VM2009/00048/00
Study No: MNK112891
Title: An open label, randomised, three-way cross-over study to evaluate the pharmacokinetics, effect of food, safety
and tolerability of a new tablet formulation of GSK1144814 in healthy male and female subjects.
Rationale: The study was conducted to assess a new formulation of GSK1114814. The formulation used in the First
Time In Human (FTIH) study and the planned repeat dose clinical study was a suspension of the tosylate salt. A new
free base tablet formulation has been developed for use in future clinical studies. The purpose of this study was to
assess the pharmacokinetic profile of the new formulation in both fed and fasted conditions.
Phase: I
Study Period: 01 SEP 2009 to 09 OCT 2009
Study Design: This was an open label, randomised, three-way cross-over study design
Centres: One study centre; GSK Medicines Research Unit Level 10 Parkes East, Prince of Wales Hospital, Randwick
New South Wales, Australia 2031.
Indication: None
Treatment: The subjects were randomly assigned to single dosing of GSK1144814 in any of the following six
sequences: A/B/C, B/C/A, C/A/B, A/C/B, B/A/C, and C/B/A; where A, B, C represented the three formulations under
study as below:
A: GSK1144814 Tablet, 100 mg in the fasted state
B: GSK1144814 Tablet, 200 mg in the fasted state
C: GSK1144814 Tablet, 100 mg in the fed state (following a high fat breakfast)
Objectives:
Pharmacokinetic (PK) Objectives:
- To evaluate the PK parameters of single oral doses of GSK1144814 administered as a tablet formulation in healthy
male and female subjects.
- To evaluate the effect of a high-fat meal on the PK of GSK1144814 tablet following single dose administration of
GSK1144814 to healthy male and female subjects.
Safety and Tolerability Objective:
- To evaluate the safety and tolerability of single oral doses of GSK1144814 tablet formulation in fed and fasted states.
Statistical Methods: The following populations were considered in the analysis: Safety Population consisting of all
subjects who received at least one dose of a study drug. PK Population consisted of all subjects for whom a PK
sample was obtained and analysed. For the analyte GSK1144814, log transformed dose normalised values (i.e. the
exposure in the 200 mg group divided by 2) of AUC(0-∞) and Cmax were analysed for Dose Proportionality
Assessment and log transformed values of AUC(0-∞) Cmax and t½ were analysed for Food Effect Interaction using a
mixed effects model. Period and treatment were fitted as fixed effects and subject was fitted as a random effect. The
ratios and 90% CIs for comparing the effects of GSK1144814 200 mg Fasted against GSK1144814 100 mg Fasted for
Dose Proportionality Assessment and GSK1144814 100 mg Fed against GSK1144814 100mg Fasted for Food Effect
Interaction were computed. The adjusted geometric means and 90% CIs of these geometric means by treatment group
for the analyte were presented. The treatment ratios were calculated by back-transforming the mean difference on the
log scale obtained from the analyses.
Statistical analysis to assess dose proportionality was conducted by comparing the 200 mg group vs the reference
dose (100 mg fasted). Food effect was assessed by comparing the 100 mg Fed group vs the 100 mg fasted.
Distributional assumptions underlying the statistical analyses were assessed by visual inspection of residual plots.
Normality was examined by normal probability plots, while homogeneity of variance was assessed by plotting the
Studentised Residuals against the predicted values for the model.
Study Population: Healthy males and females aged between 18 to 65 years (inclusive), with body weight ≥50 kg,
and body mass index (BMI) within the range 19 to 29.9 kg/m2 (inclusive); and demonstrating no evidence of mental
impairment or co-morbid psychiatric disorders were included in this study.
Number of Subjects:
Total
Number of subjects planned:
16
Number of subjects randomised, N:
16
Number of subjects included in All subjects (safety) population, n (%):
16 (100)
Number of subjects included in PK population, n (%):
16 (100)
Number of subjects completed as planned, n (%):
16 (100)
1
VM2009/00048/00
Demographics
Total
N (All subjects)
16
Females: Males
1: 15
Mean Age in Years (Range)
30.8 (22-53)
Mean Weight in Kg (Range)
76.34 (54.8-99.2)
Race, n (%)
Asian–East Asian Heritage
1 (6)
Asian–Central/ South Asian Heritage
1 (6)
White
14 (88)
Pharmacokinetics (PK) Endpoints: The PK of plasma GSK1144814 was assessed by non compartmental methods.
A summary of selected PK parameters are presented in table below:
Summary of selected GSK1144814 Pharmacokinetic Parameters
Parameter
Treatment
N
n
Geometric Mean (CV%)
95% CI
AUC(0-t) (ng.h/mL)
100 mg Fasted
16
16
4480 (55.3)
3400, 5900
200 mg Fasted
16
16
6980 (57.6)
5240, 9280
100 mg Fed
16
16
4390 (40.6)
3560, 5410
AUC(0-24) (ng.h/mL)
100 mg Fasted
16
16
3310 (69.9)
2360, 4630
200 mg Fasted
16
16
4420 (76.3)
3080, 6350
100 mg Fed
16
16
3210 (41.4)
2600, 3970
100 mg Fasted
16
14
5050 (58.6)
3690, 6920
AUC(0-∞) (ng.h/mL)
200 mg Fasted
16
16
8020 (56.6)
6050, 10600
100 mg Fed
16
16
5130 (43.8)
4100, 6420
Cmax (ng/mL)
100 mg Fasted
16
16
880 (101)
563, 1370
200 mg Fasted
16
16
795 (120)
481, 1310
100 mg Fed
16
16
572 (64.0)
420, 782
t½(h)
100 mg Fasted
16
14
26.4 (36.8)
21.5, 32.5
200 mg Fasted
16
16
26.0 (36.8)
21.5, 31.4
100 mg Fed
16
16
31.0 (42.2)
25.0, 38.4
tmax (h)1
100 mg Fasted
16
16
1.00 (0.75, 24.00)
NA
200 mg Fasted
16
16
1.00 (0.50, 24.00)
NA
100 mg Fed
16
16
3.50 (2.00, 8.00)
NA
tlag (h)1
100 mg Fasted
16
16
0.00 (0.00, 0.25)
NA
200 mg Fasted
16
16
0.00 (0.00, 0.25)
NA
100 mg Fed
16
16
0.13 0.00, 2.00)
NA
1. Median (range)
NA =Not available
The statistical summary of food effect and dose proportionality using ANOVA are presented in tables below:
Statistical Summary of GSK1144814 Food Effect Assessment
PK Parameter
Ratio1 (90% CI)
1.00 (0.80, 1.24)
AUC(0-∞)
Cmax
0.64 (0.40, 1.03)
t½
1.15 (0.96, 1.37)
1. Ratio for 100 mg Fed:100 mg Fasted
Statistical Summary of Assessment of Dose Proportionality of GSK1144814 using ANOVA
PK Parameter
Ratio1 (90% CI)
0.78 (0.63, 0.97)
AUC(0-∞)
Cmax
0.45 (0.28, 0.72)
1. Ratio is for200 mg:100 mg
2
VM2009/00048/00
Safety results: A total of 25 AEs were reported in 15 subjects, of which 24 AEs were reported by 14 subjects (88%)
after dosing (one subject had reported a pre-treatment AE of oropharyngeal pain). Somnolence (by 7 subjects) and
headache (by 3 subjects) were the most commonly reported AEs. All the AEs were mild in intensity and resolved at the
end of the study except one AE (traumatic haematoma) which was in the resolving stage. Of the 24 AEs, 11 AEs
reported in 7 subjects were considered related to the study drug by the Investigator.
Adverse Events:
GSK1144814
100 mg
200 mg
100 mg
Total
Fasted
Fasted
Fed
(N=16)
(N=16)
(N=16)
(N=16)
Any Events n (%)
7 (44)
6 (38)
6 (38)
14 (88)
Any AE related to investigational product n (%)
2 (13)
4 (25)
3 (19)
7 (44)
All AEs n (%)
Somnolence
2 (13)
3 (19)
4 (25)
7 (44)1
Headache
1 (6)
1 (6)
1 (6)
3 (19)
Lethargy
0
1 (6)
0
1 (6)
Constipation
0
0
1 (6)
1 (6)
Diarrhoea
0
1 (6)
0
1 (6)
Flatulence
1 (6)
0
0
1 (6)
Cellulitis orbital
0
0
1 (6)
1 (6)
Folliculitis
1 (6)
0
0
1 (6)
Palpitations
0
1 (6)
0
1 (6)
Catheter site haematoma
1 (6)
0
0
1 (6)
Traumatic haematoma
0
0
1 (6)
1 (6)
Rhinorrhoea
0
1 (6)
0
1 (6)
Dermatitis contact
0
0
1 (6)
1 (6)
Haematoma
1 (6)
0
0
1 (6)
1. Somnolence was reported thrice in one subject
Note: Total is total no. of subjects experiencing the event not total no. of events.
Serious Adverse Events: There were no deaths, serious adverse events, or discontinuations of subject due to AEs
reported in this study.
3