provider has been rendered here with only typographical or stylistic modifications and not with any substantive alterations of content, meaning or intent.