Bioavailability of Two Combination Products of Dutasteride (0.5mg) and Tamsulosin Hydrochloride (0.2mg) in Asian Males.
Bioavailability of Two Combination Products of Dutasteride (0.5mg) and Tamsulosin Hydrochloride (0.2mg) in Asian Males.
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.
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.
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 of child-bearing potential must agree to use one of
 the protocol-approved contraception methods .This 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 QTcB < 450 msec

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

 Exclusion Criteria:

 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.

 -  Subject is mentally or legally incapacitated.

 Medical 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.

 -  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.

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