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
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
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.
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.
Inclusion Criteria:

 A subject will be eligible for inclusion in this study only if all of the following
 criteria apply:

 -  Healthy as determined by a responsible and experienced physician, based on a medical
 evaluation including medical history, physical examination, laboratory tests and
 cardiac monitoring. A subject with a clinical abnormality or laboratory parameters
 outside the reference range for the population being studied may be included only if
 the Investigator and the GSK Medical Monitor agree that the finding is unlikely to
 introduce additional risk factors and will not interfere with the study procedures.

 -  Males between 20 and 45 years of age inclusive, at the time of signing the informed
 consent form.

 -  Japanese ancestry defined as being born in Japan, having four ethnic Japanese
 grandparents, holding a Japanese passport or identity papers and being able to speak
 Japanese, or Korean ancestry defined as being born in Korea, having four ethnic Korean
 grandparents, holding a Korean passport or identity papers and being able to speak
 Korean, or Chinese ancestry defined as being born in China, Hong Kong, Singapore or
 Taiwan, having four ethnic Chinese grandparents, holding a Chinese passport or
 identity papers and being able to speak Chinese.

 Japanese, Korean and Chinese subjects should also have lived outside their respective
 countries for less than 10 years.

 -  Male subjects with female partners of child-bearing potential must agree to use one of
 the protocol-approved contraception methods. This criterion must be followed from the
 time of the first dose of study medication until 45 days after the last dose.

 -  BMI within the range 18 -28 kg/m2 (inclusive).

 -  Capable of giving written informed consent, which includes compliance with the
 requirements and restrictions listed in the consent form.

 -  Single QTc < 450 msec; or QTc < 480 msec in subjects with Bundle Branch Block.

 -  AST, ALT, alkaline phosphatase and bilirubin less than or equal to 1.5xULN (isolated
 bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin
 <35%).

 Exclusion Criteria:

 A subject will not be eligible for inclusion in this study if any of the following criteria
 apply:

 Medical Condition Exclusions:

 -  Poor metabolizer for CYP2D6 substrates as determined by genotyping of selected CYP2D6
 variants at screening.

 -  History of postural hypotension, dizziness, poor hydration, vertigo, vaso-vagal
 reactions or any other signs and symptoms of orthostasis, which in the opinion of the
 investigator could be exacerbated by tamsulosin and result in putting the subject at
 risk of injury.

 -  Current or chronic history of liver disease, or known hepatic or biliary abnormalities
 (with the exception of Gilbert's syndrome or asymptomatic gallstones.

 -  A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody
 result within 3 months of screening.

 -  A positive test for HIV antibody.

 Medical Exclusions:

 -  Subjects must be able and willing to refrain from use of prescription or
 non-prescription drugs, including vitamins, herbal and dietary supplements (including
 St John's Wort, Black Khosh, Dong Quai, Milk Thistle, licorice) within 7 days (or 14
 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer)
 prior to the first dose of study medication, unless in the opinion of the Investigator
 and GSK Medical Monitor the medication will not interfere with the study procedures or
 compromise subject safety.

 -  History of sensitivity to tamsulosin HCl or dutasteride, components thereof or drugs
 of this class or a history of drug or other allergy that, in the opinion of the
 investigator or GSK Medical Monitor, contraindicates their participation.

 -  A history of sensitivity to heparin or heparin-induced thrombocytopenia

 -  The subject has participated in a clinical trial and has received an investigational
 product within the following time period prior to the first dosing day in the current
 study: 30 days, 5 half-lives or twice the duration of the biological effect of the
 investigational product (whichever is longer).

 -  Exposure to more than four new chemical entities within 12 months prior to the first
 dosing day.

 Lifestyle Exclusions:

 -  A positive pre-study drug/alcohol screen. A minimum list of drugs that will be
 screened for include amphetamines, barbiturates, cocaine, opiates, cannabinoids and
 benzodiazepines.

 -  History of regular alcohol consumption within 6 months of the screening visit defined
 by the following Australian guidelines:

 Males: An average weekly intake greater than 21 units or an average daily intake greater
 than 3 units. One unit is equivalent to 270 mL of full strength beer, 470 mL of light beer,
 30 mL of spirits and 100 mL of wine.

 Subjects must be able and willing to abstain from beverages and foods containing alcohol 24
 hours prior to and during the dosing day.

 -  Consumption of red wine, grapefruit juice, grapefruit and related hybrids from 7 days
 prior to the first dose of study medication.

 -  Where participation in the study would result in donation of blood or blood products
 in excess of 500 mL within a 56 day period.