Prostatic Hyperplasia Clinical Trial
Official title:
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
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).
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