Bioavailability of Two Combination Products of Dutasteride (0.5mg) and Tamsulosin Hydrochloride (0.2mg) in Asian Males.
Condition: Prostatic Hyperplasia
MeSH terms: Prostatic Hyperplasia; Hyperplasia
Study type: Interventional
Phase: Phase 1

Summary: 
      This study aims to determine the relative bioavailability of tamsulosin hydrochloride in a
      fixed dose combination capsule of dutasteride and tamsulosin hydrochloride (0.5 mg/0.2 mg)
      relative to co-administration of dutasteride 0.5 mg capsules and tamsulosin hydrochloride 0.2
      mg tablets or capsules. Two fixed dose combination capsules will be tested; one will contain
      tamsulosin hydrochloride pellets with a 15% enteric coating, and the other tamsulosin
      hydrochloride pellets with a 10% enteric coat. In addition, two formulations of tamsulosin
      hydrochloride will be tested in the co-administration with dutasteride 0.5 mg; a 0.2 mg oral
      disintegrating tablet and a 0.2 mg hard shell capsule. This will be an open-label,
      randomized, single dose, four-period crossover in healthy male subjects of North East Asian
      ancestry. Subjects will receive single oral doses in four treatment periods, each separated
      by a 5-10 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 and review of adverse events. The study will enrol approximately 30 healthy male
      subjects to ensure that 24 complete the study.
    

Detailed description: 
      This study is an open-label, randomized, single dose, four-period crossover study which aims
      to determine the relative bioavailability of tamsulosin hydrochloride in a fixed dose
      combination capsule of dutasteride and tamsulosin hydrochloride (0.5 mg/0.2 mg) relative to
      co-administration of dutasteride 0.5 mg capsules and tamsulosin hydrochloride 0.2 mg tablets
      or capsules. Two fixed dose combination capsules will be tested; one will contain tamsulosin
      hydrochloride pellets with a 15% enteric coating, and the other tamsulosin hydrochloride
      pellets with a 10% enteric coat. In addition, two formulations of tamsulosin hydrochloride
      will be tested in the co-administration with dutasteride 0.5 mg; a 0.2 mg oral disintegrating
      tablet and a 0.2 mg hard shell capsule. Subjects will receive single oral doses in four
      treatment periods, each separated by a 5-10 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 and review of adverse events. The study
      will enrol approximately 30 healthy male subjects to ensure that 24 complete the study.

      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 5 mg/day administered for 24 weeks. In single dose
      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, 2009; Harnal, 2011; Flomax, 2011]. 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. Food effect PK data exists for
      co-administration of dutasteride and tamsulosin given in a fixed dose combination (FDC)
      capsule formulation relative to the co-administration of the two components, dutasteride and
      tamsulosin HCl; GSK studies ARI109882, [GlaxoSmithKline document number ZM2007/00022/00], and
      ARI114694, [GlaxoSmithKline document number ZM2010/00028/00]. In the latter study, the dose
      of tamsulosin HCl administered was 0.2 mg versus 0.4mg administered in ARI109882. The dose of
      dutasteride was the same in both studies (0.5mg). In ARI109882, the GSK combination capsule
      was found to be bioequivalent (under both fed and fasted conditions) to the marketed products
      administered separately. ARI114694 demonstrated bioequivalence for dutasteride but not for
      tamsulosin when administered as an FDC product (of dutasteride 0.5 mg and tamsulosin 0.2 mg)
      relative to co-administration of separate commercial formulations of dutasteride (0.5 mg) and
      tamsulosin (0.2 mg) in the fed and fasted stage in different North East Asian ethnic groups.

      This study aims to investigate the bioequivalence of tamsulosin only by investigating two
      different FDC formulations with 10 % or 15% Enteric Coated Tamsulosin pellets (0.2 mg) and
      Dutasteride 0.5 mg relative to co-administration of a commercial formulation of dutasteride
      (0.5 mg) and two different commercial formulations of 0.2 mg tamsulosin,Harnal Capsule and
      Harnal-D Tablet. Specifically, the study aims to investigate the bioavailability of the
      following:

        -  FDC (with 10% enteric coated tamsulosin pellets) to a commercial formulation of
           dutasteride plus tamsulosin (Harnal-D Tablet)

        -  FDC (with 10% enteric coated tamsulosin pellets) to a commercial formulation of
           dutasteride plus tamsulosin (Harnal Capsule)

        -  FDC (with 15% enteric coated tamsulosin pellets) to a commercial formulation of
           dutasteride plus tamsulosin (Harnal-D Tablet) (also investigated in ARI114694)

        -  FDC (with 15% enteric coated tamsulosin pellets) to a commercial formulation of
           dutasteride plus tamsulosin (Harnal Capsule) Both Harnal-D tablets and Harnal capsules
           are included as comparators as bioequivalence of the 10 or 15 % FDC formulations to
           Harnal Capsules would provide a registration pathway for China, where Harnal Capsules
           are commercially available. As Harnal capsules are not available in Korea and Japan,
           bioequivalence to Harnal-D tablets would allow the FDC to be registered in China, Korea
           and Japan, where Harnal-D tablets are approved.
    

Intervention name(s): Dutasteride (0.5mg); FDC product of dutasteride (0.5mg) and tamsulosin HCl (0.2mg); Harnal D Tablets and Harnal Capsules (both comprising 0.2 mg tamsulosin HCl)
Intervention type(s): Drug; Drug; Drug
Intervention description(s): This study is an open-label, randomized, single dose, four-period cross-over study.; FDC (with 10% enteric coated tamsulosin pellets); (2): FDC (with 15% enteric coated tamsulosin pellets);; a commercial formulation of dutasteride plus tamsulosin HCl (Harnal-D Tablet); (4): a commercial formulation of dutasteride plus tamsulosin HCl(Harnal Capsule). Each dosing session will be separated by a wash-out period of 5 to 10 days
Intervention MeSH terms: Tamsulosin; Dutasteride
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Cross-over design; Pilot bioequivalence; North east Asian ancestry; GI198745; Tamsulosin hydrochloride; healthy male subjects; Bioequivalence; Dutasteride