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

Prostatic Hyperplasia Clinical Trial

Official title: An Open-label, Randomized, Single Dose, Multi-stage, Cross-over Study to Determine the Relative Bioavailability of Fixed Dose Combination Products Containing a 3-oblong Dutasteride Soft Gel Capsule and Tamsulosin (0.5 mg Dutasteride /0.2 mg Tamsulosin HCl) Pellets Having a Range of Tamsulosin Release Rates Produced by Different Mixtures of Enteric Coated and Uncoated Pellets Relative to Harnal-D Tablets, in Healthy Male Subjects of North East Asian Ancestry.

Status Completed

Clinical Trial 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.

Clinical Trial 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. ;

Related Conditions & MeSH terms

• Hyperplasia
• Prostatic Hyperplasia

• NCT number: NCT01495026
• Study type: Interventional
• Source: GlaxoSmithKline
• Status: Completed
• Phase: Phase 1
• Start date: November 6, 2011
• Completion date: April 3, 2012