Bioavailability of Two Combination Products of Dutasteride (0.5mg) and Tamsulosin Hydrochloride (0.2mg) in Asian Males. — ARI115707  

Prostatic Hyperplasia Clinical Trial

Official title: An Open-label, Randomized, Single Dose, Four-Period Crossover Study to Compare the Bioavailability of Fixed Dose Combination Capsule Formulations of Dutasteride and Tamsulosin Hydrochloride (0.5 mg/0.2 mg) With 10% and 15% of Enteric Coated Pellets With Harnal-D Tablets and Harnal Capsules Co-administered With Dutasteride (0.5 mg) Soft Gel Capsules in Healthy Male Subjects of North East Asian Ancestry

Status Completed

Clinical Trial 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.

Clinical Trial 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. ;

Related Conditions & MeSH terms

• Hyperplasia
• Prostatic Hyperplasia

• NCT number: NCT01471678
• Study type: Interventional
• Source: GlaxoSmithKline
• Status: Completed
• Phase: Phase 1
• Start date: June 30, 2011
• Completion date: September 7, 2011