Synopsis To assess the effect of single ascending oral doses of GSK598809 on nicotine metabolism in...

CONFIDENTIAL HM2008/00567/00 DAN111282

5

Synopsis

Identifier: HM2008/00567/00 Study Number: DAN111282

Title:

A placebo-controlled, single-blind, randomised, human volunteer study investigating the tolerability and pharmacokinetics of escalating single oral doses (75 mg and above) of GSK598809 in otherwise healthy smokers.

Investigator:

Dr. med.

Study centre:

Germany.

Publication(s):

None at the time of this report.

Study period:

Initiation Date: 09 June 2008.

Completion Date: 19 August 2008.

Phase of development:

Phase I.

Objectives:

Primary objectives:

• To assess the safety and tolerability of single ascending oral doses of GSK598809 in otherwise healthy male and female smokers.

• To assess the pharmacokinetics of GSK598809 after single ascending oral doses in otherwise healthy male and female smokers.

• To assess the effect of single ascending oral doses of GSK598809 on nicotine metabolism in otherwise healthy male and female smokers.

• To assess the pharmacokinetics of GSK685249 (GSK598809 metabolite) after single ascending oral doses of GSK598809 in otherwise healthy male and female smokers.


8


6

Exploratory objectives:

• To assess GSK598809 effects on the following pharmacodynamic parameters in healthy male and female smokers:

• Cigarette craving (urge to smoke).

• Cigarette consumption.

• Withdrawal symptoms.

• To investigate, if any, the relationship of plasma levels of GSK598809 with measured pharmacodynamic parameters to evaluate cotinine to trans-3’hydroxycotinine (3HC) metabolism rate as an investigative marker of cytochrome P450 2A6 (CYP 2A6) activity.

Methodology:

This was a single-blind, randomised, placebo-controlled study. Subjects, site staff and the Investigator were blinded, while staff at GlaxoSmithKline remained unblinded. An unblinded pharmacist was used. A pre-study screening visit took place within 28 days of the first dose.

There were four dosing occasions: each subject received three single doses of study drug and one dose of placebo, separated by a washout period of at least 1 week. In the first dosing session, subjects received either placebo (n=3) or the starting dose of GSK598809 75 mg (n=9). The subsequent doses of GSK598809 were 130 mg and 175 mg. The doses were established based on safety/tolerability and pharmacokinetic assessments during the previous dosing sessions.

Subjects were admitted on Day -1 and fasted for at least 10 h before dosing. Subjects were permitted to smoke from when they woke up until the time of dosing (from a minimum of one to a maximum of three cigarettes). Subjects were required to smoke the final cigarette within the time period of 30 minutes to 15 minutes pre-dose.

Subjects were given the investigational product with 240 mL of water. No food was allowed for at least 4 h post dose. Water was allowed freely except for 1 h either side of dosing. Subjects were not permitted to smoke for up to 4 h post dose and then they were allowed to smoke freely. If possible the first cigarette after dosing was to be not later than 4 h 15 minutes post dose. Across each dosing occasion subjects were to be consistent in the number and brand of cigarettes.

Standardised meals were provided at regular intervals throughout the study, with lunch at approximately 5 h post dose and dinner at approximately 10 h post dose. Subjects were to stay in the unit until all 48-h post dose assessments had been completed. Subjects were to return for the 72-h and 96-h pharmacokinetic assessments.

There was a washout period of at least 1 week between doses. Time points for all study assessments can be found in Attachment 2.


9


7

Serial blood samples for pharmacokinetic analyses of plasma GSK598809 and GSK685249 were collected at pre-dose and regular intervals over 96 h post dose. Serial blood samples for pharmacokinetic analyses of plasma nicotine, cotinine and 3HC were collected at pre-dose and regular intervals over 48 h post dose. Blood samples were analysed for GSK598809, GSK685249, nicotine and cotinine using validated analytical methods based on protein precipitation followed by high performance liquid chromatography/mass spectrometry/mass spectrometry (HPLC-MS/MS) analysis. Blood samples were analysed for 3HC using a validated analytical method based on solid-phase extraction followed by HPLC-MS/MS analysis. Pharmacokinetics were assessed by non-compartmental methods.

Dose adjustment and medication/study stopping criteria were based on safety (adverse events [AEs], liver chemistry, prolactin, circulating lipids, haematology, electrocardiogram [ECG], vital signs, movement rating scales) and pharmacokinetic criteria. All subjects had to use protocol-defined contraception methods or practise abstinence throughout the study. Restrictions were placed on the consumption of grapefruit, alcohol and tobacco and on strenuous physical exercise for defined periods during the study.

A follow-up assessment was performed between 7 and 14 days following the final dose of study medication. The total study duration from screening to follow-up for an individual subject was to be approximately 10 weeks.

Number of subjects:

Eighteen subjects (12 female and 6 male) were recruited as planned.

Subject disposition and demographics:

Subject disposition and demographic data are summarised in Table 1.


10


8

Table 1 Subject Disposition and Demographics

Number of Subjects Total Number of subjects planned, N: 18 Number of subjects randomised, N: 18 Number of subjects included in All Subjects (Safety) population, n (%): 18 (100) Number of subjects in Pharmacokinetic Concentration population, n (%): 18 (100) Number of subjects in Pharmacokinetic Parameter population, n (%): 18 (100) Number of subjects completed as planned, n (%): 17 (94) Number of subjects withdrawn (any reason), n (%): 1 (6) Number of subjects withdrawn for AE, n (%): 0 Reasons for subject withdrawal, n (%)

Subject withdrew consent 1 1 (6) Demographics Total Age in Years, Mean [Range] 38.6 [18–49] Sex, n (%)

Female: 12 (67) Male: 6 (33)

Body Mass Index in kg/m2, Mean [Range] 22.94 [19.0–30.7] Height in cm, Mean [Range] 171.5 [157–190] Weight in kg Mean [Range] 67.68 [52.1–91.9] Ethnicity, n (%)

Not Hispanic or Latino: 18 (100) Race, n (%)

White – White/Caucasian/European Heritage: 18 (100) Source Data: Table 9.1, Table 9.2, Table 9.3 1. Subject withdrew from the study for personal reasons.

This was

not considered to be an entry criteria deviation.

This subject was included in both the All Subjects

and Pharmacokinetic populations.

Of the 18 subjects in the Pharmacokinetic Parameter population, 17 received all four treatments (GSK598809 75, 130 and 175 mg and placebo).


11


9

Diagnosis and main criteria for inclusion:

Male and female subjects aged 18–50 years, inclusive, otherwise healthy smokers, with body weight ≥50 kg and body mass index within the range 18.5–29.9 kg/m2 , inclusive, were recruited. Subjects had QT interval corrected for heart rate according to Fridericia’s formula (QTcF) or QT corrected according to Bazett’s formula (QTcB) <450 msec. Subjects had smoked on average ≥20 cigarettes/day (and ≤40 cigarettes) for the past year and had not tried to quit in the 3 months prior to study start. Subjects who were poor metabolisers of CYP 2A6, as determined by genotyping, were excluded. Subjects who had a sleep disorder were also excluded.

Treatment administration:

Male subjects were randomised to one of the following sequences: ABCD, BACD, BCAD, BCDA in a 1: 1: 2: 2 ratio. Female subjects were randomised to one of the following sequences: ABCD, BACD, BCAD, BCDA in a 1: 1: 1: 1 ratio, where A = Placebo, B = GSK598809 75 mg, C = GSK598809 130 mg, D = GSK598809 175 mg.

Investigational products were as follows:

• GSK598809 5 mg oral capsules (input batch number 071137375, lot number 081161120).

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

• Matching placebo capsules (input batch number 061130161, lot number 081161125).

Criteria for evaluation:

Primary safety and tolerability endpoints comprised AEs, laboratory values, vital signs, ECG assessments; Barnes akathisia rating scale (BARS), abnormal involuntary movement scale (AIMS), Simpson Angus scale (SAS); and serum prolactin, growth hormone (GH), testosterone (free and total), luteinising hormone (LH), follicle stimulating hormone (FSH) and thyroid stimulating hormone (TSH) concentrations.

The pharmacokinetics of GSK598809, the metabolite GSK685249, nicotine, cotinine and 3HC were assessed by determining the following parameters (primary endpoints): area under the plasma concentration-time curve to last quantifiable concentration [AUC(0-t)], AUC extrapolated to infinity [AUC(0-∞)], observed elimination half-life (t½), terminal phase rate constant (λz), maximum observed concentration (Cmax) and time to Cmax (tmax) for GSK598809 and GSK685249; and AUC from zero to 4 h post dose [AUC(0-4)], AUC from zero to 12 h post dose [AUC(0-12)], Cmax(0-4), Cmax(0-12), tmax(0-4) and tmax(0-12) for nicotine, cotinine and 3HC. In addition, AUC(0-t) in the 0 to 4 h interval [AUC(0-t)(0-4)], AUC(0-t) in the 0 to 12 h interval [AUC(0-t)(0-12)], time to last quantifiable plasma concentration in the 0 to 4 h interval [tlast(0-4)] and tlast in the 0 to 12 h interval [tlast(0-12)] were determined for nicotine and cotinine.


12


10

Other primary endpoints comprised psychological assessments (including evaluation of alertness): profile of mood states questionnaire (POMS) and Bond-Lader visual analogue scale (VAS).

Exploratory endpoints comprised cigarette craving assessed via Tiffany questionnaire on smoking urges (QSU) and Westman-Levine questionnaire (cigarette evaluation scale, CES); cigarette consumption; Minnesota nicotine withdrawal scale (MNWS); cotinine to 3HC metabolism rate; and cognition/impulsivity (choice reaction time, CRT; motor impulsivity test – stop-signal task, SST).

Statistical methods:

Sample size

Sample size was based on feasibility. However, in the previous study in smokers with GSK598809 (DAN107606), a within-subject coefficient of variation (CV) of about 13% was estimated from AUC data. It was estimated that with such variability and 18 subjects treated over the planned dose range of 75, 130 and 175 mg the semi-width of the 90% confidence interval of the slope in the dose proportionality assessment would be 0.09.

In the analysis investigating the interaction between GSK598809 and 3HC/cotinine ratio an estimation approach was used to calculate the expected accuracy of the estimation of the ratio (GSK598809/placebo). In the previous GSK598809 study in smokers, a within-subject CV of about 19% was estimated for cotinine AUC(0-4). It was expected that cotinine and 3HC would have similar variability. With such variability and 18 subjects the semi-width of the 90% confidence interval for the ratio was estimated to be 0.11.

Sample size sensitivity: with a within-subject CV of about 15% it was estimated that the semi-width of the 90% confidence interval of the slope would have been 0.10.

Safety analyses

A summary of QTcF from machine-read QT intervals was produced by treatment and time. Manual readings were also derived for QTcF pre-dose, 1 h, 2 h and 4 h. Plots were produced of mean (± standard deviation, SD) QTcF and QTcF change from baseline by treatment and time.


13


11

Pharmacokinetic analyses

Pharmacokinetic analyses of plasma GSK598809, GSK685249, nicotine, cotinine and 3HC concentration-time data were conducted using non-compartmental Model 200 (for extravascular administration) of WinNonlin Professional Edition version 5.2 according to GlaxoSmithKline standard operating procedures. Actual elapsed time from dosing was used to estimate all individual plasma pharmacokinetic parameters for evaluable subjects.

Dose proportionality of GSK598809

For AUC(0-∞), AUC(0-t) and Cmax of GSK598809, statistical analysis was performed by applying the power model. A mixed effects model was fitted to data with log(dose) as a continuous covariate and subject as a random effect. The coefficient of the slope with 90% confidence intervals, on the log scale, was used to assess dose proportionality. As a secondary analysis, the analysis of variance (ANOVA) model of log-transformed dose-normalised derived parameters was performed.

Effect of GSK598809 on nicotine pharmacokinetics

Nicotine parameters AUC(0-4), AUC(0-12), Cmax(0-4) and Cmax(0-12) were loge-transformed prior to analysis. Analysis of variance models were applied to the pharmacokinetic parameters, including the factor treatment as a fixed effect and subject as a random effect. Comparisons are expressed as ratios of the pharmacokinetic parameters after each dose of GSK598809 relative to those after placebo.

Effect of GSK598809 on the ratios of cotinine vs. nicotine and 3HC vs. cotinine

Individual ratios were calculated from the pharmacokinetic parameters AUC(0-4), AUC(0-12), Cmax(0-4) and Cmax(0-12), for example, AUC(0-12)(cotinine)/ AUC(0-12)(nicotine) or AUC(0-12)(3HC)/AUC(0-12)(cotinine) and log-transformed prior to the analysis. Analysis of variance models were applied including the factor treatment as a fixed effect and subject as a random effect. Comparisons are expressed as ratios of the pharmacokinetic parameters after each dose of GSK598809 relative to those after placebo.

Pharmacodynamic analyses

Plots of mean (±SD) for each of the pharmacodynamic endpoints were generated by regimen over time for all subjects, and for males and females separately. Individual plots of prolactin, LH and FSH (females only) were also produced, separately for each regimen.

The time to the first post dose cigarette, and the number of cigarettes smoked in the first hour following the 4-h abstinence period were summarised by treatment and time.


14


12

Summary:

Safety:

There were no serious adverse events (SAEs) during the study and no withdrawals due to AEs. The most frequently reported AEs irrespective of causality were headache and dizziness, each occurring in five subjects (28%) (Table 2). Neither of these AEs appeared more frequently with increasing GSK598809 dose and both were reported following placebo as well as active doses. Adverse events of interest included akathisia (reported in one subject following both placebo and GSK598809 175 mg regimens) and involuntary muscle contractions (one subject following GSK598809 75 mg). None of the AEs were classed as severe; they were all mild or moderate in intensity.

Several subjects reported poor concentration 2 to 4 h after dosing with both active GSK598809 and placebo (during the no-smoking portion of the study); these AEs were coded under the preferred term ‘disturbance in attention’ (Table 2).

Table 2 Summary of All Adverse Events Occurring in Two or More Subjects in the Study

GSK598809 Placebo 75 mg 130 mg 175 mg Total

N = 17 N = 18 N = 17 N = 17 N = 18 Most Frequent Adverse Events

n (%) n (%) n (%) n (%) n (%) Any adverse event 5 (29) 7 (39) 7 (41) 5 (29) 13 (72) Any adverse event related to investigational product 1 3 (18) 7 (39) 6 (35) 4 (24) 13 (72) Most Frequent adverse events (≥ two subjects in the study)

Dizziness 1 (6) 1 (6) 3 (18) 2 (12) 5 (28) Headache 1 (6) 1 (6) 2 (12) 1 (6) 5 (28) Disturbance in attention 2 (12) 2 (11) 1 (6) 0 4 (22) Fatigue 1 (6) 2 (11) 0 1 (6) 3 (17) Application site reaction 0 0 1 (6) 1 (6) 2 (11) Stomach discomfort 1 (6) 0 1 (6) 0 2 (11) Vomiting 0 1 (6) 1 (6) 0 2 (11)

Source Data: Table 10.2, Table 10.3 1. In the opinion of the Investigator. Average clinical chemistry and haematology values over time showed similar patterns following all four treatment regimens including placebo (Table 10.7 and Table 10.8). No safety concerns were raised on urinalysis dipstick results (Table 10.9).

No other subjects had haematology PCI values.


15


13

None of these values were reported as AEs and all returned to normal by the follow-up visit (Table 10.15).

No changes in average vital signs values (systolic and diastolic blood pressure, heart rate and respiration rate) of potential clinical significance were noted following any of the GSK598809 treatments or placebo (Table 10.1).

Five subjects had vital signs values of PCI: one subject had an elevated diastolic blood pressure following placebo dosing in Period 1, and four subjects had low systolic blood pressure values (three subjects in the placebo dosing period and one following GSK598809 130 mg administration) (Table 10.16). None of these values were reported as AEs.

There were no ECG traces that were considered to show clinically significant abnormalities (Table 10.4). No subject reached stopping criteria for ECG (QTc >480 msec or an increase of >60 msec from baseline). Importantly, by telemetry and Holter, no ventricular arrhythmias were noted.

In the aggregate analysis however, average values for QT, QTcF, and QTcB intervals appeared to increase following all treatments including placebo, but to a greater extent following all three GSK598809 doses than with placebo (Table 10.5).

Although no individual met stopping criteria for QTc during the study, mean aggregate data revealed an apparent dose-related increase in QTcF with a maximal increase from baseline occurring in females (n=11) at 2 h after GSK598809 175 mg dosing of around 23 msec (±17), and in males (n=6) of 17 msec (±5) (Figure 10.6)

Increases in mean QTcF were observed following all GSK598809 regimens and appeared dose-related, with 175 mg showing the largest mean increase from pre-dose. At 2 h post dose, mean values for QTcF were 399 msec following placebo administration, 406 msec for the GSK598809 75 mg dose, 411 msec for the 130 mg dose and 418 msec for the 175 mg dose. GSK598809 regimens displayed mean QTcF change from baseline greater than placebo up to 24 h post dose (Figure 1).


16


14

Figure 1 Plot of Mean (Standard Deviation) QTcF Change from Baseline by Treatment and Time

Source: Figure 10.2 Data for mean (SD) increase from baseline QTcB are presented in Table 10.6.

Additional exploratory analyses of manually derived ECG parameters pre-dose through 4 h post dose confirmed the observations on QTcF.

Four subjects showed asymptomatic and self-limiting elevations in QTcB and/or QTcF (>450 msec), all of whom were female subjects following GSK598809 administration. Follow-up QTcB and QTcF values were normal in all of these subjects. The highest recorded QTcF value was 463 msec, 8 h after administration of GSK598809 175 mg in Period 4 (baseline for this subject was 419 msec, pre-dose in Period 4) (Table 10.17).

At the time of this report the Holter recordings had not been assessed for QTc and will be the subject of an addendum to this report.

Regarding the movement scales, no remarkable trends were observed in AIMS or SAS total scores for placebo or GSK598809 regimens (Figure 12.1 and Figure 12.2). The BARS did not display any remarkable results.

Pharmacokinetics:

No plasma GSK598809, GSK685249, nicotine, cotinine and 3HC concentrations were excluded from the pharmacokinetic analysis.

Assumptions underlying the statistical models were not seriously violated.


17


15

GSK598809 pharmacokinetic parameters

Pharmacokinetic parameters of GSK598809 are summarised in Table 3.

Table 3 Summary of GSK598809 Pharmacokinetic Parameters Following Single Ascending Oral Doses of GSK598809

GSK598809 Parameter GSK598809 Treatment N n Geometric Mean

(CVb%) 95% Confidence

Interval 75 mg 18 18 4570 (29.1) 3966, 5266 130 mg 17 17 10281 (29.3) 8872, 11915 AUC(0-∞) (ng.h/mL) 175 mg 17 17 14415 (23.1) 12822, 16206 75 mg 18 18 4431 (28.0) 3865, 5080 130 mg 17 17 9756 (26.7) 8525, 11165 AUC(0-t) (ng.h/mL) 175 mg 17 17 13600 (19.6) 12306, 15029 75 mg 18 18 591 (40.3) 488, 717 130 mg 17 17 1155 (29.4) 996, 1340 Cmax (ng/mL) 175 mg 17 17 1407 (31.1) 1204, 1645 75 mg 18 18 20.1 (24.0) 17.8, 22.6 130 mg 17 17 22.4 (30.0) 19.3, 26.1 t½ (h) 175 mg 17 17 23.3 (24.9) 20.6, 26.5 75 mg 18 18 0.0346 (24.0) 0.0307, 0.0389 130 mg 17 17 0.0309 (30.0) 0.0266, 0.0360 λz (1/h) 175 mg 17 17 0.0297 (24.9) 0.0262, 0.0337 75 mg 18 18 1.51 (0.98–6.02) NA 130 mg 17 17 1.50 (0.98–3.00) NA tmax (h)1 175 mg 17 17 1.98 (1.00–6.00) NA

Source Data: Table 11.6 and Table 11.11 1. Median (range). CVb = between-subject coefficient of variation; AUC(0-∞) = area under the concentration-time curve from zero (pre-dose) extrapolated to infinite time; AUC(0-t) = area under the concentration-time curve from zero (pre-dose) to last quantifiable concentration; Cmax = maximum observed plasma concentration; t½ = observed elimination half-life; λz = terminal phase rate constant; tmax = time to Cmax; NA = not applicable. GSK598809 dose proportionality

The adjusted mean slope was close to 1 for GSK598809 Cmax, which suggested dose proportionality. For GSK598809 AUC(0-∞) and AUC(0-t), the adjusted mean slope was above the value of 1, suggesting a more than proportional increase with increasing dose.

The estimated increase in dose required to double each parameter is given by 2(1/β) where β represents the adjusted mean slope (similarly for the confidence interval limits). For AUC(0-∞) the estimated increase is 1.64 (90% confidence interval: 1.60 to 1.69). That is, an increase in dose of 64% would result in the doubling of AUC(0-∞) over the dose range 75–175mg. Similarly, an increase in dose of 66% would result in the doubling of AUC(0-t), estimated increase 1.66 (90% confidence interval: 1.62 to 1.71). For Cmax, an increase in dose of 93% would result in the doubling of Cmax, estimated increase 1.93 (90% confidence interval: 1.74 to 2.26).


18


16

The criteria for statistically confirmed dose proportionality for GSK598809 AUC(0-∞) and Cmax across doses 75–175 mg were that the 90% confidence interval for the adjusted mean slope had to fall completely within the range 0.74–1.26. The 90% confidence interval for Cmax slope was contained within this range but those for AUC(0-∞) and AUC(0-t) slopes were not contained within the range (Table 4).

Table 4 Summary of Assessment of Dose Proportionality as Assessed by the Power Model for Plasma GSK598809

Parameter Adjusted Mean Slope

Standard Error

90% Confidence Interval for Slope

CV Within %

AUC(0-∞) (ng.h/mL) 1.397 0.041 (1.328, 1.467) 10.4 AUC(0-t) (ng.h/mL) 1.363 0.042 (1.292, 1.435) 10.7 Cmax (ng/mL) 1.052 0.120 (0.849, 1.255) 31.2 Source Data: Table 11.16 CV Within = within-subject coefficient of variation; AUC(0-∞) = area under the plasma concentration-time curve from time zero extrapolated to infinity; AUC(0-t) = area under the plasma concentration-time curve from time zero to last quantifiable concentration; Cmax = maximum observed plasma concentration.

In the secondary analysis (ANOVA), a 90% confidence interval contained within the range 0.80–1.25 would mean dose proportionality. For GSK598809 Cmax, the 90% confidence interval fell within this range for 175 mg but not for 130 mg. The 90% confidence intervals for AUC(0-∞) and AUC(0-t) lay outside the range; thus, the ANOVA model confirmed the interpretation of the power model of a more than proportional increase of AUC(0-∞) and AUC(0-t) with increasing dose (Table 5).

Table 5 Summary of Assessment of Dose Proportionality as Assessed by Dose-Normalised Analysis of Variance for Plasma GSK598809

Parameter Comparison LS Geometric Mean Test

LS Geometric Mean Ref.

Ratio 90% Confidence Interval for Ratio

130 mg vs. 75 mg 10504.612 4570.087 1.326 (1.255, 1.402) AUC(0-∞) (ng.h/mL) 175 mg vs. 75 mg 14727.861 4570.087 1.381 (1.307, 1.460)

130 mg vs. 75 mg 9961.186 4431.114 1.297 (1.224, 1.374) AUC(0-t) (ng.h/mL) 175 mg vs. 75 mg 13885.665 4431.114 1.343 (1.267, 1.423)

130 mg vs. 75 mg 1158.339 591.438 1.130 (0.950, 1.345) Cmax (ng/mL) 175 mg vs. 75 mg 1410.593 591.438 1.022 (0.859, 1.216) Source Data: Table 11.17 LS = least squares; Ref. = reference treatment (GSK598809 75 mg); AUC(0-∞) = area under the plasma concentration-time curve from time zero extrapolated to infinity; AUC(0-t) = area under the plasma concentration-time curve from time zero to last quantifiable concentration; Cmax = maximum observed plasma concentration.

GSK685249 pharmacokinetic parameters

Pharmacokinetic parameters of GSK685429 are summarized in Table 6.


19


17

Table 6 Summary of GSK685249 Pharmacokinetic Parameters following Single Ascending Oral Doses of GSK598809

GSK685249 Parameter GSK598809 Treatment N n Geometric Mean


Interval 75 mg 18 11 85 (28.7) 70, 102 130 mg 17 11 149 (28.3) 124, 180 AUC(0-∞) (ng.h/mL) 175 mg 17 15 203 (25.0) 177, 232 75 mg 18 18 63 (26.8) 55, 72 130 mg 17 17 113 (30.8) 97, 132 AUC(0-t) (ng.h/mL) 175 mg 17 17 158 (27.6) 138, 182 75 mg 18 18 14.2 (30.3) 12, 16 130 mg 17 17 21 (29.4) 18, 24 Cmax (ng/mL) 175 mg 17 17 25 (34.9) 21, 30 75 mg 18 16 22 (31.3) 19, 26 130 mg 17 17 33 (39.1) 27, 40 t½ (h) 175 mg 17 17 36 (28.5) 31, 42 75 mg 18 16 0.0313 (31.3) 0.0266, 0.0368 130 mg 17 17 0.0213 (39.1) 0.0175, 0.0259 λz (1/h) 175 mg 17 17 0.0193 (28.5) 0.0167, 0.0223 75 mg 18 18 1.00 (0.50-4.00) NA 130 mg 17 17 1.00 (0.52-1.52) NA tmax (h)1 175 mg 17 17 1.00 (0.50-2.00) NA

Source Data: Table 11.7 and Table 11.12 1. Median (range). CVb = between-subject coefficient of variation; AUC(0-∞) = area under the concentration-time curve from zero (pre-dose) extrapolated to infinite time; AUC(0-t) = area under the concentration-time curve from zero (pre-dose) to last quantifiable concentration; Cmax = maximum observed plasma concentration; t½ = observed elimination half-life; λz = terminal phase rate constant; tmax = time to Cmax; NA = not applicable.

Nicotine pharmacokinetic parameters

Pharmacokinetic parameters of nicotine are summarised in Table 7.


20


18

Table 7 Summary of Nicotine Pharmacokinetic Parameters

Nicotine Parameter GSK598809 Treatment N n Geometric Mean


Interval Placebo 17 17 27.6 (33.0) 23.4, 32.6 75 mg 18 18 29.5 (34.5) 24.9, 34.8 130 mg 17 17 40.6 (42.8) 32.9, 50.2 AUC(0-4) (ng.h/mL)

175 mg 17 17 38.6 (36.2) 32.2, 46.3 Placebo 17 17 124 (57.7) 94.1, 163 75 mg 18 18 167 (46.5) 134, 209 130 mg 17 17 200 (43.8) 162, 248 AUC(0-12) (ng.h/mL)

175 mg 17 17 177 (33.5) 149, 209 Placebo 17 17 13.5 (68.2) 9.85, 18.6 75 mg 18 18 15.4 (67.2) 11.3, 20.8 130 mg 17 17 21.1 (35.0) 17.7, 25.2 Cmax(0-4) (ng/mL)

175 mg 17 17 19.8 (50.2) 15.5, 25.2 Placebo 17 17 20.2 (73.8) 14.4, 28.4 75 mg 18 18 25.3 (48.1) 20.2, 31.8 130 mg 17 17 29.1 (42.8) 23.6, 36.0 Cmax(0-12) (ng/mL)

175 mg 17 17 27.9 (29.1) 24.1, 32.3 Placebo 17 17 0.00 (0.00–1.02) NA 75 mg 18 18 0.00 (0.00–1.00) NA 130 mg 17 17 0.00 (0.00–1.00) NA tmax(0-4) (h)1

175 mg 17 17 0.00 (0.00–0.50) NA Placebo 17 17 8.00 (0.00–12.05) NA 75 mg 18 18 8.01 (0.00–10.07) NA 130 mg 17 17 10.00 (1.00–12.08) NA tmax(0-12) (h)1

175 mg 17 17 7.98 (0.00–12.03) NA Source Data: Table 11.8 and Table 11.13 1. Median (range). CVb = between-subject coefficient of variation; AUC(0-4) = area under the concentration-time curve from zero (pre-dose) to 4 h; AUC(0-12) = AUC from zero (pre-dose) to 12 h; Cmax(0-4) = maximum observed concentration over 0 to 4 h interval; Cmax(0-12) = maximum observed concentration over 0 to 12 h interval; tmax(0-4) = first time of occurrence of Cmax(0-4); tmax(0-12) = first time of occurrence of Cmax(0-12). Effect of GSK598809 on nicotine pharmacokinetics

In the 12-h interval following dosing, nicotine AUC(0-12) and Cmax(0-12) were estimated, on average, to be greater following GSK598809 75 mg, 130 mg and 175 mg than placebo, although the increases did not appear to be dose-related.

In the 4-h interval, nicotine AUC(0-4) and Cmax(0-4) were estimated, on average, to be greater following GSK598809 than placebo. The effect was more modest at the lower dose (Table 8).


21


19

Table 8 Summary of Statistical Analysis of the Effect of GSK598809 on Nicotine Pharmacokinetics

Nicotine Parameter

Comparison (GSK598809)

LS Geometric Mean Test


Ratio 90% Confidence Interval for Ratio

75 mg vs. placebo 29.47 27.44 1.07 (0.91, 1.26) 130 mg vs. placebo 40.35 27.44 1.47 (1.25, 1.73)

AUC(0-4) (ng.h/mL)

175 mg vs. placebo 38.36 27.44 1.40 (1.19, 1.65) 75 mg vs. placebo 167.43 118.83 1.41 (1.22, 1.63) 130 mg vs. placebo 192.20 118.83 1.62 (1.40, 1.87)

AUC(0-12) (ng.h/mL)


Cmax(0-4) (ng/mL)


Cmax(0-12) (ng/mL)

175 mg vs. placebo 27.15 19.64 1.38 (1.15, 1.65) Source Data: Table 11.18 LS = least squares; Ref. = reference treatment (placebo); AUC(0-4) = area under the concentration-time curve from zero (pre-dose) to 4 h; AUC(0-12) = AUC from zero (pre-dose) to 12 h; Cmax(0-4) = maximum observed concentration over 0 to 4 h interval; Cmax(0-12) = maximum observed concentration over 0 to 12 h interval.

Cotinine pharmacokinetic parameters

Pharmacokinetic parameters of cotinine are summarised in Table 9.


22


20

Table 9 Summary of Cotinine Pharmacokinetic Parameters

Cotinine Parameter GSK598809 Treatment N n Geometric Mean


Interval Placebo 17 17 1077 (53.0) 834, 1391 75 mg 18 18 1025 (48.6) 815, 1288 130 mg 17 17 1200 (52.7) 930, 1548 AUC(0-4) (ng.h/mL)

175 mg 17 17 1195 (49.5) 939, 1520 Placebo 17 17 3235 (48.0) 2559, 4088 75 mg 18 18 3013 (48.3) 2400, 3784 130 mg 17 17 3581 (49.4) 2816, 4554 AUC(0-12) (ng.h/mL)

175 mg 17 17 3472 (50.8) 2714, 4443 Placebo 17 17 307 (51.3) 239, 394 75 mg 18 18 305 (48.6) 243, 383 130 mg 17 17 361 (52.0) 281, 465 Cmax(0-4) (ng/mL)

175 mg 17 17 338 (50.2) 265, 431 Placebo 17 17 320 (50.0) 251, 408 75 mg 18 18 319 (49.5) 253, 403 130 mg 17 17 374 (48.2) 295, 473 Cmax(0-12) (ng/mL)

175 mg 17 17 364 (52.6) 283, 470 Placebo 17 17 0.50 (0.00–3.03) NA 75 mg 18 18 0.75 (0.00–2.02) NA 130 mg 17 17 0.52 (0.00–3.00) NA tmax(0-4) (h)1


175 mg 17 17 1.00 (0.00–12.00) NA Source Data: Table 11.9 and Table 11.14 1. Median (range). CVb = between-subject coefficient of variation; AUC(0-4) = area under the concentration-time curve from zero (pre-dose) to 4 h; AUC(0-12) = AUC from zero (pre-dose) to 12 h; Cmax(0-4) = maximum observed concentration over 0 to 4 h interval; Cmax(0-12) = maximum observed concentration over 0 to 12 h interval; tmax(0-4) = first time of occurrence of Cmax(0-4); tmax(0-12) = first time of occurrence of Cmax(0-12). Effect of GSK598809 on the ratio of cotinine vs. nicotine

Estimated ratios of cotinine vs. nicotine for AUC(0-12) were, on average, lower following GSK598809 doses from 75 mg to 175 mg than with placebo.

The ratio of cotinine vs. nicotine AUC(0-4) was lower following GSK598809 dosing compared with placebo. The effect was more modest at the lower dose (Table 10).


23


21

Table 10 Summary of Statistical Analysis of the Effect of GSK598809 on the Ratio of Cotinine vs. Nicotine

Parameter Comparison (GSK598809)



Ratio 90% Confidence

Interval 75 mg vs. placebo 34.76 38.91 0.89 (0.77, 1.04) 130 mg vs. placebo 29.49 38.91 0.76 (0.65, 0.88)

Cotinine AUC(0-4)/ nicotine AUC(0-4)


Cotinine AUC(0-12)/ nicotine AUC(0-12)

175 mg vs. placebo 20.10 26.70 0.75 (0.66, 0.86) Source: Table 11.19 LS = least squares; Ref. = reference treatment (placebo); AUC(0-4) = area under the concentration-time curve from zero (pre-dose) to 4 h; AUC(0-12) = AUC from zero (pre-dose) to 12 h.

Trans-3-hydroxycotinine

Pharmacokinetic parameters of 3HC are summarized in Table 11.


24


22

Table 11 Summary of Trans-3-Hydroxycotinine Pharmacokinetic Parameters

Trans-3-Hydroxycotinine Parameter

GSK598809 Treatment N n Geometric Mean


Interval Placebo 17 16 324 (41.7) 261, 401 75 mg 18 17 350 (39.6) 288, 426 130 mg 17 16 355 (45.0) 282, 446 AUC(0-4) (ng.h/mL)

175 mg 17 16 299 (58.9) 224, 400 Placebo 17 16 942 (38.3) 773, 1147 75 mg 18 17 991 (41.3) 808, 1216 130 mg 17 16 1040 (43.7) 833, 1300 AUC(0-12) (ng.h/mL)

175 mg 17 16 859 (57.9) 645, 1144 Placebo 17 16 90.4 (38.9) 74.0, 110 75 mg 18 17 98.2 (38.6) 81.1, 119 130 mg 17 16 98.4 (43.1) 78.9, 123 Cmax(0-4) (ng/mL)

175 mg 17 16 85.1 (53.6) 65.1, 111 Placebo 17 16 91.1 (38.4) 74.8, 111 75 mg 18 17 100 (39.7) 82.1, 122 130 mg 17 16 102 (41.9) 82.0, 126 Cmax(0-12) (ng/mL)

175 mg 17 16 86.1 (53.7) 65.9, 113 Placebo 17 16 1.49 (0.00–4.10) NA 75 mg 18 17 1.00 (0.00–4.02) NA 130 mg 17 16 1.00 (0.00–4.08) NA tmax(0-4) (h)1


175 mg 17 16 0.24 (0.00–6.00) NA Source Data: Table 11.10 and Table 11.15 1. Median (range). CVb = between-subject coefficient of variation; AUC(0-4) = area under the concentration-time curve from zero (pre-dose) to 4 h; AUC(0-12) = AUC from zero (pre-dose) to 12 h; Cmax(0-4) = maximum observed concentration over 0 to 4 h interval; Cmax(0-12) = maximum observed concentration over 0 to 12 h interval; tmax(0-4) = first time of occurrence of Cmax(0-4); tmax(0-12) = first time of occurrence of Cmax(0-12). Effect of GSK598809 on the ratio of trans-3-hydroxycotinine vs. cotinine

The estimated ratio of 3HC vs. cotinine decreased with dose, on average, for all parameters investigated. A substantial lack of interaction, with confidence intervals contained within or very close to the standard acceptance range of 0.8–1.25, was observed with GSK598809 doses of 75 mg and 130 mg while the decrease was more evident at 175 mg (Table 12).


25


23

Table 12 Summary of Statistical Analysis of the Effect of GSK598809 on the Ratio of Trans-3-Hydroxycotinine vs. Cotinine Pharmacokinetics

Ratio 3HC/ Cotinine Comparison (GSK598809)



Ratio 90% Confidence

Interval 75 mg vs. placebo 0.31 0.29 1.10 (0.95, 1.26) 130 mg vs. placebo 0.28 0.29 0.97 (0.85, 1.12)

3HC AUC(0-4) / cotinine AUC(0-4)


3HC AUC(0-12) / cotinine AUC(0-12)


3HC Cmax(0-4) / cotinine Cmax(0-4)


3HC Cmax(0-12) / cotinine Cmax(0-12)

175 mg vs. placebo 0.22 0.27 0.81 (0.72, 0.92) Source Data: Table 11.19 3HC = trans-3’hydroxycotinine; LS = least squares; Ref. = reference treatment (placebo); AUC(0-4) = area under the concentration-time curve from zero (pre-dose) to 4 h; AUC(0-12) = AUC from zero (pre-dose) to 12 h; Cmax(0-4) = maximum observed concentration over 0 to 4 h interval; Cmax(0-12) = maximum observed concentration over 0 to 12 h interval.

Pharmacodynamics:

For the Bond-Lader VAS, no obvious patterns were observed for placebo or GSK598809 regimens (Figure 12.4 to Figure 12.6).

For mean POMS scores the fatigue-inertia domain showed an increase following all GSK598809 regimens at 4 h post dose, although this did not appear dose-related. This pattern was only present in females and not in males (Figure 12.3).

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

Smoking questionnaires

Due to the small sample size and the exploratory nature of the endpoints, no inferences can be drawn from the results.

In general there were no remarkable trends observed for placebo and GSK598809 regimens (Figure 12.8). The Tiffany QSU Factor I scores (intention and desire to smoke and anticipation of positive reinforcement) showed decreases for GSK598809 175 mg compared with placebo and other doses up to 3 h post dose (Figure 12.7). The QSU


26


24

Factor II (anticipation of negative reinforcement) showed higher mean scores for GSK598809 75 mg than other regimens, although this was also present pre-dose.

For the Westman-Levine CES aversion factor, GSK598809 75 mg, 175 mg and placebo regimens displayed increased mean score at 4 h post dose, but this was not seen following GSK598809 130 mg (Figure 12.11). No noticeable trends were observed in the remaining factors of the CES (Figure 12.9 to Figure 12.13).

Plots of mean MNWS showed no noticeable trends in either the placebo or GSK598809 regimens (Figure 12.21). Following statistical analysis of MNWS all estimates were close to zero, across all time points for each dose difference from placebo. There was no clear signal of a difference between GSK598809 and placebo on MNWS total score (Table 12.3).

Choice reaction time

No trends were observed for CRT percentage of correct responses on placebo and GSK598809 regimens. Reaction time of correct responses showed slight increases with dose at 2 h post dose for males only. This trend was not observed in female subjects (Figure 12.14 and Figure 12.15).

Stop-signal test

For SST, no obvious patterns were observed for go and stop reaction times for placebo or GSK598809 regimens. Commission errors showed fairly stable trends over time (Figure 12.16 to Figure 12.19).

There were slight increases in omission errors for GSK598809 regimens at 2 h post dose, whereas a slight decrease was observed for placebo (Figure 12.19).

Cigarette consumption

No obvious patterns were observed in plots of cigarette consumption over time, for placebo or GSK598809 regimens (Figure 12.20). Time to first post dose cigarette and number of cigarettes smoked in the first hour following the 4-h abstinence period showed no remarkable trends between placebo and GSK598809 (Table 12.1 and Table 12.2).

Hormones

Mean prolactin pre- and post dose (24 h) were not noticeably different in male or female subjects (Figure 12.22).

There were no clinically significant changes in mean GH, TSH, free testosterone, total testosterone, LH and FSH concentrations at the two time points tested, pre- and post dose (24 h) (Figure 12.22 and Figure 12.23).


27


25

Conclusions:

• GSK598809 was generally well tolerated in otherwise healthy smokers. There were no SAEs reported and no withdrawals due to AEs.

• No subject reached stopping criteria for safety laboratory results, nor were there any changes of clinical significance in either the safety laboratory or the pharmacodynamic hormonal assessments.

• No subject reached stopping criteria for vital signs or ECG changes. There were no individual ECG traces that were considered to show clinically significant abnormalities.

• Aggregate analysis showed apparent dose-related increases in mean QTcF for GSK598809 up to 24 h post dose.

• The AIMS, SAS and BARS scores showed no trends in placebo or GSK598809 regimens.

• After single doses of GSK598809, dose-proportional increases in Cmax but more than dose-proportional increases in AUC(0-∞) and AUC(0-t) were observed for GSK598809 in the dose range 75 to 175 mg.

• Nicotine Cmax and AUC over the 4-h and 12-h intervals were, on average, greater following GSK598809 doses 75 to 175 mg compared with placebo; however, the increases did not appear to be dose-related.

• Ratios of cotinine vs. nicotine for AUC over the 4-h and 12-h intervals were on average lower following GSK598809 for doses 75 to 175 mg compared with placebo.

• Ratio of 3HC vs. cotinine was estimated, on average, to decrease with dose for AUC(0-4), AUC(0-12), Cmax(0-4) and Cmax(0-12) with the confidence intervals contained or very close to the standard acceptance range of 0.80 to 1.25 for the 75 and 130 mg doses, and a decrease being more evident for 175 mg.

• The analyses of nicotine, cotinine and 3HC pharmacokinetics suggested a possible minor inhibition of CYP2A6-mediated metabolism at the GSK598809 175 mg dose. Doses lower than 175 mg did not suggest inhibition of metabolism.

• Bond and Lader VAS did not show any trends in placebo or active GSK598809 regimens.

• Mean POMS fatigue-inertia domain displayed slight increases for GSK598809 regimens at 4 h post dose, although this did not appear dose-related.

• No significant trends were observed in any of the exploratory analyses (Tiffany QSU, Westman-Levine CES, MNWS) between placebo and GSK598809. However, the Tiffany QSU Factor I scores (intention and desire to smoke and anticipation of positive reinforcement) showed decreases for GSK598809 175 mg compared with placebo up to 3 h post dose.

• There were no noticeable trends in cigarette consumption.


28


26

• There were no remarkable patterns for either CRT or SST with placebo and GSK598809 regimens.

• Mean prolactin concentrations pre- and post dose (24 h) were not noticeably different in male or female subjects. There were no clinically significant changes in mean GH, TSH, free testosterone, total testosterone, LH and FSH concentrations at pre- and post dose (24 h).

Date of Report:

June 2009


29

Synopsis To assess the effect of single ascending oral doses of GSK598809 on nicotine metabolism in...

Documents

Transcript of Synopsis To assess the effect of single ascending oral doses of GSK598809 on nicotine metabolism in...