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CONFIDENTIAL HM2009/00101/00 DAN106591

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Synopsis

Identifier: HM2009/00101/00 Study Number: DAN106591

Title:

A Study to Investigate Potential Interactions between GSK598809 and Ethanol in Healthy Subjects.

Investigator:

Study centre:

The Netherlands.

Publication:

None at the time of this report.

Study period:

Initiation Date: 29 September 2008

Completion Date: 03 December 2008

Phase of development:

Phase I.

Objectives:

Primary objectives:

• To investigate the safety and tolerability of the co-administration of GSK598809 at 175 mg and ethanol in healthy volunteers.

• To examine the potential pharmacokinetic interactions between GSK598809 administered at 175 mg and ethanol in healthy volunteers.

• To determine if co-administration of GSK598809 at 175 mg with ethanol potentiates the subjective and central nervous system (CNS) impairing effects of ethanol in healthy volunteers.

• To determine the effects of co-administration of GSK598809 at 175 mg with ethanol as compared to placebo with ethanol.


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Secondary objectives:

• To determine if GSK598809 administered at a dose of 175 mg affects selected CNS function in healthy volunteers.

• To investigate the effects of ethanol on selected CNS function in healthy volunteers.

Methodology:

This was a single-blind, randomised, placebo-controlled, double-dummy, four-period crossover study to investigate the psychomotor and cognitive effects of GSK598809 alone and in combination with ethanol in healthy subjects. Subjects were screened within 3 weeks before the start of the study and were trained to familiarise them with the pharmacodynamic tests.

The duration of each treatment session was 5 study days. Subjects reported to the clinic during the evening of Day -1 in a fasted condition (approximately 8 h before the collection of fasting blood samples) and remained in the clinic for 2 nights. There was a washout period of at least 5 days between treatment sessions.

On the morning of study Day 1, two intravenous cannulae (one cannula for blood sampling and another cannula for infusion of the ethanol/placebo) were inserted. Before the start of the ethanol/placebo infusion a light breakfast was given. The ethanol/placebo infusion started in the morning, between approximately 09:30 h and 10:00 h and lasted for 5 h, followed by a 3 h infusion-free washout period. GSK598809 or matching placebo was administered orally 30 minutes after the start of the ethanol/placebo infusion. A standardised lunch was given at approximately 3.5 h post-dose and dinner approximately 9 h post-dose.

Subjects were discharged after the completion of study assessments and adverse event (AE) review on Day 2 if deemed appropriate by the Investigator or designee. On Days 3 and 4, subjects returned to the study unit to attend outpatient visits for the collection of pharmacokinetic samples and review of any AEs.

During each session, a range of CNS functions was tested. In addition, blood samples were taken to determine plasma levels of GSK598809 and GSK685249 (GSK598809 metabolite). Breath alcohol and blood alcohol levels were also measured. Time points for all study assessments can be found in Attachment 1.

The follow-up visit took place approximately 7 days post-final treatment.

Safety stopping criteria were based on liver chemistry, QTc and vital signs. All subjects had to use protocol-defined contraception methods or practise abstinence throughout the study. Restrictions were placed on the consumption of grapefruit or grapefruit juice, alcohol and tobacco and on strenuous physical exercise for defined periods during the study.

Study administration information is detailed in Attachment 2 and a time and events table for the study can be found in Attachment 1.


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Alcohol clamping method:[Zoethout, 2008(a)]

Ethanol 10% w/v solution in 5% glucose or glucose 5% (placebo) was given intravenously. To avoid local pain in the beginning of the ethanol infusion, a parallel infusion with glucose 5% was given.

The infusion rate for the first and the second five minutes was determined for each subject individually (before the start of the infusion) based on a level of ethanol clamping of 0.6 g L-1 and on the demographic data (weight, height, age and gender) entered in the clamping spreadsheet. The initial infusion rates were determined based on the Watson estimate of body water with an average for healthy male Caucasians of around 60 g hr-1 for the first five minutes and 45 g hr-1 during the second five minutes (set point 0.6 g L-1). The clamping spreadsheet was subsequently used on-line to guide dosing, according to the paradigm described in the protocol.

A hand-held Honac Alco-Sensor meter was used to measure breath alcohol concentrations (BrAC). Minimum intervals between BrAC samples were at least 5 minutes to avoid fatigue. For this reason, two different measurement devices were alternated during the study. The BrAC was entered into the online-spreadsheet that automatically calculated a new infusion rate to keep the alcohol levels at 0.6 g L-1 for 5 h with minimal variability of the ethanol plasma concentrations.

Simulations indicate that for the 0.6 g L-1 set point on average 73.3 gram of ethanol was infused over 300 minutes (sd: 16.2, min: 37, max: 116). This corresponded to the consumption of less than one bottle of wine for the average subject, over a period of 5 h.

Number of subjects:

A sufficient number of healthy male and female subjects were to be enrolled such that approximately 20 subjects completed dosing and critical assessments. A total of 20 subjects (10 male and 10 female) were enrolled into the study.


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Subject disposition and demographics:

Nineteen (95%) subjects completed the study.

Subject disposition and demographics are displayed in the table below.

Number of Subjects Total Number of subjects planned, N 20 Number of subjects randomised, N 20 Number of subjects included in All Subjects (Safety) population, n (%) 20 (100) Number of subjects included in Pharmacokinetic population, n (%) 20 (100) Number of subjects completed as planned, n (%) 19 (95) Number of subjects withdrawn (any reason), n (%) 1 (5) Number of subjects withdrawn for serious adverse event, n (%) 0 Number of subjects withdrawn for adverse event, n (%) 0 Primary reason for subject withdrawal, n (%)

Protocol deviation 1 (5) Demographics Total Age in years, Mean (range) 32.8 (18–55) Sex, n (%)

Female 10 (50) Male 10 (50)

Height in cm, Mean (range) 176.3 (158–195) Weight in kg, Mean (range) 73.53 (54–108) Body mass index in kg/m2, Mean (range) 23.595 (18.47–29.75) Ethnicity, n (%)

Not Hispanic or Latino: 20 (100) Race, n (%)

White Caucasian 17 (85) Mixed Race 2 (10) African American/African Heritage 1 (5)

Diagnosis and main criteria for inclusion:

Healthy males or females between 18 and 65 years of age with body weight ≥ 50 kg and body mass index within the range 18–30 kg/m2 (inclusive) were recruited. Occasional smokers who were non-daily smokers could have been enrolled in the study, but were not permitted to smoke while in the unit. Subjects were excluded if they had a history of, or findings on evaluation consistent with, any Axis I or Axis II disorder as defined in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition.


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Treatment administration:

Subjects were assigned to one of four sequences (ABDC, BCAD, CDBA and DACB) in accordance with the randomisation schedule generated by Discovery Biometrics, GlaxoSmithKline, prior to the start of the study, using validated internal software. Treatment descriptions are presented below.

Treatments Treatment Description A A 5 h alcohol-clamp at a level of 0.6 g·L-1 in combination with GSK598809 at a dose

of 175 mg (interaction) B A 5 h placebo-clamp in combination with GSK598809 at a dose of 175 mg

(GSK598809) C A 5 h alcohol-clamp at a level of 0.6 g·L-1 in combination with matched

GSK598809-placebo (alcohol) D A 5 h placebo-clamp in combination with matched GSK598809-placebo (placebo)

Investigational products were as follows:

• GSK598809 25 mg capsule (batch number 071149318, lot number 081161674).

• Placebo for GSK598809 capsules (batch number 061130161, lot number 081169392).

The agents used for the 5 h intravenous infusion were as follows:

• Ethanol solution (10% w/v in 5% glucose).

• Placebo to match ethanol (5% glucose).

Criteria for evaluation:

Safety and tolerability endpoints: Vital sign measurement, 12-lead electrocardiogram (ECG) and telemetry during dosing; clinical chemistry, haematology and urinalysis (including prolactin and lipid measurements); AE monitoring; Barnes Akathisia Scale (BAS); Simpson-Angus Scale (SAS) and Abnormal Involuntary Movement Scale (AIMS).

Pharmacokinetics: BrAC, blood ethanol concentrations and pharmacokinetic parameters of GSK598809 and its metabolite (GSK685249) (including area under the plasma concentration-time curve extrapolated to infinity (AUC(0-∞)), maximum observed plasma concentration (Cmax), time to Cmax (tmax) and terminal phase half-life (t½)).

Pharmacodynamic: Saccadic eye movements (saccadic reaction time, saccadic peak velocity and saccadic accuracy), smooth pursuit eye movements (percentage of time the subject’s eyes were in smooth pursuit of the target), body sway (antero-posteral sway in mm/2 minutes), adaptive tracking and Visual Verbal Learning Test (VVLT).

Pharmacodynamic/biomarker endpoints: Bond-Lader Visual Analogue Scales (VAS) to assess mood, alertness and calmness and VAS for ‘alcohol effects’ to assess the subjective effects of ethanol.


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Statistical methods:

Sample Size Assumptions:

Sample size was based on feasibility and past experience. A sufficient number of subjects (approximately, 20 healthy volunteers) were recruited. This was considered sufficient for the objectives of the study. Precision calculations were performed to look at the half-width of the 95% confidence intervals around the treatment comparisons. Relevant point estimates obtained from previous CHDR ethanol studies in healthy volunteers were also considered. A previous study found significant differences of 9.7% for smooth pursuit, 21% for body sway and 3.4% for tracking.

Smooth Pursuit: Based on a standard deviation of the differences of 4.020 and a sample size of 20 evaluable subjects, it was estimated that the lower and upper bounds of the 95% confidence interval for the difference between treatments of smooth pursuit was within approximately 3.72 percentage points of the point estimate. For a point estimate of 9.7% the 95% confidence interval was (5.98, 13.42).

Body Sway: Based on a log standard deviation of the differences of 0.270 and a sample size of 20, it was estimated that the lower and upper bounds of the 95% confidence intervals of the ratios for the treatment comparisons were obtained by dividing/multiplying the point estimate by a factor of 1.28. For example if the estimate of the ratio was 1.21, the 95% confidence interval was (0.95, 1.55).

Tracking: Based on a standard deviation of the differences of 1.630 and a sample size of 20 evaluable subjects, it was estimated that the lower and upper bounds of the 95% confidence interval for the difference between treatments of smooth pursuit were within approximately 1.51 percentage points of the point estimate. For a point estimate of 3.4% the 95% confidence interval was (4.95, 1.89).

Sample Size Sensitivity:

No sample size sensitivity calculations were performed.

Sample Size Re-estimation:

No sample size re-estimation was performed.

Interim Analyses:

There was no formal interim analysis.

Final Analysis:

Safety: Mean (±SD) plots of prolactin were produced by treatment and time. This plot was produced for all subjects as well as for both genders separately.

Mean (±SD) plots of QTcF and QTcF change from baseline were produced by treatment and time. Individual plots of QTcF were also produced. These figures were produced for


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all subjects, as well as by gender. ECG summary tables and listings were also provided.

Pharmacokinetic: Effect of GSK598809 on ethanol pharmacokinetic: Breath and Serum AUC(0-4) and systemic clearance (CL), as well as dose parameters were loge-transformed prior to analysis. Analysis of variance models were performed, on the pharmacokinetic parameters, including the factors treatment and period as fixed effects and subject as random effect. Comparisons were expressed as ratios of the pharmacokinetic parameters after GSK598809+ethanol relative to those after ethanol alone.

Effect of ethanol on GSK598809: AUC(0-∞), AUC(0-t) and Cmax pharmacokinetic parameters were loge-transformed prior to analysis. Analysis of variance models were performed, on the pharmacokinetic parameters, including the factors treatment and period as fixed effects and subject as random effect. Comparisons were expressed as ratios of the pharmacokinetic parameters after GSK598809+ethanol relative to those after GSK598809 alone.

Pharmacodynamic: Plots of Bond and Lader by domain and Alcohol VAS were produced for all subjects as well as by gender. Listings were produced for Barnes Akathisia Scale (BAS), Simpson Angus Scale (SAS) and Abnormal Involuntary Movement Scale (AIMS).

Plots for each of the pharmacodynamic endpoints (Saccadic eye movement, Smooth Pursuit, Body Sway and Adaptive Tracking) were generated by regimen over time. Plots were also produced for VVLT by treatment.

Repeated measures mixed effects models were used to assess the effect of GSK598809+ethanol compared with both placebo and ethanol alone for the Cognitive battery (Saccadic eye movement, Body Sway and Adaptive Tracking). Treatment, timepoint, period, sex and treatment*timepoint were included in the model as fixed effects. Subject was included as a random effect. Pre-dose timepoints were not included in the models. Estimates and 95% confidence intervals were calculated and presented with LSmeans. Secondary comparisons were produced for Saccadic eye movements to assess the effect of both GSK598809 and ethanol compared with placebo.

A mixed effects model was used to assess the effect of GSK598809+ethanol compared with both placebo and ethanol alone for the VVLT. Treatment, period and sex were included in the model as fixed effects. Subject was included as a random effect. Estimates and 95% confidence intervals were calculated and presented with LSmeans. A similar mixed effects model was used for the mean scores over 1–5 h post dose for the cognitive battery (Saccadic eye movements, Body Sway and Adaptive Tracking). Boxplots by treatment were produced for mean scores over 1–5 h post dose, for Smooth Pursuit.


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Changes in conduct of the study or planned analyses:

Individual plots of Prolactin by time including day of last menstrual period could not be produced as the date of last menstrual period was only collected at screening.

An additional plot was produced to separate the Individual QTcF by Treatment and time also by Gender.

Only one pharmacokinetic population was defined. This included all Subjects who had at least one post-dose pharmacokinetic sample of either GSK598809 or ethanol.

Summary:

Safety:

No formal statistical analysis of safety data was conducted.

There were no serious adverse events reported in this study and no subjects were withdrawn due to AEs.

All 20 subjects (100%) reported AEs during the study. All of the AEs in the study were classed as mild or moderate and there were no AEs of severe intensity. Nervous system disorders were the most frequently reported AE type (total: 18 subjects [90%]), occurring in seven subjects (37%) following placebo, 12 subjects (60%) following ethanol, 11 subjects (58%) following GSK598809 and 14 subjects (74%) following GSK598809+ethanol.

Fewer subjects (47%) reported AEs after placebo than after the other treatment regimens (range: 74–90%), although there were no notable differences between ethanol (90%), GSK598809 (74%) and GSK598809+ethanol (79%). The most frequently reported AEs were headache and somnolence, occurring in a total of 14 subjects (70%) and 13 subjects (65%), respectively. No notable differences were observed between treatment regimens for headache. For somnolence a higher reporting rate was observed for GSK598809+ethanol (58%) compared with ethanol (20%), GSK598809 (16%) and placebo (5%). There was also a higher reporting rate for fatigue observed for GSK598809+ethanol (37%) compared with ethanol (20%), GSK598809 (5%) and placebo (16%). For nausea, a higher reporting rate was observed in both GSK598809 alone (16%) and GSK598809+ethanol regimens (16 %) compared with ethanol (5%) and placebo (0). Akathisia was only reported in the GSK598809 alone (5%) and GSK598809+ethanol regimens (5%). A summary of all AEs occurring in two or more subjects in the study is presented below.


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Placebo

N=19

Ethanol

N=20

GSK598809

N=19

GSK598809+ethanol N=19

Total

N=20

Most Frequent Adverse Event

n (%) n (%) n (%) n (%) n (%) Any AE 9 (47) 18 (90) 14 (74) 15 (79) 20 (100) Any AE related to investigational product

8 (42) 15 (75) 13 (68) 14 (74) 18 (90)

Most Frequent AEs (≥ two subjects on any regimen) Headache 6 (32) 9 (45) 5 (26) 7 (37) 14 (70) Somnolence 1 (5) 4 (20) 3 (16) 11 (58) 13 (65) Feeling drunk 0 7 (35) 0 6 (32) 12 (60) Dizziness 1 (5) 6 (30) 6 (32) 5 (26) 11 (55) Fatigue 3 (16) 4 (20) 1 (5) 7 (37) 10 (50) Nausea 0 1 (5) 3 (16) 3 (16) 6 (30) Infusion site pain

0 3 (15) 0 2 (11) 5 (25)

Vomiting 0 1 (5) 4 (21) 0 5 (25) Akathisia 0 0 1 (5) 1 (5) 2 (10) Catheter site related reaction

0 1 (5) 1 (5) 0 2 (10)

Dry mouth 0 0 0 2 (11) 2 (10) Dysmenorrhoea 1 (5) 0 0 1 (5) 2 (10) Oropharyngeal discomfort

1 (5) 0 0 1 (5) 2 (10)

Skin reaction 1 (5) 1 (5) 0 0 2 (10) Upper respiratory tract infection

0 2 (10) 0 0 2 (10)

AE = adverse event

No other subjects had haematology PCI values.

Seven subjects had clinical chemistry values of PCI:

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No subjects reached the liver chemistry stopping criteria (alanine aminotranferase ≥ 3x upper limit of normal (ULN) and bilirubin ≥ 1.5xULN (> 35% direct) or alanine aminotranferase ≥ 3xULN) and none of the haematology or chemistry values of PCI were reported as AEs. No safety concerns were raised on urinalysis dipstick results.

Plots of the mean (±SD) for prolactin were produced by treatment and time. Post-dose transient increases in prolactin were observed for all subjects on both GSK598809 alone and GSK598809+ethanol regimens. The increase was much greater for females than for males. These observations are consistent with previous clinical studies of GSK598809.

None of the laboratory values were listed as AEs or considered clinically significant.

Fourteen subjects had vital sign values (heart rate and systolic and diastolic blood pressure) of PCI. None of the values of PCI was reported as an AE or were considered clinically significant.

No subjects met the QTc withdrawal criteria for this study (QTc 60 msec > baseline or > 500 msec).

Exclusion of this subject made no significant changes to the overall analysis.

Notable increases in QTCF were observed for both GSK598809 alone and GSK598809+ethanol regimens at 2 and 4 h post-dose (see figure below).

No 12-lead ECG traces were considered to show clinically significant abnormalities, nor were any of the Holter monitor studies (data not shown).

For the movement scales, there was no evidence of treatment related differences in scores for SAS. In general, post-treatment values were in line with pre-dose values. Eight subjects had SAS scores greater than 0. However, scores greater than 0 generally occurred in Period 1.

All BAS and AIMS scores (with the exception of one subject on placebo at the 2 h post-dose time point) were zero for each subject on each treatment. Together these results imply that there was not treatment related effect on extrapyramidal symptoms.


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Pharmacokinetics:

Statistical analyses of pharmacokinetic data were performed under the direct auspices of Clinical Pharmacology Statistics & Programming, GlaxoSmithKline, Philadelphia.

Data was released to Discovery Biometrics by CPK via HARP. Main results of the summary statistics are presented to the accuracy of the raw data. All summary statistics were carried out using SAS 8.02 for UNIX running under the HARP environment.

GSK598809 Concentration Data

Individual plasma GSK598809 concentration listings and associated summary statistics were prepared. Individual plasma GSK598809 concentration-time profiles are displayed with actual time on both semi-logarithmic and linear scales by subject and treatment. Descriptive statistics for plasma GSK598809 concentration data at each planned relative time are presented by treatment. Mean and median steady-state plasma GSK598809 concentration-time profiles for all treatments were displayed with scheduled time and were presented on both semi-logarithmic and linear scales.

No plasma GSK598809 concentrations were excluded from the pharmacokinetics analysis.

GSK598809 concentrations were above the limit of quantification at pre-dose for 7 subjects. However, the concentrations were less than 5% of the Cmax and thus were kept in the analysis. In each of these cases, the study period with a detectable pre-dose level was preceded by a period in which GSK598809+ethanol was administered. A summary of GSK598809 concentrations above the limit of quantification at pre-dose is presented below.

Following oral administration of GSK598809 175 mg, with or without ethanol, GSK598809 concentration-time profiles depicted an apparent bi-exponential decline following the peak. Plasma concentrations were measurable between 1 and 72 h in all the subjects whatever the treatment.


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GSK685249 Concentration Data

Individual plasma GSK685249 metabolite concentration listings and associated summary statistics were prepared. Individual plasma GSK685249 concentration-time profiles are displayed with actual time on both semi-logarithmic and linear scales by subject and treatment. Descriptive statistics for plasma GSK685249 concentration data at each planned relative time are presented by treatment. Mean and median steady-state plasma GSK685249 concentration-time profiles for all treatments are displayed with scheduled time and are presented on both semi-logarithmic and linear scales.

No plasma GSK685249 concentrations were excluded from the pharmacokinetic analysis. All pre-dose plasma GSK685249 concentrations were non quantifiable (NQ).

Following oral administration of GSK598809 175 mg, with or without ethanol, GSK685249 metabolite concentration-time profiles depicted an apparent bi-exponential decline following the peak. Plasma concentrations were measurable between 1 or 2 h and 48 h in all the subjects whatever the treatment. At 72 h after dosing, GSK685249 was still measurable in 11 subjects after GSK598809+placebo and in 18 subjects after GSK598809+ethanol.

Ethanol Concentration Data

Individual serum and breath ethanol concentration listings and associated summary statistics were prepared. Individual serum and breath ethanol concentration-time profiles are displayed with actual time on both semi-logarithmic and linear scales by subject and treatment. Descriptive statistics for serum and breath ethanol concentration data at each planned relative time are presented by treatment. Mean and median steady-state serum and breath ethanol concentration-time profiles for all treatments are displayed with scheduled time and are presented on both semi-logarithmic and linear scales.

No serum or breath ethanol concentrations were excluded from the pharmacokinetic analysis. All pre-dose serum or breath ethanol concentrations were NQ.

Following intravenous infusion of 0.6 g/L of ethanol, with or without GSK598809, ethanol serum concentration-time profiles increased rapidly and remained constant all over the time of infusion (between 1 and 4 h). Thereafter serum concentrations decline rapidly. At 6 h after dosing, ethanol was still measurable in 18 subjects out of 19 after ethanol alone and in all the subjects after GSK598809+ethanol.

Similar profiles were observed when considering breath concentrations.


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GSK598809 Pharmacokinetic Parameters

Selected GSK598809 pharmacokinetic parameters are summarized below.

GSK598809 Alone GSK598809+ethanol GSK598809 pharmacokinetic parameters1 n n AUC(0-∞) (ng.hr/mL) 11 14000 (32) 15 16600 (23) AUC(0-t) (ng.hr/mL) 19 14000 (28) 19 15700 (27) Cmax( ng/mL) 19 1320 (39) 19 1190 (39) tmax (hr) 2 19 2.07 (2.00-6.05) 19 3.03 (2.00-7.87) t1/2 (hr) 11 19.3 (33) 15 21.6 (27) 1. geometric mean (CV%) 2. median (range) After dosing with GSK598809 alone, GSK598809 maximal plasma concentrations occurred between 2 and 6 h (median time of 2 h). After dosing with GSK598809 in combination with ethanol, similar median GSK598809 tmax values to those after GSK598809 alone were observed with a median tmax of 3 h and a range of 2 to 8 h.

The apparent t½ of GSK598809 was determined using at least three data points based on visual inspection. Terminal elimination half-life could not be reported in 8 subjects out of 19 after GSK598809 alone and in 4 subjects out of 19 after GSK598809+ethanol due to a high percentage of AUC extrapolated (>20%). After GSK598809 alone, the t½ values ranged from approximately 13 to 33 h in individual subjects. The mean t½ value was about 19 h. After GSK598809 in combination with ethanol, GSK598809 t½ were within the same ranges to those measured after GSK598809 alone (14 to 31 h).

Inter-subject variability was comparable between the two treatments, about 28 to 39% after GSK598809 alone and 23 to 39% after GSK598809+ethanol.

GSK685249 Pharmacokinetic Parameters

Selected GSK685249 pharmacokinetic parameters are summarized below.

GSK598809 Alone GSK598809+ethanol GSK685249 pharmacokinetic parameters1 n n AUC(0-t) (ng.hr/mL) 19 117 (35) 19 121 (29) Cmax( ng/mL) 19 16.1 (50) 19 12.2 (42) tmax (hr) 2 19 2.03 (1.00-6.05) 19 2.02 (1.00-6.07) t1/2 (hr) 16 34.1 (43) 15 41.7 (45) 1. geometric mean (CV%) 2. median (range) After dosing with GSK598809 alone, GSK685249 maximal plasma concentrations occurred between 1 and 6 h (median time of 2 h). After dosing with GSK598809 in combination with ethanol, similar median GSK685249 tmax values to those observed after GSK598809 alone were observed.


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The apparent t½ of GSK685249 was determined using at least three data points based on visual inspection. Terminal elimination half-life could not be reported in 3 subjects out of 19 after GSK598809 alone and in 4 subjects out of 19 after GSK598809+ethanol, due to impossible fitting. After GSK598809 alone, the t½ values ranged from approximately 19 to 72 h in individual subjects. The mean t½ value was about 34 h. After GSK598809 in combination with ethanol, GSK685249 t½ were slightly longer to those measured after GSK598809 alone (20 to 99 h).

With a 72-h sampling period, the AUC% extrapolated (%AUCex) values was higher than 20% in the majority of cases thus AUC(0-∞) was not reported for any subjects.

Inter-subject variability was comparable between the two treatments, about 35 to 50% after GSK598809 alone and 29 to 45% after GSK598809+ethanol.

Serum Ethanol Pharmacokinetic Parameters

Selected ethanol pharmacokinetic parameters are summarized below.

Ethanol alone Ethanol + GSK598809 Serum Ethanol pharmacokinetic parameters1 n n AUC(0-4) (mg.hr/mL) 20 2.58 (7.2) 18 2.50 (7.1) CL (L/hr) 20 0.0886 (16) 18 0.0950 (20) Dose (g) 20 0.229 (18) 18 0.238 (23) 1. geometric mean (CV%) After dosing with ethanol alone, based on serum concentrations, ethanol AUC(0-4) and CL were similar to those obtained after GSK598809+ethanol.

Inter-subject variability of AUC and CL was comparable between the two treatments, about 7 to 16% after ethanol alone and 7 to 20% after GSK598809+ethanol.

Breath Ethanol Pharmacokinetic Parameters

Selected breath ethanol pharmacokinetic parameters are summarized below.

Ethanol alone Ethanol + GSK598809 Breath Ethanol pharmacokinetic parameters1 n n AUC(0-4) (µg.hr/L) 20 1020 (6.4) 19 1020 (4.6) CL (L/hr) 20 224 (19) 19 228 (25) Dose (g) 20 0.229 (18) 19 0.233 (24) 1. geometric mean (CV%) After dosing with ethanol alone, based on breath concentrations, ethanol AUC(0-4) and CL were similar to those obtained after GSK598809+ethanol.

Inter-subject variability of AUC and CL was comparable between the two treatments, about 6 to 19 % after ethanol alone and 5 to 25% after GSK598809+ethanol.


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Statistical Analyses of Pharmacokinetic Parameters

A summary of the statistical analysis of the effect of GSK598809 on ethanol serum and breath pharmacokinetics is presented below.

LSGeometric mean Response Variable Test Ref.

Ratio 90% CI

Serum AUC(0-4) (mg*hr/mL) 2.504 2.580 0.970 (0.938 , 1.004 ) Ethanol CL (L/hr) 0.094 0.089 1.059 (1.007 , 1.115 ) Breath AUC(0-4) (µg*hr/L) 1030.113 1035.361 0.995 (0.968 , 1.022 ) Ethanol CL (L/hr) 257.478 254.514 1.012 (0.955 , 1.072 ) Dose (g) 0.265 0.264 1.006 (0.963 , 1.050 ) *All comparisons GSK598809+Ethanol vs Ethanol alone LS = least square, CI = confidence interval, Ref. = reference treatment There was no notable difference between GSK598809+ethanol compared with ethanol alone for any of the pharmacokinetic parameters (Serum AUC(0-4) and CL, Breath AUC(0-4), CL and Dose) of ethanol.

A total of 19 subjects received GSK598809+ethanol and GSK598809 alone. Area under the plasma concentration-time curve extrapolated to infinity was only calculated for 11 sessions after treatment with GSK598809 alone and 15 sessions after treatment with GSK598809+ethanol. A summary of the statistical analysis of the effect of ethanol on GSK598809 pharmacokinetics is presented below.

LSGeometric mean Response Variable Test Ref.

Ratio 90% CI

AUC(0-∞) (ng*hr/ml) 16654.58 14472.81 1.15 (1.02 , 1.30) AUC(0-t) (ng*hr/mL) 15750.42 13948.91 1.13 (1.07 , 1.19) Cmax (ng/mL) 1197.94 1318.50 0.91 (0.83 , 1.00) All comparisons GSK598809+Ethanol vs GSK598809 alone LS = least square, CI = confidence interval, Ref. = reference treatment On average, there was a 15% higher AUC(0-∞) of GSK598809 when taken with ethanol compared with GSK598809 alone. The 90% confidence interval indicates that the true difference lies between an increase of 2% and an increase of 30%. Slightly lower increases ‘(+13%) were observed for AUC(0-t).

On average, there was a 9% lower Cmax of GSK598809 when dosed with ethanol compared with GSK598809 alone. The 90% confidence interval indicates that the true difference lies between a decrease of 17% and no difference. This lies within the standard bioequivalence range (0.8-1.25).

Pharmacodynamics:

Results for AIMS, SAS and BAS are detailed in the Safety section above.


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Saccadic eye movement

A plot of means (±SD) for saccadic inaccuracy (%) is presented in the figure below.

A plot of means (±SD) for peak velocity (degrees/s) is presented in the figure below.

A plot of means (±SD) for reaction times (sec) is presented in the figure below.


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Clear trends were observed for both peak velocity and reaction times. As expected, ethanol 0.6 g·L-1 caused a decrease in saccadic peak velocity and an increase in saccadic reaction time vs placebo (comparable with data observed at the same site in different studies). A less clear picture was found for saccadic inaccuracy.

When on GSK598809+ethanol, subjects had a reduction in peak velocity (degrees/sec) and longer reaction times, in comparison with GSK598809 alone, ethanol or placebo. This difference was most evident at 4.5 h post-dose. The results of the statistical analysis, including the primary contrasts are presented below.

LSGeometric mean Response Variable

Comparison Test Ref.

Ratio 95% CI

809+Ethanol vs Ethanol 6.665 6.038 1.104 ( 1.009 , 1.208) Inaccuracy (%) 809+Ethanol vs Placebo 6.665 6.029 1.106 ( 1.011 , 1.209)

809 vs Placebo 6.257 6.029 1.038 ( 0.950 , 1.134) Ethanol vs Placebo 6.038 6.029 1.002 ( 0.916 , 1.095)

809+Ethanol vs Ethanol 447.171 469.604 0.952 ( 0.927 , 0.978) Peak Velocity (degrees/s) 809+Ethanol vs Placebo 447.171 481.108 0.929 ( 0.905 , 0.955) 809 vs Placebo 471.327 481.108 0.980 ( 0.954 , 1.006) Ethanol vs Placebo 469.604 481.108 0.976 ( 0.950 , 1.002)

809+Ethanol vs Ethanol 0.216 0.202 1.065 ( 1.034 , 1.097) Reaction Time (sec) 809+Ethanol vs Placebo 0.216 0.197 1.093 ( 1.061 , 1.126) 809 vs Placebo 0.202 0.197 1.022 ( 0.993 , 1.053) Ethanol vs Placebo 0.202 0.197 1.026 ( 0.997 , 1.057) LS = least square, CI = confidence interval, 809 = GSK598809, Ref. = reference treatment On average, subjects were ~10% less accurate when dosed with GSK598809+ethanol than compared with either ethanol alone or placebo. On average, subjects had a 5% reduction in peak velocity when dosed with GSK598809+ethanol than compared with


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ethanol alone and a 7% reduction when compared with placebo. On average, subjects took 7% longer to react when dosed with GSK598809+ethanol than compared with ethanol alone and 9% longer when compared with placebo.

No significant differences were observed for the secondary comparisons (GSK598809 vs placebo or ethanol vs placebo) for any of the saccadic eye movement endpoints. However, GSK598809 alone showed a trend similar to ethanol in decreasing saccadic peak velocity and in increasing saccadic reaction time. Similar results were observed from the mean estimates over the 5-hour clamp.

Smooth pursuit eye movement

There is a trend for a reduction in smooth pursuit performance post-dose in both ethanol (comparable with data observed at the same site in different studies) and ethanol + GSK598809 regimens. There is no notable difference observed on either placebo or GSK598809 regimens. No formal statistical analysis was performed on smooth pursuit as the endpoint was neither normal nor log-normal. As specified in the reporting and analysis plan, an additional boxplot figure was produced to make simple comparisons between treatments using the summary measure of mean across the 5-hour clamping period, see figure below.

Body sway

Clear trends were observed for anterior-posterior body sway at eyes closed. As expected, ethanol 0.6 g·L-1 caused an increase in body sway vs placebo. Subjects also moved more when dosed with GSK598809+ethanol regimens.

There was no notable difference between GSK598809 and placebo. Greater variability (larger standard deviations) was observed on the ethanol alone regimen relative to the


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other 3 regimens. The results of the statistical analysis of mean body sway over the 5-hour clamp can be seen below.

LSGeometric mean Comparison Test Ref.

Ratio 95% CI

GSK809+Ethanol vs Ethanol 511.116 466.068 1.097 ( 0.915 , 1.314) GSK809+Ethanol vs placebo 511.116 334.773 1.527 ( 1.274 , 1.830) GSK809 vs Placebo 371.924 334.773 1.111 (0.927 , 1.332) Ethanol vs Placebo 466.068 334.773 1.392 (1.162 , 1.668) LS = least square, CI = confidence interval, Ref. = reference treatment On average, over the 5-hour clamp, subjects moved 39% more when dosed with ethanol alone and 53% more when dosed with GSK598809+ethanol when compared with placebo. No differences were observed when comparing GSK598809+ethanol and ethanol alone and when comparing GSK598809 and placebo. Similar results were observed for the primary comparisons from the MMRM statistical analysis.

Adaptive tracking

Average performance shows decreases in accuracy for all active regimens. As expected, ethanol 0.6 g·L-1 caused a decrease in adaptive tracking performance vs placebo (although the difference between ethanol and placebo was smaller than the difference obtained at the same site in another study). The greatest reduction in accuracy occurred at 4.5 h post-dose on the GSK598809+ethanol regimen. A plot of the mean (±SD) for average performance on adaptive tracking (%) can be viewed below.

This general trend was supported by the results of the statistical analysis on average performance on Adaptive Tracking (%), see table below.


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Arithmetic mean Comparison Test Ref.

Difference 95% CI

GSK809+Ethanol vs Ethanol 11.682 15.398 -3.716 (-5.455 , -1.978) GSK809+Ethanol vs Placebo 11.682 17.216 -5.533 (-7.277 , -3.790) CI = confidence interval, Ref. = reference treatment On average, subjects performance was six percentage points poorer on the adaptive tracking task when dosed with GSK598809+ethanol compared with placebo. Subjects also performed worse when dosed with GSK598809+ethanol compared with ethanol alone. Similar results were observed from the mean estimates over the 5-hour clamp.

Of note, ethanol alone and GSK598809 alone showed similar impairment of adaptive tracking performance.

Visual Verbal Learning Test

No clear trend was observed across the VVLT endpoints (immediate word recall, delayed word recognition, delayed word recall) for all the treatment arms. This is supported by the results of the statistical analysis.

Pharmacodynamic/ Biomarker:

Bond & Lader VAS

There was some evidence of increases in drowsiness (alertness domain) on all active treatments (ethanol, GSK598809, GSK598809+ethanol) compared with placebo for males. For females there were slight increases in drowsiness on both GSK598809+ethanol and ethanol alone regimens compared with placebo. No notable difference was observed between GSK598809 and placebo for females.

Alcohol VAS

There were clear increases in the feeling of being drunk up to 6.5 h post-dose on both GSK598809+ethanol and ethanol alone, see figure below. These differences were greater in males than in females. There were no notable differences between ethanol and GSK598809+ethanol regimens for this scale. Similarly, no differences between placebo and GSK598809 alone were shown.


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Conclusions:

• GSK598809 175 mg alone or in addition to ethanol was generally well tolerated in healthy volunteers. There were no serious AEs or withdrawals due to AEs.

• Increases in QTcF at 2 and 4 h post dose were observed with GSK598809 alone or with ethanol. No differences in QTcF changes were seen when comparing GSK598809+ethanol with GSK598809 alone.

• There were no treatment related effects on extrapyramidal symptoms.

• No effect of GSK598809 on ethanol pharmacokinetic parameters was observed.

• GSK598809 exposure during ethanol infusion was lower in Cmax (9% decrease) and higher in AUC (13-15% increase). The observed difference in the exposure pattern was not considered clinically meaningful.

• Significant differences (reduction in performances) were observed for adaptive tracking and saccadic eye movements when comparing GSK598809+ethanol with either ethanol alone or placebo. Significant increases in body sway were also observed when comparing GSK598809+ethanol with placebo, whereas no difference was observed when comparing ethanol alone with ethanol plus GSK598809. Compared with ethanol, GSK598809 alone seems to show a similar impairment of adaptive tracking performance.

• No differences were observed for the VVLT. No formal statistical analysis was performed for smooth pursuit. However, there was a trend for reduced accuracy post-dose for both ethanol and ethanol plus GSK598809.

• Ethanol alone and ethanol plus GSK598809 had similar post-dose increases in drowsiness (Bond and Lader alertness domain) and feeling of being drunk (Alcohol VAS).

References

O'Connor S, Morzorati S, Christian J et al. Clamping breath alcohol concentration reduces experimental variance: Application to the study of acute tolerance to alcohol and alcohol elimination rate. Alcoholism-Clinical and Experimental Research 1998; 22(1):202-210.

Zoethout RWM, van Gerven JMA, Dumont GJH, Paltansing S, Van Burgel ND, Van der Linden M, Dahan A, Cohen AF, Schoemaker RC. A novel method for attaining constant ethanol levels. Br J Clin Pharmacol 2008; 66:674–681.

Date of Report:

June 2009


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synopsis - amazon s3 · synopsis identifier: hm2009/00101/00 study number: dan106591 title: a study...

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