Population Pharmacokinetic Analysis on Silodosin in Patients with Lower Urinary Tract Symptoms Associated with Benign Prostatic Hyperplasia

Silodosin is a potent selective α 1A-adrenoceptor antagonist used for the treatment of lower urinary tract symptoms associated with benign prostatic hyperplasia (BPH).In the present study,we conducted a population pharmacokinetic (PPK) analysis using silodosin plasma concentration data obtained in a Phase III long-term study in order to evaluate the pharmacokinetic characteristics of silodosin in patients with BPH.In this study,we analyzed 1,553 samples taken at the steady state following repetitive oral administration to 258 patients based on a nonlinear mixed effects model according to a onecompartment model which was parameterized in terms of oral clearance (CL/F) and apparent volume of distribution (V/F).In the PPK analysis,the effects of age,serum creatinine,alanine aminotransferase (ALT),C-reactive protein (CRP),and concomitant substrates or inhibitors of CYP3A4 on the pharmacokinetics of silodosin were evaluated.The results suggested that age,ALT and CRP affected both CL/F and V/F of silodosin,and that serum creatinine affected CL/F.Both CL/F and V/F decreased with an increase in these covariates.On the other hand,the concomitant substrates or inhibitors of CYP3A4 were not significant covariates for CL/F.Among these factors,ALT had the most significant effect on plasma silodosin concentration.For example,after repetitive oral administration,the trough concentration for patients with an ALT value of 82.6 IU/L was 2.45 times higher than that for patients with an ALT value of 22.6 IU/L.These results indicate that liver function and CRP affect the pharmacokinetics of silodosin,and the effect of liver function is the most significant.