An Open Label Positron Emission Tomography Study in Healthy Male Subjects to Investigate Brain DAT and SERT Occupancy,Pharmacokinetics and Safety of Single Oral Doses of GSK1360707, Using 11C- PE2I and 11C-DASB as PET Ligands

• Status: Completed
• Trial end date: 2009-10-12
• Target enrollment: 0
• Participant gender: Male

Summary

GSK1360707 is a potent re-uptake inhibitor of the neurotransmitters dopamine, norepinephrine and serotonin. This is a single dose PET study in healthy subjects.A final analyses of safety data following exposure to single oral doses, from the first time in human study, with GSK1360707 has demonstrated that the compound is well tolerated up to a dose of 150mg. This imaging study will be an open label, non-randomised PET occupancy study using healthy male volunteers. The degree and time course of DAT and SERT occupancy by GSK1360707 will be determined. The PK/PD relationship between plasma concentrations of GSK1360707 and DAT and SERT occupancy will be described.This protocol amendment includes the flexibility to split the total dose into two doses e.g. 120mg per day could be split into two doses of 60mg. Splitting the total dose is most likely required to maintain therapeutic occupancy on the transporters over the course of the day; in addition it is expected that splitting the dose may reduce effects on vital signs. Therefore collecting data following split dosing will enable best predictions of therapeutic doses to be progressed in subsequent clinical studies.

• Phase: Phase 1
• Accepts Healthy Volunteers?: Accepts Healthy Volunteers

Details

• Lead Sponsor: GlaxoSmithKline
• Treatments: Dopamine; Dopamine Agents; Neurotransmitter Agents; Norepinephrine; Serotonin

Criteria

Inclusion Criteria:

• 1. Healthy as determined by a responsible physician, based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring. A subject with a clinical abnormality or laboratory parameters outside the reference range for the population being studied may be included only if the

• Investigator and the GSK Medical Monitor agree that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures.

2.Systolic blood pressure <140 mmHg, diastolic blood pressure <90 mmHg and heart rate <90 beats/min.

3. Male subjects between 35-55 years of age. 4.Male subjects must agree to use one of the contraception methods as listed in Section 8.1.

5.Body Mass Index (BMI) within the range 19 - 30 kg/m2 (inclusive) at screening visit.

6. Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form 7.QTcB or QTcF < 450 msec (if the first QTcB reading exceeds the limits above, perform two more ECGs separated at least 5 min apart. Then take the average of the three QTcB to determine if the average satisfies the above criteria).

Exclusion Criteria:

• 1.Evidence or history of clinically significant hematological, renal, urinary / prostatic, endocrine, pulmonary, gastrointestinal, cardiovascular or other heart disease, glaucoma, diabetes, hepatic, neurologic (e.g. including but not limited to seizures, stroke, cerebrovascular disease or other brain conditions), or allergic disease (except for untreated, asymptomatic, seasonal allergies at time of dosing).

2. Psychiatric illness currently or within the past year, or any lifetime history of bipolar disorder, major depressive disorder, anxiety disorder, schizophrenia or other psychotic disorder, or substance abuse or dependence (except past history of nicotine abuse/dependence if >6 months prior to screening.

3. Subjects who, in the investigator's judgment, pose a suicidal or homicidal risk, or any subject with a history of suicidal or homicidal attempts or behaviour.

4. The subject has a positive pre-study drug/alcohol screen. 5. A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening.

6. A positive test for HIV antibody. 7. History of regular excessive alcohol consumption within 6 months of the study defined as: an average weekly intake of greater than 21 units or an average daily intake of greater than 3 units. One unit is equivalent to a half-pint (220mL) of beer or 1 (25mL) measure of spirits or 1 glass (125mL) of wine. 8. The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 90 days , 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).

9. Exposure to more than four new chemical entities within 12 months prior to the first dosing day.

10. Use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements (including St John's Wort) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study medication, unless in the opinion of the Investigator and GSK Medical Monitor the medication will not interfere with the study procedures or compromise subject safety.

11. History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or GSK Medical Monitor contraindicates their participation. 12. Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period.

13. Unwillingness or inability to follow the procedures outlined in the protocol.

14. Urinary cotinine levels indicative of smoking or history or regular use of tobacco- or nicotine-containing products within 6 months prior to screening.

15. Consumption of red wine, seville oranges, grapefruit or grapefruit juice and/or pummelos, exotic citrus fruits, grapefruit hybrids or fruit juices from 7 days prior to the first dose of study medication. 16. Controlled or uncontrolled hypertension, or systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥ 90 mmHg at screening or prior to the first dose of study medication.

17. Previous inclusion in a research and/or medical protocol involving nuclear medicine, PET or radiological investigations with significant radiation burden (a significant radiation burden being defined as ICRP category IIb or above: No more than 10 mSv in addition to natural background radiation, in the previous 3 years including the dose from this study).

18. History of, or suffers from, claustrophobia or feels that he will be unable to lie still on his back in the PET or MRI scanner for a period of 1-2 hours.

19. Presence of a cardiac pacemaker or other electronic device or ferromagnetic metal foreign bodies as assessed by a standard pre-MRI questionnaire.

20. Subjects who are smokers will be excluded from this study.