Clinical trial NCT00976066: [11C]Carfentanil PET Study of GSK1521498
Official title: An Open-label, Non-randomized [11C]Carfentanil PET Study in Healthy Male Subjects to Investigate Brain Mu-opioid Receptor Occupancy, Pharmacokinetics, and Pharmacodynamics of Single Oral Doses of GSK1521498 and Naltrexone.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Obesity
Keywords: Obesity
Naltrexone
Carfentanil
Receptor Occupancy
mu-opioid Receptor
PET (Positron Emission Tomography)
BOLD-fMRI
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2009-09-14
Enrollment: 26
Sex: MALE
Minimum age (years): 25
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

Brief summary: The purpose of this study is to determine whether GSK1521498 attaches to sites in the brain called mu-opioid receptors that are involved in the liking reactions to palatable high fat and high sugar foods. We hope that blocking these receptors may modify certain behaviours that may lead to obesity.

Detailed description: This imaging study will be an open-label, non-randomised PET receptor occupancy study in healthy male volunteers. The degree and time course of μ-opioid receptor occupancy (RO) following single oral doses of GSK1521498 will be estimated by \[11C\]carfentanil displacement. Previous pre-clinical and human PET studies indicate that \[11C\]carfentanil is selective for the μ-opioid receptor and can be used to estimate μ-opioid receptor occupancy in vivo.

The PK/PD relationship between plasma concentrations of GSK1521498 and μ-opioid RO will be described. Potential relationships between μ-opioid RO and functional magnetic resonance imaging (fMRI) endpoints, measured in a food reward paradigm, will be assessed as an exploratory aim. Additionally, the PK/PD relationships between plasma concentrations of naltrexone (a generic μ-opioid receptor antagonist), μ-opioid receptor occupancy, and fMRI measures of reward processing will also be investigated.

Eligibility criteria: Inclusion Criteria:

* Healthy male subjects aged between 25 and 65 years old inclusive.
* Body weight ≥ 50 kg and BMI within the range 18.5.0 - 30.0 kg/m2 (inclusive).
* Normal ECG.
* The subject is able to read, comprehend and record information.
* A signed and dated written informed consent is obtained from the subject.
* Compliance with birth control methods as described in the study protocol.

Exclusion Criteria:

A subject will not be eligible for inclusion in this study if any of the following criteria apply:

* The subject has a positive pre-study drug/alcohol screen.
* History of hepatitis B and /or C
* A positive result for an HIV test.
* Abnormal thyroid function
* Positive evaluation for depression.
* History of heavy alcohol use as described in the study protocol.
* The subject has participated in a clinical trial and has received an investigational product within: 90 days.
* Participation in other drug studies within a calendar year.
* Use of prohibited medications as described in the study protocol.
* History of sensitivity to any of the study medications.
* Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period
* Unwillingness or inability to follow the procedures outlined in the protocol.
* Past or present use of tobacco products.
* Consumption of red wine, seville oranges, grapefruit or grapefruit juice from 7 days prior to the first dose of study medication.
* Previous radiation dosages in excess of levels acceptable to take part in this study.
* History of claustrophobia or history of neurological conditions.
* Presence of a cardiac pacemaker.
* Works as a welder, metal worker or machinist

Primary outcomes:
measure: The degree and time-course of mu-opioid receptor occupancy by GSK1521498 in brain regions of interest as measured by PET
timeFrame: Assessed at various endpoints to be determined based on emerging results
measure: The relationship between plasma concentration and mu-opioid receptor occupancy by GSK1521498
timeFrame: Assessed at various endpoints to be determined based on emerging results
Secondary outcomes:
measure: Adverse events and clinically relevant changes in electrocardiography (ECG); vital signs (blood pressure, heart rate); POMS, Bond and Lader VAS, laboratory safety data and physical examination
timeFrame: Duration of study
measure: Pharmacokinetic endpoints will be: AUC(0-∞), AUC(0-t), maximum observed plasma drug concentration (Cmax), time to maximum observed plasma drug concentration (Tmax), terminal elimination half-life (t½).
timeFrame: PK samples will be collected throughout the study
measure: The degree and time-course of mu-opioid receptor occupancy by naltrexone in brain regions of interest as measured by PET
timeFrame: Assessed at various endpoints to be determined based on emerging results
measure: The relationship between mu-opioid receptor occupancy by GSK1521498 and naltrexone and fMRI responses during expectation and receipt of a pleasant tasting reward (juice)
timeFrame: During fMRI scanning sessions
Other outcomes:
Locations:
city: London
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Rabiner EA, Beaver J, Makwana A, Searle G, Long C, Nathan PJ, Newbould RD, Howard J, Miller SR, Bush MA, Hill S, Reiley R, Passchier J, Gunn RN, Matthews PM, Bullmore ET. Pharmacological differentiation of opioid receptor antagonists by molecular and functional imaging of target occupancy and food reward-related brain activation in humans. Mol Psychiatry. 2011 Aug;16(8):826-35, 785. doi: 10.1038/mp.2011.29. Epub 2011 Apr 19.