A Study to Determine the Bioavailability of a Fixed Dose Combination Product of Dutasteride (0.5mg) and Tamsulosin Hydrochloride (0.2mg) Relative to Co-administration of the Individual Components in Healthy Male Subjects of North East Asian and Non-Asian Ancestry.
Condition: Prostatic Hyperplasia
MeSH terms: Prostatic Hyperplasia; Hyperplasia
Study type: Interventional
Phase: Phase 1

Summary: 
      This study will be an open-label, randomized, single dose, two-period crossover study to
      determine the bioavailability of a fixed dose combination capsule formulation of dutasteride
      and tamsulosin hydrochloride (0.5mg/0.2mg) relative to co-administration of dutasteride 0.5mg
      capsules and tamsulosin hydrochloride 0.2mg tablets in healthy male subjects of North East
      Asian and non-Asian ancestry. Subjects will receive single oral doses of a combination
      capsule formulation of dutasteride 0.5 mg/ tamsulosin 0.2 mg in a fed or fasted state or
      concomitant dosing of dutasteride 0.5 mg and the Japan-sourced Harnal-D 0.2 mg in a fed or
      fasted state. Each dose of study medication will be separated by a 28-day washout period.
      Blood samples for pharmacokinetic analysis will be taken at regular intervals after dosing.
      Safety will be assessed by measurement of blood pressure, heart rate, safety laboratory data,
      and review of adverse events. The study will enrol 88 healthy male subjects to ensure that 80
      complete the study. At least twenty percent of the study population will be of Japanese
      ancestry, approximately 20% will be of Chinese ancestry and approximately 20% of Korean
      ancestry while the remainder of the population will be of non-Asian ancestry.
    

Detailed description: 
      Description:

      This study will be an open-label, randomized, single dose, two-period crossover study to
      determine the bioavailability of a fixed dose combination capsule formulation of dutasteride
      and tamsulosin hydrochloride (0.5mg/0.2mg) relative to co-administration of dutasteride 0.5mg
      capsules and tamsulosin hydrochloride 0.2mg tablets in healthy male subjects of North East
      Asian and non-Asian ancestry. Subjects will receive single oral doses of a combination
      capsule formulation of dutasteride 0.5 mg/ tamsulosin 0.2 mg in a fed or fasted state or
      concomitant dosing of dutasteride 0.5 mg and the Japan-sourced Harnal-D 0.2 mg in a fed or
      fasted state. Each dose of study medication will be separated by a 28-day washout period.
      Blood samples for pharmacokinetic analysis will be taken at regular intervals after dosing.
      Safety will be assessed by measurement of blood pressure, heart rate, safety laboratory data,
      and review of adverse events. The study will enrol 88 healthy male subjects to ensure that 80
      complete the study. At least twenty percent of the study population will be of Japanese
      ancestry, approximately 20% will be of Chinese ancestry and approximately 20% of Korean
      ancestry while the remainder of the population will be of non-Asian ancestry.

      Background:

      Dutasteride (AVODART ™) is an approved potent 5-alpha-reductase inhibitor indicated for the
      treatment of symptomatic benign prostatic hyperplasia (BPH) in men with an enlarged prostate
      to improve symptoms, reduce the risk of acute urinary retention and reduce the risk of the
      need for BPH-related surgery [AVODART Package Insert, 2009].

      In humans, dutasteride is well-tolerated in single doses up to 40mg/day, multiple doses up to
      40mg/day administered for 7 days, and 5mg/day administered for 24 weeks. In clinical studies,
      the overall incidence and type of adverse events (AEs) was similar across the dutasteride,
      placebo, and finasteride treatment groups.

      Tamsulosin (Harnal, Harnal D, Flomax) is an alpha-1-adrenoceptor blocking agent approved for
      the treatment of signs and symptoms of benign prostatic hyperplasia. Tamsulosin HCl is
      extensively metabolized, with less than 10% of the dose excreted in the urine unchanged
      [Harnal, 2009a; Harnal, 2009b; Flomax, 2009]. In human liver microsomes and human
      lymphoblastoid cells expressing CYP cDNAs in vitro, tamsulosin HCl is metabolized by both
      CYP3A4 and CYP2D6 [Matsushima, 1998].

      Clinical data exist to support that tamsulosin (an alpha-1-adrenoceptor antagonist), when
      used in combination with dutasteride (a 5-alpha reductase inhibitor), offers a more effective
      treatment for the symptoms of benign prostatic hyperplasia than either drug used alone [GSK
      study ARI40005, GlaxoSmithKline document number HM2002/00171/01]. In addition, data from a
      large, multi-centre National Institutes of Health-sponsored Medical Therapy of Prostatic
      Symptoms (MTOPS) study revealed greater benefits of combination alpha-1-adreoceptor
      antagonist and 5-alpha-reductase inhibitor therapy compared with either monotherapy in males
      with BPH [McConnell, 2002].

      Clinical drug interaction studies have shown no pharmacokinetic or pharmacodynamic
      interactions between dutasteride and tamsulosin. Dutasteride may be administered with or
      without food. Tamsulosin should be administered with food. While there is food effect PK data
      on dutasteride and tamsulosin when administered individually, an objective of this study is
      to evaluate the effect of food (high fat meal state versus fasted state) on the absorption of
      dutasteride and tamsulosin HCl when given in a combination capsule formulation relative to
      the co-administration of the two components, dutasteride and tamsulosin HCl. A previous
      study, ARI109882, [GlaxoSmithKline document number ZM2007/00022/00], also determined the
      bioequivalence and food effect of the combination capsule formulation relative to the
      co-administration of each component administered separately. In that study, the GSK
      combination capsule was found to be bioequivalent (under both fed and fasted conditions) to
      the marketed products administered separately. In the present study, the dose of tamsulosin
      HCl administered will be lower than in ARI109882 (0.2 mg versus 0.4mg administered in
      ARI109882). The dose of dutasteride is the same in both studies (0.5mg).
    

Intervention name(s): Dutasteride (0.5mg); Tamsulosin hydrochloride (0.2mg); fixed dose combination product of duatsteride (0.5mg) and tamsulosin hydrochloride (0.2mg)
Intervention type(s): Drug
Intervention description(s): In the first dosing session, twenty-two subjects of each cohort will receive the FDC capsule (dutasteride and tamsulosin hydrochloride (0.5mg/0.2mg) and the other 22 will receive commercial capsules of dutasteride 0.5mg and commercial tablets of tamsulosin hydrochloride 0.2mg co-administered. Following a wash-out period of at least 28 days, those subjects who received the FDC capsule in session 1, will be co-administered commercial capsules of dutasteride 0.5mg and commercial tablets of tamsulosin hydrochloride 0.2mg while those who were co-administered commercial capsules of dutasteride 0.5mg and commercial tablets of tamsulosin hydrochloride 0.2mg in session 1 will receive the FDC capsule in the second dosing session.
Intervention MeSH terms: Tamsulosin; Dutasteride
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: GI198745; Tamsulosin hydrochloride; Dutasteride; food effect; healthy male subjects; north-east Asian ancestry; Bioequivalence; cross-over design; Pilot bioequivalence