Safety and Pharmacokinetic Studies of Silodosin, a New .ALPHA.1A-Adrenoceptor Selective Antagonist, in Healthy Chinese Male Subjects

Abstract

Benign prostatic hyperplasia (BPH) is a common clinical disorder in elderly males. It causes a variety of urological symptoms, including a poor stream of urine flow, dribbling and nocturia. Adrenergic a-receptors are the molecular target for the clinical treatment of arterial hypertension and benign prostatic hyperplasia. Adrenergic a 1 -receptor (a 1 -AR) blockers are widely used as first-line drugs in treating lower urinary tract symptoms resulting from BPH 1,2) because they are able to improve rapidly subjective symptoms by improving the functional obstruction.Silodosin (KMD-3213) is a new and highly selective a 1A -AR antagonist. In a study with Chinese hamster ovary cells expressing three human a 1 -AR subtypes, the selectivity of silodosin to the a 1A -AR subtype was 38 times higher than that of tamsulosin hydrochloride, 3) indicating a specificity to the lower urinary tract (LUT) where a 1A -AR is the predominant subtype. 4,5) In comparative studies with rat and dog models, silodosin produced more favorable uroselectivity as compared to tamsulosin or prazosin.6,7) Silodosin improves not only urinary dysfunction but also irritative symptoms associated with BPH. 8,9) Silodosin was approved in Japan for treating BPH (4 mg, bid) in January 2006, and was approved by the Food and Drug Administration (FDA, U.S.A.) for the same indication (8 mg, once a day (qd)) in October 2008. Currently, silodosin is under submission for registration with the China State Food and Drug Administration (SFDA) for treating BPH so clinical trials must be performed in the national clinical trial bases. The objectives of the present study were to assess the safety and pharmacokinetics of silodosin in Chinese subjects after oral administration. MATERIALS AND METHODSThe study was approved by the Research Ethics Committee of Peking University First Hospital (Beijing, China) and the State Food and Drug Administration of China (2004L00051). It was conducted in accordance with Good Clinical Practices for Trials of Medicinal Products as well as the Declaration of Helsinki and its amendments. All subjects provided written informed consent before participation in the study.Volunteers Eighty-two healthy male Chinese volunteers (aged 20-35 years old; body mass index, 19.0-27.0 kg/m 2 ) were included in this study. All subjects met the following criteria: nonsmokers with no clinical abnormalities based on clinical examinations and laboratory analyses. Subjects were excluded from the study for any of the following reasons: known hypersensitivity to any medications; conditions that might affect drug absorption, metabolism or excretion; untreated mental illness, current drug addiction, abuse or alcoholism; habitual daily coffee drinker; blood donation in the past 90 d; confirmed diagnosis of chronic liver disease (e.g., chronic hepatitis B, autoimmune disease); positive symptoms for human immunodeficiency virus; history of clinically significant cardiovascular, pulmonary, endocrine, neurological, metabolic or psychiatric disease; ingestion of any dr...

Vertigo/dizziness as a Drugs' adverse reaction

“…Safety studies of silodosin, a new α1A-adrenoceptor selective antagonist, in healthy Chinese male subjects showed that mild adverse events, including dizziness, postural hypotension, and headache, were observed. [56] Pantoprazole (40 mg once daily) appears to be well tolerated during short term oral administration, with diarrhea (1.5%), headache (1.3%), dizziness (0.7%), pruritus (0.5%), and skin rash (0.4%) representing the most frequent adverse events. [57] Acute aripiprazole poisonings most commonly result in vertigo or dizziness, sedation, sinus tachycardia, nausea / vomiting, or dystonic reactions.…”

Determination of silodosin and its active glucuronide metabolite KMD‐3213G in human plasma by LC–MS/MS for a bioequivalence study

“…The literature reveals very few methods for the determination of SLD in biological samples or pharmaceutical formulations (Nair, Kumar, Sharma, & Karia, ; Shaik, Saladi, & Sait, ; Vishnuvardhan et al, ; Wang, Xiang, Cui, Zhao, & Zhou, ; Zhao et al, ; Zhou et al, ). A liquid chromatography–tandem mass spectrometry (LC–MS/MS) method has been reported for the estimation of SLD in human plasma with a sensitivity of 0.5 ng/mL (Zhao et al, ).…”

Novel LC–MS/MS Method for the Quantification of Silodosin and its Metabolites in Human Plasma

“…Such increased selectivity for α 1A -AR is envisaged to provide additional relief from LUTS in patients with BPH without increasing the rate of serious adverse cardiovascular events [5]. In this editorial, we evaluate the capabilities and scope of the existing bioanalytical methods and propose a novel fit-for-purpose liquid chromatography-tandem mass spectroscopy (LC-MS/MS) method in human plasma that can meet the current requirements for the analysis of silodosin and its metabolites.Bioanalytical platforms for silodosin: past, present & future Since its approval in 2008, there have been very few bioanalytical methods developed for the quantitation of silodosin [6][7][8]. LC-MS/MS so far has been the preferred technique for analysis; however, a complete account of bioanalytical method development incorporating sample extraction, chromatographic separation and mass spectrometric detection is currently limited.…”

“…Bioanalytical platforms for silodosin: past, present & future Since its approval in 2008, there have been very few bioanalytical methods developed for the quantitation of silodosin [6][7][8]. LC-MS/MS so far has been the preferred technique for analysis; however, a complete account of bioanalytical method development incorporating sample extraction, chromatographic separation and mass spectrometric detection is currently limited.…”

“…Although the method developed here is sensitive and rapid enough to quantify silodosin in human plasma, it does not allow the analysis of KMD-3213G. The other two methods have essentially used the same approach to study the safety and pharmacokinetics of silodosin [7] and the effect of genetic polymorphisms on silodosin pharmacokinetics in healthy Chinese subjects [8].…”