Pharmacology The Journal of Clinical

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May 24, 2011 - The online version of this article can be found at: DOI: 10.1177/ ... preferentially increase intake of energy-rich foods high in fat and .... tolerability in a limited number of participants follow- .... ation of perceived creaminess, sweetness, and fat con- tent (ie ... The model included subject as a random effect and.
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Opioid Receptor Modulation of Hedonic Taste Preference and Food Intake: A Single-Dose Safety, Pharmacokinetic, and Pharmacodynamic Investigation With GSK1521498, a Novel µ-Opioid Receptor Inverse Agonist Pradeep J. Nathan, Barry V. O'Neill, Mark A. Bush, Annelize Koch, Wenli X. Tao, Kay Maltby, Antonella Napolitano, Allison C. Brooke, Andrew L. Skeggs, Craig S. Herman, Andrew L. Larkin, Diane M. Ignar, Duncan B. Richards, Pauline M. Williams and Edward T. Bullmore J Clin Pharmacol published online 24 May 2011 DOI: 10.1177/0091270011399577 The online version of this article can be found at: http://jcp.sagepub.com/content/early/2011/05/24/0091270011399577

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Opioid Receptor Modulation of Hedonic Taste Preference and Food Intake: A Single-Dose Safety, Pharmacokinetic, and Pharmacodynamic Investigation With GSK1521498, a Novel µ-Opioid Receptor Inverse Agonist Pradeep J. Nathan, PhD, FCP, Barry V. O’Neill, PhD, Mark A. Bush, PhD, Annelize Koch, MBChB, Wenli X. Tao, PhD, Kay Maltby, BSc(Hons), Antonella Napolitano, MD, PhD, Allison C. Brooke, DipN, Andrew L. Skeggs, BSc(Hons), Craig S. Herman, PharmD, Andrew L. Larkin, MSc, Diane M. Ignar, PhD, Duncan B. Richards, DM, MRCP, Pauline M. Williams, MBBCh, and Edward T. Bullmore, MB, PhD

Endogenous opioids and µ-opioid receptors have been linked to hedonic and rewarding aspects of palatable food intake. The authors examined the safety, pharmacokinetic, and pharmacodynamic profile of GSK1521498, a µ-opioid receptor inverse agonist that is being investigated primarily for the treatment of overeating behavior in obesity. In healthy participants, GSK1521498 oral solution and capsule formulations were well tolerated up to a dose of 100 mg. After single doses (10-150 mg), the maximum concentration (Cmax) and area under the curve (AUC) in plasma increased in a dose-proportional manner. GSK1521498 selectively reduced sensory hedonic

ratings of high-sugar and high-fat dairy products and caloric intake of high-fat/high-sucrose snack foods. These findings provide encouraging data in support of the development of GSK1521498 for the treatment of disorders of maladaptive ingestive behavior or compulsive consumption.

M

linked to the function of the endogenous opioid system, especially the µ-opioid receptors.1-8 Animal studies have shown that µ-opioid receptor agonists preferentially increase intake of energy-rich foods high in fat and sucrose, as well as tasty noncaloric foods high in saccharin and salt.5,9-15 In contrast, µ-opioid receptor antagonists, such as naloxone and naltrexone, reduce food intake of palatable or high-caloric food and drinks.16-33 In humans, the µ-opioid receptor antagonists, including naloxone, naltrexone, and nalmefene, have been shown to decrease short-term food intake (decreases between 11% and 29%)8,34 and reduce affective or subjective pleasantness (ie, hedonic preference) of palatable foods (including sucrose solution, sugar and fat mixtures, sweetened milk, and actual food).35-41 Longer term studies have, however, yielded disappointing

echanisms of appetite control and, in particular, hedonic processes associated with food evaluation, consumption, and orosensory reward have been

From the Clinical Unit Cambridge (Dr Nathan, Dr O’Neill, Dr Koch, Ms Maltby, Dr Napolitano, Ms Brooke, Mr Skeggs, Dr Bullmore), Clinical Pharmacokinetics (Dr Bush), Discovery Biometrics (Dr Tao), Academic Discovery Performance Unit (Mr Herman, Dr Richards, Dr Williams, Dr Bullmore), Metabolic Pathways Centre for Excellence in Drug Discovery (Dr Larkin, Dr Ignar), GlaxoSmithKline, Cambridge, UK, and the Department of Psychiatry, University of Cambridge, Cambridge, UK (Dr Nathan, Dr O’Neill, Dr Bullmore). Dr Nathan and Dr O’Neill are joint first authors. Supplementary data for this article are available at http://jcp.sagepub.com/ supplemental/. Submitted for publication September 17, 2010; revised version accepted January 14, 2011. Address for correspondence: Pradeep J. Nathan, GlaxoSmithKline, Clinical Unit Cambridge, Hills Road, Cambridge CB2 2GG, UK; e-mail: [email protected]. DOI: 10.1177/0091270011399577

Keywords: µ-Opioid receptor; pharmacokinetics; food intake; taste preference; hedonic; reward; pharmacodynamic; obesity; binge eating Journal of Clinical Pharmacology, XXXX;XX:xxx-xxx © 2011 The Author(s)

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Nathan et al by 27% to 69%, at doses equivalent to 59% to 82% µ-opioid receptor occupancy.42 GSK1521498 has also been shown to reduce preference for high-sucrose concentrations in a rat model of food liking and to reduce operant responding to obtain a palatable food reward in a progressive ratio model of motivation.42 Here we report the findings of a first-time-in-human (FTIH) study of GSK1521498 in healthy participants. The objectives of the study were (1) to investigate the safety profile of single, ascending oral doses of GSK1521498; (2) to investigate the pharmacokinetics and dose proportionality of single, ascending oral doses of GSK1521498; and (3) to investigate the pharmacodynamic effects of GSK1521498 on experimental models of hedonic taste preference and ad libitum food intake. Figure 1.  The chemical structure of GSK1521498 (N-{[3,5-difluoro3′-(1H-1,2,4-triazol-3-yl)-4-biphenylyl]methyl}-2,3-dihydro-1H-inden2-amine phosphate (1:1)).

effects on weight loss,8 although apparently, poor efficacy could be explained by a number of methodological issues (ie, small sample size, suboptimal patient population) and pharmacological factors8 (ie, µ-opioid receptor selectivity, potency, metabolites, intrinsic activity). The balance of evidence from animal and short-term human studies suggests that inhibition of µ-opioid receptor-mediated hedonic and motivation processes, which drive consumption of highly palatable foods, may be a promising therapeutic approach for disorders of maladaptive ingestive behavior. It may also present an opportunity for more mechanistically aligned development of µ-opioid receptor ligands for disorders such as obesity. GSK1521498, (N-{[3,5-difluoro-3′-(1H-1,2,4-triazol3-yl)-4-biphenylyl]methyl}-2,3-dihydro-1H-inden-2amine phosphate (1:1)) (GlaxoSmithKline, Research Triangle Park, North Carolina) (Figure 1), is a µ-opioid receptor inverse agonist that is being investigated primarily for the treatment of overeating behavior in obesity and secondarily for addictive disorders and other forms of maladaptive ingestive behavior or compulsive consumption. It has higher affinity for µ (14-20-fold selectivity) than for kappa (κ) and delta (δ) subtypes of the opioid receptor.42 In vitro functional studies have shown that it is differentiated from naltrexone by inverse agonist properties at the µ-opioid receptor under conditions of constitutive activity.42 In preclinical rodent models of obesity, GSK1521498 caused a dosedependent reduction in intake of palatable chow and commensurate reductions of body weight. In the dietinduced obesity model in rats, food intake was reduced

Methods This study was performed at the GlaxoSmithKline Clinical Unit Cambridge (CUC) (ClinicalTrials.gov identifier: NCT00857883). The study was approved by the Welwyn Clinical Pharmacology Ethics Committee, University of Hertfordshire, and written informed consent was obtained from all study participants. The study was conducted in 3 parts: part A (single, ascending oral doses of GSK1521498/placebo), part B (relative bioavailability of GSK1521498 oral solution vs capsule and food-pharmacokinetic interaction), and part C (efficacy in experimental models of hedonic taste preference and ad libitum food intake). Participants Fifty-six healthy male volunteers participated in parts A, B, and C (part A, n = 24, mean age 33.5 years; part B, n = 12, mean age 30.7 years; and part C, n = 20, mean age 36.2 years). All participants had a body weight of ≥45 kg and a body mass index (BMI) between 20 and 30 kg/m2 for parts A and B (mean BMIs for part A and part B were 25.2 kg/m2 and 24.4 kg/m2, respectively) and between 25 and 35 kg/m2 for part C (mean BMI 28.6 kg/m2). Participants included in the study were drug naive (for at least 14 days or 5 halflives, whichever was longer) and free of current or past history of any physical, neurological, or psychiatric disorders. Design Part A used a single-blind, placebo-controlled, and randomized design, with up to 4 dosing periods. In cohort A1, participants received GSK1521498 10 mg

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Pharmacology of Gsk1521498 or placebo. Three participants received active drug (oral solution), and 2 participants received placebo. Cohort A1 was the sentinel group to monitor for safety/ tolerability in a limited number of participants following the first exposure in humans. Cohorts A2 and A3 comprised escalating GSK1521498 doses of 10, 25, 50, 100, and 150 mg and placebo. Each participant received up to 2 doses of placebo and up to 3 ascending doses of GSK1521498 oral solution. Part B used an open-label, randomized, 3-session crossover design. Each participant received a single dose of GSK1521498 (25 mg) oral solution (fasted), GSK1521498 (25 mg) capsule (fasted), and GSK1521498 (25 mg) capsule (fed). Part C used a randomized, double-blind, placebo-controlled, singledose, 2-way crossover design. Each participant received a single dose of placebo and a single dose of GSK1521498 25 mg (capsule) in a randomized fashion with a 14-day washout between sessions.

Mood States–Brief questionnaire (POMS-B).44 Participants were also examined for neurological side effects (including assessment of ptosis and nystagmus).

Procedures

Assessment of mood and alertness. Subjective changes in mood and alertness were measured using the VAMS43 and POMS-B.44 The VAMS consisted of 16 bipolar scales, anchored at each end of a 100-mm line. Participants placed a mark on each line that best described their current mood state. In factor analyses, these scales reduce to 3 subscales: alertness (9 items), contentedness (5 items), and calmness (2 items). The POMS-B consisted of 30 adjectives rated on a scale from 0 (not at all) to 4 (extremely), which were compiled into 6 mood dimensions, including anger, vigor, anxiety, fatigue, depression, and confusion.

After giving written informed consent, all participants underwent a medical screen within 30 days prior to the first dosing session to determine whether they were eligible to participate in the study. All participants checked into the CUC the evening of day -1 for each study visit and remained in the unit until discharge after all 24-hour assessments had been completed, following satisfactory review by a physician. Participants returned to the unit for outpatient visits at 48 and 72 hours postdose. Participants fasted from approximately 22:00 hours the evening before dosing until approximately 4 hours after study drug administration (apart from those receiving food in part B). Pharmacodynamic assessments in part C were performed between 2 and 4 hours postdose (approximately 12-14 hours of fasting). Small quantities of water were allowed until dosing. For each dosing session in part A, safety, tolerability, and pharmacokinetic data were reviewed before the next dose administration. Dosing periods were separated by ≥6 days. All participants returned for a follow-up visit 7 to 10 days after the last dosing period. The duration of each volunteer’s participation in the study from screening to follow-up visit was approximately 10 weeks. Safety and Tolerability The primary safety and tolerability end points investigated were adverse events (AEs), safety laboratory, vital signs, electrocardiogram (ECG), Bond and Lader Visual Analogue Mood Scale (VAMS),43 and the Profile of

Adverse events and serious adverse events. AE and serious adverse event (SAE) data were collected and recorded on day 1 (dosing day), continuing until the follow-up visit. Vital signs and ECG. Systolic and diastolic blood pressure, pulse rate, and single 12-lead ECGs were recorded at regular intervals. Twenty-four-hour Holter continuous ambulatory ECG monitoring was performed for approximately 24 hours at screening and at each dosing visit (starting just prior to dosing). In addition, continuous cardiac telemetry was performed on day 1 from at least 15 minutes prior to dosing until at least 6 hours after dosing.

Pharmacokinetic Assessments In parts A and B, blood samples for determination of plasma GSK1521498 concentrations were collected at predose and 0.5, 1, 2, 4, 6, 8, 12, 24, 48, and 72 hours postdose. In part C, blood samples for determination of GSK1521498 plasma concentrations were collected at predose and 1, 2, 4, 6, 8, 12, 24, 48, and 72 hours postdose. Plasma samples were analyzed for GSK1521498 using a validated analytical method based on protein precipitation, followed by high-performance liquid chromatography/tandem mass spectrometry analysis. The lower limit of quantification was 1 ng/mL using a 50-µL aliquot of EDTA plasma. The upper limit of quantification was 1000 ng/mL. Quality control (QC) samples, containing GSK1521498 at 3 different concentrations and stored with study samples, were analyzed with each batch of samples against separately prepared calibration standards. For the analysis to be acceptable, no

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Nathan et al more than one-third of the QC results were to deviate from the nominal concentration by more than 15%, and at least 50% of the results from each QC concentration should be within 15% of nominal. The applicable analytical runs met all QC acceptance criteria. Plasma concentrations were used to calculate the following GSK1521498 pharmacokinetic parameters: the area under the plasma concentration-time curve extrapolated to infinity (AUC0-∞, ng · h/mL), the maximum plasma concentration (Cmax, ng/mL) and its time of occurrence (tmax, h), and the apparent terminal halflife (t1/2, h). Pharmacodynamic Assessment

Before the first dosing occasion (at the screening visit or day -1), participants completed a food preference checklist and provided hedonic ratings for each of the food types using a 9-point hedonic preference scale. The participants were shown photographs of the different snack foods and selected 2 foods from each category that they rated most highly. These food types (a total of 8) were then used for the evaluation of food intake on day 1 of each dosing period and were presented in approximate 420-kJ (100-kcal) portions on a tray. The participants were informed that they could eat any of the food on the tray in any order but must complete the entire portion chosen before selecting another food. Statistical Analysis

Hedonic taste preference and taste perception (part C). Participants evaluated 20 samples of sweetened commercial dairy products, with varying sucrose and fat content, for taste and hedonic preference as previously described and validated for naloxone by Drewnowski and colleagues.41 The sucrose/fat ratios of the dairy products were identical to those previously reported.41 A 4 × 5 factorial design was used; dairy products containing 4 different levels of fat (whole milk, 3.5%; evaporated milk, 9%; single cream, 19.1%; whipping cream, 38.9%) were sweetened with 5 levels of sucrose (2%, 4%, 8%, 16%, and 32% weight/weight). The samples were chilled to approximately 5°C and presented to the participants in 10-mL aliquots in a random order. Participants tasted the sample, spat it out, and then rinsed their mouth thoroughly with water before testing the next sample. For the evaluation of pleasantness or hedonic preference, based on taste, texture, and smell, the participants rated their preference on a standard 9-point hedonic preference scale that ranged from dislike extremely to like extremely. For the evaluation of perceived creaminess, sweetness, and fat content (ie, taste perception), the participants provided a rating on unipolar category scales, with each quality ranging from absent to extreme. Food intake (ad libitum snacking) (part C). An ad libitum snack intake paradigm previously validated for naloxone41 was used in this study. A selection of 16 common snack foods each containing different amounts of sugar and fat were used as food stimuli; these foods were grouped into 4 categories according to sugar and fat content: low sugar/ low fat, low sugar/high fat, high sugar/low fat, and high sugar/high fat. The macronutrient content (ie, percentage of carbohydrate, protein, and fat) was calculated for each food in each of the 4 categories (see Supplemental Table S1 for a list of food items in each category and percentage macronutrient content).

Safety and tolerability (from parts A, B, and C). No formal statistical analyses were conducted for AEs, vital signs, and ECG. Treatment comparisons of change from baseline in each subscale from VAMS and POMSB (excluding depressed/dejected and anger/hostility) were conducted as planned in the study part C using a repeated-measures analysis of covariance (ANCOVA). The model included subject as a random effect and treatment, study day, and treatment-by-study day as fixed effects. Two covariates, period-level baseline and subject-level baseline, were included in the model. For depressed/dejected and anger/hostility subscales in POMS-B, a simple ANCOVA model rather than planned repeated-measures analysis was used as there was insufficient variability in the data for repeatedmeasures analysis. For part A, a post hoc analysis of treatment comparisons of maximum change from baseline in the 3 factors of VAMS was conducted by using ANCOVA. The model included treatment as a fixed effect and baseline subscale score as a covariate. Pharmacokinetic analyses (parts A and B). For part A, dose proportionality of AUC0-∞ and Cmax for plasma GSK1521498 were assessed using both the power model (y = α * doseβ) and analysis of variance (ANOVA) after a loge-transformation of the data. In the power model, a mixed effect model was fitted with loge-transformed dose as a fixed effect and the intercept and slope as random effects. Mean slope and corresponding 90% confidence intervals (CIs) were estimated. Dose proportionality was inferred if the slope was close to 1 and the 90% CI fell within the range 0.80 to 1.25. A secondary ANOVA analysis was performed for logetransformed, dose-normalized AUC0-∞ and Cmax with dose as a fixed effect and subject as a random effect. Pairwise comparisons were conducted between each of the test doses and the reference dose (10 mg). Point

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Pharmacology of Gsk1521498 Table I  Summary of Drug-Related Adverse Events Occurring in 2 or More Participants With Any Treatment

Preferred Term

Participants with any drugrelated adverse event Fatigue Somnolence Nausea Headache Anorexia Vomiting Muscle fatigue Dysgeusia Diarrhea

GSK1521498 Oral Solution (Single Dose)

Placebo (n = 18), No. (%)

10 mg (n = 9), No. (%)

25 mg (n = 6), No. (%)

50 mg (n = 6), No. (%)

100 mg (n = 6), No. (%)

150 mg (n = 6), No. (%)

4 (22)

7 (78)

1 (17)

4 (67)

4 (67)

6 (100)

0 1 (6) 0 2 (11) 1 (6) 0 0 0 0

5 (56) 1 (11) 0 0 0 0 0 0 0

0 1 (17) 0 0 0 0 0 0 0

1 (17) 0 2 (33) 0 0 1 (17) 0 0 0

2 (33) 2 (33) 0 1 (17) 1 (17) 0 1 (17) 0 0

5 (83) 1 (17) 3 (50) 1 (17) 2 (33) 2 (33) 2 (33) 2 (33) 2 (33)

estimates and corresponding 90% CIs were constructed and were back-transformed to provide point estimates and 90% CIs for the geometric mean ratios. Relative bioavailability and food effect of GSK1521498 AUC0-∞ and Cmax were assessed using mixed effects ANOVA after loge-transformation of the data. The model included the treatment and period as fixed effects and subject as a random effect. Pairwise comparisons were conducted between each of the test doses and the reference doses. Point estimates and corresponding 90% CIs were constructed for comparisons of capsule fasted vs oral solution fasted and capsule fasted vs capsule fed. These were then backtransformed to provide point estimates and corresponding 90% CIs for geometric mean ratios. Pharmacodynamic analyses (part C). Treatment comparisons of change from baselines in the hedonic taste preference and sensory taste perception scores were performed using a mixed effect ANCOVA model. The model included subject as a random effect and period, treatment, sucrose, fat, sucrose × treatment, fat × treatment, and sucrose × fat × treatment as fixed effects. Period-level baseline and subject-level baseline were included in the model as covariates. Treatment comparisons of energy intake from ad libitum snacking were performed separately for 4 food categories and 3 macronutrient contents using a mixed model ANCOVA as described above. For the treatment comparisons among 4 food categories, a mixed model was fit for energy intake and included terms for treatment, period, and food category as fixed effects and treatment × food category as interactions. Similarly, for the treatment comparisons among macronutrient

contents, a mixed model was fit for energy intake and included terms for treatment, period, and macronutrient content as fixed effects and treatment × macronutrient content as interactions. Subject was fit as a random effect. SAS PROC MIXED procedure was used to fit all the described models with restricted maximum likelihood (REML) and the Kenward and Roger method of degrees of freedom. No multiplicity adjustments were employed for any pairwise treatment comparisons. Results Safety and Tolerability Adverse events and serious adverse events. There were no serious adverse events and no withdrawals due to AEs in any part of the study. Single GSK1521498 doses up to 100 mg were generally well tolerated. The most frequently reported AEs in part A were fatigue, somnolence, and nausea in participants given GSK1521498 (Table I). The highest dose, 150 mg, was not well tolerated, with treatment-related clinical findings of fatigue, muscle fatigue, anorexia, nausea, and/or vomiting for up to 3 days. In part B, GSK1521498 (25 mg) was generally well tolerated, both as an oral solution and capsule and whether fasted or fed. The most frequently reported AEs were fatigue, somnolence, and nausea. A similar AE profile was also noted with GSK1521498 (25 mg) in part C. Vital signs and ECG. Within the constraints of a study of this size, no clinically significant changes were seen

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Figure 2.  Mean (a) and dose-normalized (b) pharmacokinetic profile of GSK1521498 oral solution at different doses.

in vital signs (supine heart rate, blood pressure, and temperature) in any individual participant in part A, B, or C. However, mean heart rate change from baseline was greater following GSK1521498 150 mg compared with placebo treatment between 2 and 4 hours postdose (an increase of 8.3 bpm following GSK1521498 compared with a decrease of 4.7 bpm following placebo). Consistent with this, in participants given GSK1521498 150 mg, there was a 5- to 10-mm Hg increase in systolic blood pressure from 4 to 24 hours postdose. Of note, several participants in this group reported nausea (3/6) and vomiting (2/6). There was also evidence for heart rate increases of a smaller magnitude in participants receiving GSK1521498 50-mg and 100-mg doses compared with placebo. No clear trend on blood pressure could be discerned at these doses. There were no abnormal findings on any ECG traces that were reported as clinically significant, and an exploratory exposure/QT analysis found no evidence for an effect of GSK1521498 concentration on QT interval over the broad range of concentrations observed in part A. Assessment of mood and alertness. In part A, there were mild to moderate decreases in alertness following the 100-mg dose (11.9 mm in placebo-controlled maximum change from baseline; t = 2.88, df = 44, P = .006) and 150-mg dose (14.3 mm in placebo-controlled maximum change from baseline; t = 3.54, df = 44, P = .001). Decreases in alertness of a similar magnitude (up to 9 mm in placebo-controlled maximum change from baseline) were also noted following the 25-mg dose in part C between 2 and 8 hours postdose (t = 3.44, df = 26, P = .002), with the greatest effect at 4 hours

(t = 3.42, df = 26, P = .0021). In part A, participants also reported less contentedness (10.6 mm and 6.95 mm in placebo-controlled maximum change from baseline) at the 150-mg dose (t = 3.97, df = 44, P < .001) and 10-mg dose (t = 3.01, df = 44, P = .004), respectively, and less calmness at the 50-mg (t = 2.27, df = 44, P = .0028) and 150-mg (t = 2.18, df = 44, P = .035) doses (up to 12.63 mm in placebo-controlled maximum change from baseline; see Supplemental Figure S1 for mean changes in alertness, calmness, and contentedness over time). There were, however, no significant or clinically relevant changes in mood observed on the POMS-B on dimensions of anger, vigor, anxiety, fatigue, depression, and confusion across all time points, except at the 4-hour time point in part C (with the 25-mg dose), where there was a significant increase in the fatigue-inertia score (t = 2.24, df = 30, P = .032). Pharmacokinetic Assessment Systemic exposure to GSK1521498 (AUC0-∞ and Cmax) increased in proportion to dose following administration of single doses ranging from 10 to 150 mg as an oral solution. For both AUC0-∞ and Cmax, the estimated mean slope from the power model was approximately 1, and the corresponding 90% CIs contained unity, consistent with a dose-proportional increase in GSK1521498 exposure with increasing dose. Results of ANOVA analysis were consistent with a conclusion of dose-proportional pharmacokinetics based on the power model analysis. Figure 2a,b shows the mean and dose-normalized mean pharmacokinetic profiles for the groups dosed in part A. There were

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Pharmacology of Gsk1521498 Table II  Pharmacokinetic Parameters for GSK1521498 Oral Solution GSK1521498 Dose Parameter

AUC0-∞, ng·h/mL Cmax, ng/mL tmax, h t1/2, h

10 mg (n = 9)

1678.9 84.1 2 22.8

(28) (35) (1, 4) (27)

25 mg (n = 6)

3922.6 197.6 1.5 24.1

(18) (27) (1, 2) (19)

50 mg (n = 6)

7444.6 385.8 2 19.9

(26) (23) (1, 2) (28)

100 mg (n = 6)

13 322.0 722.4 1 23.2

(34) (17) (1, 2) (31)

150 mg (n = 6)

26 491.6 1439.0 1 23.4

(13) (28) (1, 4) (15)

Parameters summarized as geometric mean (% coefficient of variation [CV]) with the exception of tmax, which is summarized as median (minimum, maximum).

Table III  Summary of the Effects of Food and Formulation on GSK1521498 Pharmacokinetic Parameters GSK1521498 25-mg Treatment Parameter

Oral Solution, Fasted (n = 12)

Capsule, Fasted (n = 12)

AUC0-∞, ng·h/mL Cmax, ng/mL tmax, h t1/2, h

3850.8 201.6 1.0 21.8

3264.1 135.0 2.0 22.6

(25) (30) (1, 2) (19)

(35) (41) (2, 4) (23)

Capsule, Fed (n = 12)

3609.0 145.8 5.0 23.3

(22) (32) (2, 6) (32)

Parameters summarized as geometric mean (% coefficient of variation [CV]) with the exception of tmax, which is summarized as median (minimum, maximum).

no relationships between any of the pharmacokinetic parameters and measures of safety, ECG, or mood and alertness. GSK1521498 was associated with a geometric mean t1/2 ranging from approximately 20 to 24 hours with no apparent dose dependence. Median tmax occurred within 1 to 2 hours postdose with no apparent dose dependence. The specific pharmacokinetic parameters are summarized in Table II. Relative bioavailability for the oral solution and capsule formulations was evaluated for AUC0-∞ and Cmax. The oral solution was associated with slightly greater exposure than the capsule formulation, and food was associated with a small increase in exposure following administration of the capsule formulation. The ratios for exposures (fed/fasted) were slightly greater than unity for AUC0-∞ and Cmax with 90% CIs exceeding the upper limit of the standard bioequivalence range (0.8-1.25). Administration of the capsule formulation with food was also associated with a prolongation of tmax (Table III). Pharmacodynamic Assessment Hedonic taste preference. There was a significant main effect of treatment across all levels of sucrose and fat, with GSK1521498 suppressing hedonic preference

compared with placebo (F(1,735) = 9.02; P = .0028). No significant interaction effects were detected for treatment × fat, treatment × sugar, and treatment × fat × sucrose. Pairwise comparisons showed a significant effect of GSK1521498 compared with placebo in reducing hedonic ratings at the 2 highest levels of fat, 38.9% (t = -2.32, df = 735, P = .02) and 19.1% (t = -2.06, df = 735, P = .04) (averaged across all levels of sucrose). GSK1521498 compared with placebo also reduced hedonic rating at the highest level of sucrose, 32% (t = -2.43, df = 735; P = .016; averaged across all levels of fat; Figure 3a,b). As expected, perceived rating of sweetness, fatness, and creaminess was significantly affected by sucrose and fat levels. GSK1521498 compared with placebo had no effects on perceived sweetness (t = -0.88, df = 727, P = .38) or fatness (t = -0.7, df = 726, P = .48) but increased perception of creaminess (t = 2.57, df = 724, P = .01). Food intake (ad libitum snacking). There was a significant main effect of treatment on caloric intake, with GSK1521498 reducing snack food intake by 27% across all food categories compared with placebo (t = -2.36, df = 132, P = .02). Pairwise analyses showed that GSK1521498 caused the greatest suppression (ie, 39% suppression) of snack food intake in the high-fat/ high-sugar category, with a significant reduction in

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Nathan et al

Figure 3.  (a, b) Hedonic taste preference (change from baseline) shown and (c, d) ad libitum food intake following placebo and GSK152498 (25 mg). (a, b) A reduction is shown in hedonic ratings for the highest levels of fat (19.1%; t = -2.06, df = 735, *P = .04) and (38.9%; t = -2.32, df = 735, *P = 0.02) and sucrose (32%; t = -2.43, df = 735, *P = .016) for GSK1521498 compared with placebo. (c) A reduction is shown in intake of food for all categories of fat and sugar (t = -2.36, df = 132, **P = .02) and for the high-fat/high-sugar category (t = -2.42, df = 132, *P = .017) following GSK1521498 compared with placebo. (d) A reduction is shown in intake of all macronutrients (t = -2.55, df = 94, **P = .012) and carbohydrate (t = -2.33, df = 94, *P = .022) following GSK1521498 compared with placebo. LF, low fat; HF, high fat; LS, low sugar; HS, high sugar.

caloric intake by 102 kcal (t = -2.42, df = 132, P = .017; Figure 3c). In addition, there was a significant main effect of treatment on macronutrient content, with GSK1521498 reducing intake across all macronutrient categories, compared with placebo (t = -2.55, df = 94, P = .012). Pairwise analyses showed the greatest effect of GSK1521498 on consumption of carbohydrates, with a significant reduction in intake by 104.8 kcal (t = -2.33, df = 94, P = .022; Figure 3d). There were no relationships between pharmacokinetic parameters and measures of hedonic taste preference or measures of food/energy intake, although we note that this relationship was examined with data

from a single dose level, with low between-subject variability and a narrow range of exposures. Discussion This FTIH acute dose-ranging study investigated the safety pharmacokinetic and pharmacodynamic profile of the µ-opioid receptor inverse agonist GSK1521498, administered as an oral solution and as a capsule formulation in healthy participants. Single doses of GSK1521498 oral solution and capsule formulations up to 100 mg were well tolerated in healthy participants. The most common adverse event

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Pharmacology of Gsk1521498 reported was an increase in fatigue and a decrease in alertness. The maximum effects on fatigue and alertness were of mild to moderate degree (approximately 10-mm change on the VAMS scale) and consistent with findings observed with other µ-opioid receptor antagonists.45 However, no significant or clinically relevant changes on the POMS-B mood and anxiety dimensions (including anger, anxiety, depression, and confusion) were observed at any dose. The highest dose (150 mg) was not well tolerated with greater treatment-related clinical findings of fatigue, muscle fatigue, anorexia, nausea, and/or vomiting for up to 3 days. At this dose, there was also an increase in heart rate and blood pressure most likely due to the concurrent incidence of nausea and vomiting. It is, however, possible that these changes could be linked to antagonism of µ-opioid receptors in specific brain areas associated with cardiovascular control, although the exact mechanisms have not been identified.46,47 Although the 100-mg dose was considered to be the highest welltolerated dose based on the adverse event profile, the dose range predicted to be clinically effective (between 5 and 25 mg) is approximately 4- to 20-fold lower and hence expected to have a good tolerability profile with minimal effects on fatigue, alertness, and mood. Systemic exposure to GSK1521498 as indexed by the AUC0-∞ and Cmax values increased in proportion to dose following administration of single doses ranging from 10 to 150 mg administered as an oral solution. The absorption of GSK1521498 oral solution was rapid, with tmax occurring approximately 1 to 2 hours after dosing, followed by a biphasic decline in plasma concentration, suggesting distribution of GSK1521498 to the deep tissue compartment (consistent with its high permeability) and subsequent elimination. GSK1521498 had a half-life between 20 and 24 hrs, making a once-daily dosing regimen possible for longterm administration. This pharmacokinetic profile is in contrast to other µ-opioid antagonists such as naltrexone, naloxone, and nalmefene, which have shorter half-lives (less than 15 hours)48,49,50 and some requiring multiple daily dosing regimens. Exposures were greatest for the oral solution but were only modestly reduced for the capsule formulation in the fasted and fed states. The capsule formulation in the fasted state was associated with a delayed tmax compared with the oral solution formulation administered in the fasted state. The capsule formulation in the fed state delayed initiation of absorption and caused additional delay in tmax. The approximate 2.5-hour delay in tmax may be the result of prolonged gastric emptying due to the presence of food. Nonclinical data suggest that the bioavailability of GSK1521498 may be limited by dissolution rate or

solubility at higher doses. Interestingly, there was an increase in the AUC0-∞ and Cmax values in the fed compared with fasted state, which may be due to dietinduced increases in bile secretion and gastrointestinal fluid volume, potentially providing better solubility and hence greater absorption of GSK1521498. The modest increase in exposure is unlikely to be clinically significant given the good tolerability profile observed at doses likely to be sufficient for clinical efficacy. GSK1521498 (25 mg) caused a significant reduction in hedonic taste preference particularly for dairy mixtures with the highest concentrations of fat and sucrose. Consistent with this observation, GSK1521498 selectively reduced caloric intake of snack foods in the highfat/high-sugar category (a 39% or 102-kcal reduction) while having no effects on the low-fat and low-sugar categories. The reduction in caloric intake was predominantly driven by a reduction in carbohydrate intake (a reduction of 104.8 kcal), although smaller reductions were also observed on fat ingestion. These findings are consistent with a methodologically analogous study by Drewnoski and colleagues,41 where naloxone similarly reduced the hedonic taste preference for sensory stimuli containing sugar and fat in normal, and obese women, which was accompanied by a selective reduction in intake of high-fat/high-sugar food. Interestingly, the reduction in food intake previously reported for naloxone was only observed in binge eaters (ie, patients with bulimia nervosa and/or binge-eating disorder who frequently overeat). In our study, diagnosis or assessment of binge eating was not performed, and hence we were unable to determine if GSK1521498 had a more pronounced effect in binge eaters, although this will be examined in future studies. The effects of GSK1521498 on hedonic taste preference and food intake are consistent with the role of µ-opioid receptors in hedonic or pleasurable aspects of palatable food consumption.7 Specifically, the findings are consistent with human studies that have shown shortterm reductions in high-caloric food intake34,40,41 and affective or subjective pleasantness of palatable foods,35-41 as well as animal studies that have shown reduced consumption of palatable or high-caloric food and drinks16-33 following µ-opioid receptor antagonism. Data from preclinical models of feeding suppression suggest a linear relationship between GSK1521498 receptor occupancy and suppression of food intake, with substantial effects observed at occupancies more than 60%.42 A human positron emission tomography (PET) receptor occupancy study with GSK1521498 has been completed (ClinicalTrials.gov Identifier: NCT00976066), and findings from this study will guide dose selection in humans. PET studies with µ-opioid receptor antagonists, such as naltrexone,

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Nathan et al have shown that therapeutically efficacious doses (typically 50 mg/d) result in ~95% occupancy of the µ-opioid receptor.51 However, in vitro studies of GSK1521498 suggest inverse agonist properties, which may be consistent with efficacy at proportionally lower doses and lower receptor occupancies. In summary, single doses of GSK1521498 were well tolerated at doses up to 100 mg. Systemic exposure increased in proportion to dose following administration of single doses ranging from 10 to 150 mg. Consistent with the role of µ-opioid receptors in hedonic and consummatory aspects of palatable food intake, GSK1521498 showed selective attenuation of sensory hedonic rating of high-sugar and high-fat dairy products and reduction in caloric intake of high-fat/high-sucrose snack foods. These findings provide encouraging data in support of the development of GSK1521498 for the treatment of disorders of maladaptive ingestive behavior or compulsive consumption. Financial disclosure: This study was sponsored and funded by GlaxoSmithKline (GSK) Pharmaceuticals, the developer of GSK1521498. All authors are employees of GSK and hold shares and options in the company. All authors contributed to the design and conception of the study, acquisition of data, or analysis and interpretation of data and have provided approval for the paper to be published.

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