5 hours (range 1.03.0), AUC 433±286 ng • h/ml.
Distribution
Silodosin has a volume of distribution of 0.81 l/kg and is 96.6 % bound to plasma proteins. It does not distribute into blood cells.
Protein binding of silodosin glucuronide is 91 %.
Biotransformation
Silodosin undergoes extensive metabolism through glucuronidation (UGT2B7), alcohol and aldehyde dehydrogenase and oxidative pathways, mainly CYP3A4. The main metabolite in plasma, the glucuronide conjugate of silodosin (KMD3213G), that has been shown to be active in vitro, has an extended half-life (approximately 24 hours) and reaches plasma concentrations approximately four times higher than those of silodosin. In vitro data indicate that silodosin does not have the potential to inhibit or induce cytochrome P450 enzyme systems.
Elimination
Following oral administration of 14C-labelled silodosin, the recovery of radioactivity after 7 days was approximately 33.5 % in urine and 54.9 % in faeces. Body clearance of silodosin was approximately 0.28 l/h/kg. Silodosin is excreted mainly as metabolites, very low amounts of unchanged drug are recovered in urine. The terminal half-life of parent drug and its glucuronide is approximately 11 hours and 18 hours, respectively.
Special populations
Geriatric
Exposure to silodosin and its main metabolites does not change significantly with age, even in subjects of age over 75 years
Paediatric
Silodosin has not been eva luated in patients less than 18 years of age.
Hepatic impairment
In a single-dose study, the pharmacokinetics of silodosin was not altered in nine patients with moderate hepatic impairment (Child-Pugh scores 7 to 9), compared to nine healthy subjects. Results from this study should be interpreted with caution, since enrolled patients had normal biochemistry values, indicating normal metabolic function, and they were classified as having moderate liver impairment based on ascites and hepatic encephalopathy.
The pharmacokinetics of silodosin in patients with severe hepatic impairment has not been studied.
Renal impairment
In a single-dose study, exposure to silodosin (unbound) in subjects with mild (n=8) and moderate renal impairment (n=8) resulted, on average, in an increase of Cmax (1.6fold ) and AUC (1.7fold ) relative to subjects with normal renal function (n=8). In subjects with severe renal impairment (n=5) increase of exposure was 2.2fold for Cmax and 3.7fold for AUC. Exposure to the main metabolites, silodosin glucuronide and KMD3293, was also increased.
Plasma level monitoring in a Phase III clinical study showed that levels of total silodosin after 4 weeks of treatment did not change in patients with mild impairment (n=70), compared to patients with normal renal function (n=155), while the levels were doubled on average in patients with moderate impairment (n=7).
A review of safety data of patients enrolled in all clinical studies does not indicate that mild renal impairment (n=487) poses an additional safety risk during silodosin therapy (such as an increase in dizziness or orthostatic hypotension) as compared to patients with normal renal function (n=955). Accordingly, no dose adjustment is required in patients with mild renal impairment. Since only limited experience exists in patients with moderate renal impairment (n=35), a lower starting dose of 4 mg is recommended. In patients with severe renal impairment administration of Urorec is not recommended.
5.3 Preclini |
