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.
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.
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.
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).
Inclusion Criteria:

 -  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 who are either pregnant or suspected of being
 pregnant must agree to the use of a condom during sexual activity. This criterion must
 be followed from the time of the first dose of study medication until 28 days after
 the last dose of study medication.

 -  BMI : For Caucasians: BMI within the range 18 -30 kg/m2 (inclusive); weight range
 55-95 kg (inclusive) For East Asians: BMI within the range 18 -28 kg/m2 (inclusive)
 and height 1.55m-1.85m (inclusive).

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

 -  Single QTcB < 450 msec.

 -  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:

 Medical Conditions 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.

 -  Subject is mentally or legally incapacitated.

 Medication Exclusions:

 -  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 hydrochloride or durasteride, 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.

 -  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, jufen
 grapes 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.

 -  Unwillingness or inability to follow the procedures outlined in the protocol.