Japanese, Korean and Chinese subjects had also lived outside their respective countries for less than 10 years.

Transcription

1 The study listed may include approved and non-approved uses, formulations or treatment regimens. The results reported in any single study may not reflect the overall results obtained on studies of a product. Before prescribing any product mentioned in this Register, healthcare professionals should consult prescribing information for the product approved in their country. Study No: ARI 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 (0.5 mg/0.2 mg) relative to coadministration of dutasteride 0.5 mg capsules and tamsulosin hydrochloride 0.2 mg tablets in healthy male subjects of north east Asian and non-asian ancestry Rationale: The study was designed to assess the bioavailability of a fixed-dose combination (FDC) formulation of dutasteride 0.5 mg and tamsulosin hydrochloride (HCl) 0.2 mg, which is being developed for the treatment of symptomatic benign prostatic hyperplasia in patients prescribed a combination therapy of both drugs in Japan and other East-Asian countries, relative to coadministration of separate commercial formulations of dutasteride 0.5 mg and tamsulosin HCl 0.2 mg in healthy Asian and non-asian subjects. Phase: I Study Period: The study was initiated on 10 September 2010 and completed on 21 December Study Design: Open-label, randomized, single-dose, two-period crossover Centres: All subjects were enrolled and treated at 1 study centre in Australia. Indication: None Treatment: Subjects received concomitant single oral doses of tamsulosin HCl 0.2 mg and dutasteride 0.5 mg and a single oral dose of the FDC capsule (dutasteride 0.5 mg/tamsulosin HCl 0.2 mg), in a random sequence, either following a high-fat breakfast (, Regimens A and B, respectively) or in the fasted state (, Regimens C and D, respectively). Objectives: The primary objective was to investigate the bioavailability of a combination capsule formulation of dutasteride 0.5 mg/ tamsulosin hydrochloride (HCl) 0.2 mg relative to concomitant dosing of dutasteride 0.5 mg capsules and the Japan-sourced Harnal-D tamsulosin 0.2 mg tablets in the fed and fasted states Statistical Methods: The PK Parameter population comprised all subjects who provided data for one or more PK parameters. Dutasteride and tamsulosin PK parameters were derived from serum concentration-time data by noncompartmental methods. After loge transformation, AUC(0-t), AUC(0-inf) (for tamsulosin only) and Cmax in each dosing state (fed and fasted) were separately analyzed using a mixed effects model with fixed effect terms for period, ethnicity, treatment, and treatment by ethnicity interaction. Subjects were treated as a random effect in the model. Point estimates and their associated 90% confidence intervals (CIs) were constructed for the differences B A, D C, A C and B D and then backtransformed to provide point estimates and 90% CIs for the ratios B:A, D:C, A:C and B:D. Results for the same treatment comparisons were constructed for each ethnic group. Tmax in each dosing state (fed and fasted) was separately analyzed using the nonparametric Wilcoxon Matched Pairs method to compute point estimates and associated 90% CIs for the median differences B A and D C. The nonparametric Mann-Whitney method was used to compute point estimates and associated 90% CIs for the median differences A C and B D. The safety population included all subjects who received at least 1 dose of study medication. Safety data were listed and summarized; no formal statistical analyses of the safety data were performed. Study Population: Healthy male subjects who were years of age, inclusive, with a body mass index (BMI) of kg/m2 (Caucasians) or kg/m2 (East-Asians) were eligible to participate in the study. For Asian subjects, ethnicity was defined as follows: Japanese ancestry: subject was born in Japan, had four ethnic Japanese grandparents, held a Japanese passport or identity papers, and was able to speak Japanese, Korean ancestry: subject was born in Korea, had four ethnic Korean grandparents, held a Korean passport or identity papers, and was able to speak Korean, 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 had also lived outside their respective countries for less than 10 years. Of the 86 enrolled subjects, 22 (26%) subjects were of Japanese ancestry (10 in, 12 in ), 9 (10%) subjects were of Chinese ancestry (4 in, 5 in ), and 13 (15%) subjects were of Korean ancestry (6 in, 7 in ), according to the above definition. The remaining 42 (49%) subjects (22 subjects in, 1

2 20 subjects in ), were classified as non-asian. Number of Subjects: Planned N Dosed N Completed n (%) 40 (95) 43 (98) Total Number Subjects Withdrawn N (%) 2 (5) 1 (2) Withdrawn due to Adverse Events n (%) 0 0 Withdrawn due to Lack of Efficacy n (%) 0 0 Withdrawn for Other Reasons n (%) 2 (5) 1 (2) Demographics N (ITT) Females: Males 0: 42 0: 44 Mean Age in Years (sd) 27 (6) 28 (5) Mean Weight in Kg (sd) 73.4 (8.6) 71.3 (9.9) White n (%) 20 (48) 16 (36) Pharmacokinetics (PK): Selected serum PK parameters for dutasteride are summarized for all subjects in the table below. AUC(0-t) Cmax tmax Treatment N (ng hr /ml) 1 (ng/ml) 1 (hr) 2 A (43.5) (36.7) ( ) B (77.6) (40.0) ( ) C (54.1) (42.5) ( ) D (67.2) (47.5) ( ) 1. Geometric mean (CVb%) 2. Median (range) 2

3 Selected serum PK parameters for tamsulosin are summarized for all subjects in the table below. AUC(0- ) AUC(0-t) Cmax t1/2 Tmax Treatment N (ng hr/ml) 1 (ng hr/ml) 1 (ng/ml) 1 (hr) 1 (hr) 2 A (35.7) (36.8) (30.5) (21.4) ( ) B (37.3) (39.2) (35.7) (23.5) ( ) C (46.2) (47.5) (32.8) (34.9) ( ) D (41.1) (43.4) (37.1) (29.0) ( ) 1. Geometric mean (CVb%) 2. Median (range) Summary results of the statistical analysis of dutasteride PK parameters are presented in the table below. The FDC capsule and coadministered commercial products were bioequivalent for dutasteride, based on Cmax and AUC(0-t) in the whole study population, in both the fed and fasted states. Parameter Comparison Least Squares Mean 1 90% Confidence (units) Test vs. Ref Test Ref Point Estimate 2 Interval CVw (%) B : A (0.89, 0.98 ) AUC(0-t) D : C (0.90, 1.00 ) (ng hr/ml) A : C (0.72, 1.11 ) B : D (0.71, 1.09 ) B : A (0.81, 0.97 ) Cmax (ng/ml) tmax (hr) D : C (0.86, 1.02) A : C (0.78, 1.03 ) B : D (0.74, 0.97 ) B A ( 0, 1.50) D C ( 0, 0.50) A C (0, 1.00) B D (1.00, 2.00) Note: B:A and D:C comparisons are cross-over comparisons while A:C and B:D are parallel comparisons. Ref=Reference 1. Median reported for tmax. 2. Estimated difference reported for tmax

4 Summary results of the statistical analysis of tamsulosin PK parameters are presented in the table below. The FDC capsule and coadministered commercial products were not bioequivalent for tamsulosin. The FDC capsule and commercial products were equivalent in the whole study population under both dosing conditions based on AUC; however, Cmax values were approximately 15-20% lower for the FDC capsule compared to the commercial products in both the fed and fasted states. Parameter Comparison Least Squares Mean 1 90% Confidence (units) Test vs. Ref Test Ref Point Estimate 2 Interval CVw (%) B : A (0.86, 1.01 ) AUC(0- ) (ng hr/ml) AUC(0-t) (ng hr/ml) Cmax (ng/ml) tmax (hr) D : C (0.87, 1.01 ) A : C (0.75, 1.00 ) B : D (0.75, 0.99 ) B : A (0.85, 1.00 ) D : C (0.87, 1.01 ) A : C (0.75, 1.00 ) B : D (0.74, 0.99 ) B : A (0.74, 0.88 ) D : C (0.78, 0.92 ) A : C (0.59, 0.74 ) B : D (0.56, 0.71 ) B A ( 0, 1.99) D C (0.50, 1.50) A C (1.00, 2.00) B D (0, 2.00) Note: B:A and D:C comparisons are cross-over comparisons while A:C and B:D are parallel comparisons. Ref=Reference 1. Median reported for tmax. 2. Estimated difference reported for tmax. Safety results: An on-therapy adverse event (AE) or serious adverse event (SAE) was defined as an AE/SAE with onset after the first dose of study medication and on or before the follow-up contact. The most frequently reported AEs (i.e., those occurring in >1 subject in the study) are summarized in the table below. Adverse Events: Regimen A Regimen B Regimen C Regimen D N (ITT) No. subjects with AEs n (%) 14 (34) 14 (34) 16 (37) 16 (36) Most Frequent AEs Headache 6 (15) 4 (10) 7 (16) 5 (11) Dizziness postural 3 (7) 2 (5) 4 (9) 6 (14) Dizziness 2 (5) 3 (7) 4 (9) 3 (7) Abdominal discomfort 0 1 (2) 1 (2) 3 (7) Fatigue (7) 0 Rhinorrhoea 0 2 (5) 1 (2) 0 Syncope 1 (2) 0 1 (2) 1 (2) Serious Adverse Events, n (%) [n considered by the investigator to be related, possibly related, or probably related to study medication]: No SAEs were reported during the study

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