A Study Assessing a Range of Formulations of the Fixed Dose Combination Product Containing Dutasteride (0.5mg) and Tamsulosin Hydrochloride (0.2mg) to Find a Formulation Which is Bioequivalent to Harnal-D Tablets (Tamsulosin Hydrochloride, 0.2mg) in Healthy Male Subjects From North East Asia
Condition: Prostatic Hyperplasia
MeSH terms: Prostatic Hyperplasia; Hyperplasia
Study type: Interventional
Phase: Phase 1

Summary: 
      This study is an open-label, randomized, single dose, multi-stage, cross-over study in
      healthy male subjects of North East Asian ancestry. The aims are to:

        -  evaluate the pharmacokinetic parameters of several formulations of a fixed dose
           combination (FDC) 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 in the fasted state in order to define a formulation which
           is bioequivalent to a 0.2 mg orally disintegrating tamsulosin tablet, (Harnal-D Tablets)

        -  determine the effect of food on the relative bioavailability of tamsulosin in the FDC
           product which is assessed to be bioequivalent to Harnal-D Tablets in the fasted state

        -  assess the effect of water on the relative bioavailability of tamsulosin in Harnal-D
           Tablets in the fasted state

        -  assess the safety and tolerability of dosing with the different FDC capsule formulations
           Subjects will receive single oral doses in at least one treatment period; treatment
           periods will be 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. Each
           stage of the study will enrol 18 subjects to ensure 16 complete. Subjects may consent to
           participate in more than one stage.
    

Detailed description: 
      This study is an open-label, randomized, single dose, multi-stage, cross-over study in
      healthy male subjects of North East Asian ancestry. The aims are to:

        -  evaluate the pharmacokinetic parameters of several formulations of a fixed dose
           combination (FDC) 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 in the fasted state in order to define a formulation which
           is bioequivalent to a 0.2 mg orally disintegrating tamsulosin tablet, (Harnal-D Tablets)

        -  determine the effect of food on the relative bioavailability of tamsulosin in the FDC
           product which is assessed to be bioequivalent to Harnal-D Tablets in the fasted state

        -  assess the effect of water on the relative bioavailability of tamsulosin in Harnal-D
           Tablets in the fasted state

        -  assess the safety and tolerability of dosing with the different FDC capsule formulations
           Subjects will receive single oral doses in at least one treatment period; treatment
           periods will be 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. Each
           stage of the study will enrol 18 subjects to ensure 16 complete. Subjects may consent to
           participate in more than one stage.

      BACKGROUND:

      Dutasteride:

      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:

      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].

      Dutasteride and Tamsulosin:

      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.

      A subsequent GSK study, ARI115707, therefore investigated the relative bioavailability of
      tamsulosin (0.2mg tamsulosin HCl) only in the FDC product. Two different enteric-coated
      formulations of tamsulosin were administered with a 3-oblong dutasteride soft gel (0.5 mg) as
      a FDC capsule relative to co-administration of Harnal Capsules or Harnal-D Tablets with
      unbranded AVODART (0.5mg dutasteride). The two FDC formulations consisted of: 10% (weight
      gain) enteric coated tamsulosin pellets with a 3-oblong dutasteride soft gel and 15% (weight
      gain) enteric coated tamsulosin pellets with a 3-oblong dutasteride soft gel. Specifically,
      the study aimed to investigate the relative 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).

      ARI115707 results showed that the GSK combination capsule with 10% enteric coated tamsulosin
      pellets was bioequivalent to the Harnal Capsule. None of the two GSK formulations was found
      to be bioequivalent to the Harnal-D Tablet.

      In this study ARI115708, the relative bioavailability of tamsulosin (0.2mg tamsulosin HCl) is
      further investigated in several different formulations administered with a 3-oblong
      dutasteride soft gel as a FDC capsule relative to co-administration of Harnal-D Tablets (0.2
      mg) with unbranded AVODART (dutasteride, 0.5mg). All formulations will be administered in the
      fasted state except in the last stage where the effect of food on the FDC will be assessed as
      well as the effect of water on the administration of Harnal-D Tablets. As Harnal Capsules are
      not available in Korea or Japan, bioequivalence to Harnal-D Tablets would allow the FDC to be
      registered in China, Korea, Taiwan and Japan, where Harnal-D Tablets are approved. Therefore,
      in ARI115708, only Harnal-D Tablets are used as the comparator.
    

Intervention name(s): Dutasteride (0.5mg, fasted state); Dutasteride (0.5mg, fed state); Fixed dose combination capsule containing dutasteride 0.5mg and tamsulosin 0.2mg (fasted state); Fixed dose combination capsule containing dutasteride 0.5mg and tamsulosin 0.2mg (fasted state); Fixed dose combination capsule containing dutasteride 0.5mg and tamsulosin 0.2mg (fasted state); Fixed dose combination capsule containing dutasteride 0.5mg and tamsulosin 0.2mg (fed state); Harnal-D Tablets with water (fasted state); Harnal-D Tablets with water (fed state); Harnal-D tablets without water (fasted state)
Intervention type(s): Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug
Intervention description(s): Open-label, randomized, single dose, multi-stage, cross-over study; Commercial formulation of Dutasteride 0.5mg; FDC with 85%, 65% and 0% of the dose as enteric-coated pellets and with X and/or Y% of the dose as enteric-coated pellets (X and Y to be determined from PK results from Stage 1); FDC containing faster-release enteric-coated pellets; FDC bioequivalent to Harnal-D tablets; FDC bioequivalent to Harnal-D tablets; Commercial formulation of Harnal-D Tablets; Commercial formulation of Harnal-D Tablets; Commercial formulation of Harnal-D Tablets
Intervention MeSH terms: Tamsulosin; Dutasteride
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Healthy male subjects; North-East Asian ancestry; Bioequivalence; Food effect; Tamsulosin hydrochloride; Cross-over design; Pilot bioequivalence; Dutasteride (GI198745)