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. GSK Medicine: GSK1349572+GR109714+GI265235 Study Number: ING114580 Title: An Evaluation of the Bioequivalence of a Combined Formulated Tablet (50mg/600mg/300mg dolutegravir/abacavir/lamivudine) Compared to One Dolutegravir 50mg Tablet and One EPZICOM (600mg/300mg abacavir/lamivudine) Tablet Administered Concurrently and the Effect of Food on Bioavailability of the Combined Formulation in Healthy Adult Subjects Rationale: GSK1349572 (dolutegravir, DTG) is a next-generation integrase inhibitor (INI) currently under clinical development. Fixed-dose combinations (s) have greatly simplified the treatment of patients with HIV, and a tablet of DTG plus abacavir (ABC; GI265235) and lamivudine (3TC; GR109714) is an attractive treatment option. This was a two-part study, with Part A conducted to evaluate bioequivalence between an tablet formulation of DTG 50mg, ABC 600mg, and 3TC 300mg compared with separate tablet co-administration of DTG 50mg plus the marketed tablet formulation of EPZICOM (ABC 600mg + 3TC 300mg), and with Part B conducted to assess the effect of a high fat meal on the bioavailability of the tablet. Phase: Phase I Study Period: 20 June 2012-21 September 2012 Study Design: This was a single center, randomized, two-part, open-label, crossover study in healthy adult subjects to evaluate the bioequivalence of a single combined formulated tablet of DTG 50mg, ABC 600mg and 3TC 300mg compared to co-administration of the separate tablet formulations of DTG 50mg and EPZICOM (EPZ) in the state, and to evaluate the effect of food on the bioavailability of the combined formulation. The study consisted of screening, treatment and follow-up phases. The treatment phase was divided into two parts (Part A and Part B). Part A consisted of 2 single dose treatment sequences (AB, BA) in a randomized, two-period, crossover design, with a 7 day washout between doses. Twelve subjects who completed Part A participated in Part B and received a single dose of the combined formulated tablet administered with a high fat meal ( C). There was a 7 day washout between the second dose in Part A and the dose in Part B. The follow-up phase was scheduled for 7 to 14 days post last dose of study drug. Center: 1 center in the United States Indication: HIV-1 s: A tablet, DTG 50 mg/abc 600 mg/3tc 300 mg tablet, B DTG+EPZ, DTG 50 mg tablet plus a single EPZICOM tablet, C tablet, DTG 50 mg/abc 600 mg/3tc 300 mg tablet with a high fat meal Objectives: The primary objective was to evaluate the bioequivalence between a single fixed dose combination () tablet formulation of DTG 50mg, ABC 600mg and 3TC 300mg versus co-administration of the separate tablet formulations of DTG 50mg plus EPZICOM (ABC 600mg / 3TC 300mg), with each dose given in the state. Primary Outcome Variable: The primary endpoints were plasma DTG, ABC, and 3TC pharmacokinetic (PK) parameters: area under the concentration time curve from time zero (pre-dose) to the time of the last quantifiable concentration (AUC(0-t)), area under the plasma concentration curve from time zero (pre-dose) extrapolated to infinity (AUC(0- )) and maximum observed plasma concentration (Cmax). Secondary Outcome Variables: The secondary endpoints included safety and tolerability parameters as assessed by change from baseline in 12-lead electrocardiogram (ECG) and vital signs (blood pressure [BP] and heart rate [HR]), and number of subjects with adverse events and toxicity grading of clinical laboratory tests. Other secondary endpoints included additional PK parameters: lag time before observation of drug concentration in plasma (tlag), time of occurrence of Cmax (tmax), terminal phase half-life (t1/2), apparent clearance (CL/F), apparent volume of distribution (Vz/F), and DTG concentration 24 hours post dose administration (C24). Statistical Methods: Frequent sampling up to 48 hours was performed after each treatment dose for assay of DTG, ABC and 3TC concentrations in plasma and subsequent determination of associated PK parameters by standard noncompartmental methods. Bioequivalence (BE) assessment included data from Part A only. Following loge-transformation, the PK parameters Cmax, AUC(0-t), AUC(0- ), t1/2, CL/F, and Vz/F for DTG, ABC and 3TC were separately analyzed using a mixed effects analysis of variance (ANOVA) model with fixed effect terms for Sequence, Period and, and with Subject treated as a random effect. Point estimates and their associated 90% confidence intervals (CIs) were 1
constructed for the differences, test treatment (A) reference treatment (B), and were then back-transformed to provide point estimates and 90% CIs for the ratios, test/reference, on the original scale. Food effect assessment included data from the subset of subjects who received both A in Part A and C in Part B. The statistical analysis for food effect was the same as that for BE assessment except that was the only fixed effect term included in the ANOVA model. Study Population: Healthy subjects between 18 and 55 years of age inclusive, body weight 50 kg (110 lbs) for males and 45 kg (99 lbs) for females, body mass index (BMI) 18.5 to 31 kg/m 2 (inclusive), and with negative HLA-B*5701 allele at the screening assessment. Part A Part B Number of Subjects: Fasted DTG + EPZ Fasted Overall Fed Planned, N 66 66 66 12 Randomized, N 65 65 66 12 Completed, n (%) 63 (97) 62 (95) 61 (92) 12 (100) Total Number Subjects Withdrawn, N (%) 2 (3) 3 (5) 5 (8) 0 Withdrawn due to Adverse Events n (%) 1 (2) 0 1 (2) 0 Lost to follow-up 0 1 (2) 1 (2) 0 Investigator discretion 1 (2) 2 (3) 3 (5) 0 Demographics Part A Part B Fasted Fed (N=12) N (Safety Population) 65 65 12 Females: Males 22: 43 22: 43 4: 8 Mean Age, years (SD) 29.3 (9.59) 29.3 (9.55) 33.8 (11.06) White, n (%) 34 (52) 34 (52) 7 (58) SD=Standard deviation Pharmacokinetic Results: In study Part A, 62 subjects received both treatments ( and DTG+EPZ ) and provided evaluable PK parameters. In study Part B, 12 subjects who participated in Part A received the tablet with a high fat meal. Study Part A: Plasma DTG, ABC, and 3TC Pharmacokinetic s for Bioequivalence Assessment 1 Summary of Plasma DTG Pharmacokinetic s 1 DTG PK Fasted AUC(0- ) ( g.h/ml) 44.8 (33) 47.4 (34) AUC(0-t) ( g.h/ml) 40.9 (31) 43.4 (32) Cmax ( g/ml) 2.44 (28) 2.54 (29) C24 ( g/ml) 0.73 (35) 0.76 (38) CL/F (L/hr) 1.12 (33) 1.05 (34) t1/2 (h) 12.8 (20) 12.9 (18) tlag (h) (0.0, 0.5) (0.0, 0.5) tmax (h) 3.00 (1.0, 8.0) 3.00 (0.5, 8.0) Vz/F (L) 20.5 (28) 19.6 (32) 2
Summary of Plasma ABC Pharmacokinetic s 1 ABC PK Fasted AUC(0- ) ( g.h/ml) 13.9 (26) 14.5 (24) AUC(0-t) ( g.h/ml) 13.9 (26) 14.5 (24) Cmax ( g/ml) 4.02 (24) 4.37 (26) CL/F (L/hr) 43.1 (26) 41.4 (24) t1/2 (h) 2.56 (32) 2.54 (27) tlag (h) (0.0, 0.5) tmax (h) 2.00 (0.5, 3.0) 2.00 (0.5, 5.0) Vz/F (L) 159 (36) 151 (34) Summary of Plasma 3TC Pharmacokinetic s 1 3TC PK Fasted AUC(0- ) ( g.h/ml) 12.8 (25) 13.1 (21) AUC(0-t) ( g.h/ml) 12.3 (26) 12.8 (21) Cmax ( g/ml) 2.11 (29) 2.28 (26) CL/F (L/hr) 23.5 (25) 22.9 (21) t1/2 (h) 14.5 (53) 12.7 (41) tlag (h) tmax (h) 3.00 (1.0, 5.0) 2.00 (1.0, 4.0) Vz/F (L) 492 (64) 420 (44) Study Part B: Plasma DTG, ABC, and 3TC Pharmacokinetic s for Food Effect Assessment 1 Compound and DTG ABC 3TC PK AUC(0- ) ( g.h/ml) 40.5 (35) 60.1 (27) 13.0 (31) 12.0 (32) 12.1 (34) 12.6 (29) AUC(0-t) ( g.h/ml) 37.4 (32) 54.9 (24) 12.9 (31) 12.0 (32) 11.6 (37) 12.2 (30) Cmax ( g/ml) 2.25 (25) 3.08 (20) 3.84 (23) 2.97 (39) 1.95 (41) 1.87 (33) CL/F (L/hr) 1.23 (35) 0.83 (27) 46.3 (31) 50.0 (32) 24.8 (34) 23.8 (29) t1/2 (h) 12.4 (16) 12.7 (15) 2.23 (27) 2.76 (32) 15.2 (66) 16.3 (37) tlag (h) 0.25 (0.0, 0.5) tmax (h) 3.00 (1.0, 5.0) 4.50 (2.0, 8.0) 2.00 (0.5, 3.0) 3.00 (2.0, 5.0) 3.00 (1.0, 4.0) 3.50 (2.0, 6.0) Vz/F (L) 22.0 (23) 15.2 (19) 149 (33) 199 (40) 544 (86) 559 (52) 3
Statistical Results: Study Part A: Statistical Comparison of Selected Plasma PK s for Bioequivalence Assessment Ratio of GLS Means [90% CI] Fasted vs DTG PK s AUC(0- ) 0.945 [0.889, 1.00] AUC(0-t) 0.943 [0.888, 1.00] Cmax 0.961 [0.906, 1.02] ABC PK s AUC(0- ) 0.960 [0.939, 0.980] AUC(0-t) 0.960 [0.939, 0.980] Cmax 0.920 [0.867, 0.977] 3TC PK s AUC(0- ) 0.972 [0.940, 1.01] AUC(0-t) 0.960 [0.928, 0.994] Cmax 0.926 [0.885, 0.968] GLS=Geometric least squares Study Part B: Statistical Comparison of Selected Plasma PK s for Food Effect Assessment Ratio of GLS Means [90% CI] Fed vs Fasted DTG PK s AUC(0- ) 1.48 [1.36, 1.62] AUC(0-t) 1.47 [1.35, 1.60] Cmax 1.37 [1.26, 1.48] ABC PK s AUC(0- ) 0.926 [0.899, 0.953] AUC(0-t) 0.924 [0.898, 0.952] Cmax 0.774 [0.662, 0.905] 3TC PK s AUC(0- ) 1.04 [0.971, 1.12] AUC(0-t) 1.05 [0.963, 1.14] Cmax 0.960 [0.879, 1.05] GLS=Geometric least squares Safety Results: Adverse events (AEs) and serious adverse events (SAEs) were collected and recorded in the CRF from Period 1, Day 1 through the follow-up visit (7-14 days after the last dose of study drug). Only SAEs related to study participation (e.g. invasive procedures) were recorded prior to dosing with investigational product. Adverse events occurring in 2 or more subjects in any treatment group in Part A are summarized below. No AE was reported for Part B of the study. Fasted Subjects with any AE(s), n(%) 26 (40%) 25 (38%) Nausea 11 (17%) 19 (29%) Headache 4 (6%) 5 (8%) Somnolence 5 (8%) 2 (3%) Abdominal pain 0 2 (3%) : Fasted=DTG 50 mg/abc 600 mg/3tc 300 mg tablet DTG + EPZ =DTG 50 mg tablet plus a single EPZICOM tablet Serious Adverse Events - On-Therapy: No deaths or SAEs were reported during the study. 4
Conclusion: Dosing with EPZ +DTG and were well tolerated and demonstrated similar tolerability during Part A. Dosing of the tablet with a high fat meal was well tolerated during Part B. Bioequivalence was demonstrated between the tablet formulation and the separate co-administered tablet formulations of DTG plus EPZICOM. Administration of the tablet with a high fat meal resulted in increases in plasma DTG Cmax and AUC, but these are not considered clinically significant. The effects of food on ABC and 3TC exposures were very similar to prior effects seen with EPZICOM, which may be taken with or without food. These results support the recommendation that the tablet can be given without regard to meals. 5