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
Condition: Depressive Disorder
MeSH terms: Depressive Disorder
Study type: Interventional
Phase: Phase 1

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.
    

Detailed description: 
      GSK1360707 has been shown to exhibit pharmacological action in a wide array of in vivo models
      for dopaminergic activity and has been shown to significantly increase levels of the three
      neurotransmitters in the frontal cortex and nucleus accumbens in rats.

      GSK1360707 has demonstrated antidepressant-like effects in the forced swimming test after
      oral administration in mice and rats. Inhibition of the three monoamines, alone or in some
      combination, has been implicated in the mechanism of action for currently marketed
      antidepressants (e.g., paroxetine [selective serotonin reuptake inhibitor], venlafaxine
      [serotonin and norepinephrine reuptake inhibitor], and bupropion [selective dopamine and
      norepinephrine reuptake inhibitor]). The known effectiveness of compounds that enhance
      dopaminergic, serotonergic, and/or norepinephrine activity in the treatment of depression,
      combined with the pre-clinical data for GSK1360707, suggests that GSK1360707 may be an
      effective treatment for Major Depressive Disorder (MDD). GSK1360707 has recently completed a
      FTIH single dose, dose escalation study in healthy young subjects (study SNV111914). The
      highest single dose studied was 150 mg. Single doses up to and including 150 mg were
      generally well-tolerated. In the FTIH study, apparent dose-dependent increases in diastolic
      and systolic blood pressure were observed in the dose range of 60 - 150 mg. The maximum
      increase in blood pressure occurred at approximately Tmax and generally continued for less
      than 6 h from Tmax. Preliminary data indicated, for systolic blood pressure, the maximum mean
      value postdose was 135 mmHg (150mg, 6 h post-dose), the maximum individual value was 164 mmHg
      (60mg, 3 h post-dose). For diastolic blood pressure the maximum mean value post-dose was 79
      mmHg (150mg) and the maximum individual value was 113 mmHg (30mg dose). The levels of blood
      pressure attained post-dose with GSK1360707 is similar to the levels which occur in
      middle-aged men and women who were healthy or had stable cardiovascular conditions during
      sexual activity and exercise on treadmill [Palmeri, 2007]. This study constitutes the second
      clinical investigation of this compound, and will be a PET investigation of a total dose of
      GSK1360707 in healthy male subjects; this study will also include assessment of the
      pharmacokinetic parameters of GSK1360707 as well as an assessment of safety and tolerability.
      For serotonin reuptake inhibitors (as a class) therapeutic effects are achieved after chronic
      treatment generally when SERT occupancy is ≥ 80% [Meyer, 2004], therapeutic effects mediated
      by DAT inhibition are generally achieved when occupancy is in the region of 30% [Volkow,
      2005], and abuse liability is usually avoided when DAT inhibition is <50% and there is an
      appropriately slow brain kinetic [Volkow, 2005]. As in vitro affinity data is not always
      consistent with in vivo data, information derived from in vivo assessments of target
      occupancy have the potential to greatly enhance the process of dose selection for phase IIa,
      and prediction of abuse liability. With that in mind a PET study has been conducted in Papio
      Anubis using [11C] DASB (a SERT ligand) and [11C]PE2I (a DAT ligand) to determine the
      relative in vivo affinities of GSK1360707 at SERT and DAT, and the time course of occupancy
      of GSK1360707 at SERT and DAT. In Papio Anubis GSK1360707 blocked both the [11C] DASB and
      [11C] PE2I signals indicating brain penetrancy and target binding in vivo. The in vivo
      affinities of GSK1360707 for DAT and SERT were found to be equivalent (EC50 ~ = 20 ng/ml @ 15
      min post dose; EC50 ~ = 10 ng/ml @ 2-2.5 hr post dose), and as was the time course of
      GSK1360707 washout inferred from the occupancy data (t1/2 of effective free concentration = 3
      hr). The lack of a suitable PET radioligand means that the degree of NAT [NET] occupancy
      exhibited by GSK1360707 cannot be assessed in this study. This human study will use an
      adaptive design to assess the time course of plasma exposure-DAT and SERT occupancy
      relationship in humans. The data will be used to aid dose selection for future studies. The
      prediction of the effective exposure in man was based on transporter occupancy [also referred
      to in some places as RO or receptor occupancy] (RO) due to the poor predictive power of the
      animal disease model (forced swimming test in rat).Predictions of human therapeutic dose for
      GSK1360707 are based on dissociation constant (pKi) for human SERT and DAT transporters, on
      transporter occupancies of GSK1360707 observed in preclinical PET studies, and on experience
      with our lead TRUI, GSK372475. Exposure to GSK1360707 is linear with dose and the compound
      shows a Tmax of approximately 2 hours, and a Cmax of approximately 50ng/mL at the highest
      tolerated dose of 150mg; a short terminal half-life was calculated (in the range 5-6 hours)
      so that plasma concentrations at 24 hours were close to the lower limit of detection (1ng/mL)
      or not quantifiable at all doses tested.
    

Intervention name(s): GSK1360707 is a potent re-uptake inhibitor of the neurotransmitters dopamine, norepinephrine and serotonin
Intervention type(s): Drug
Intervention description(s): This is an open label, adaptive design, daily dosing, non-randomized PET occupancy study in healthy adult males.A range of doses may be evaluated. The initial dose, given in the study as a single dose was 150mg GSK1360707. The remaining subjects will be dosed either as a single or split dose, as determined by the PET and tolerability data collected in the preceding subjects. The total dose will not exceed 150mg per day, the maximum total dose given in the FTIH study.If dosing is conducted as a single dose, the dose will be administered after the baseline scan, If a dosing is performed in a split dose manner, dosing will occur after the baseline scan, and up to 12 hours later. The time period between doses will be determined by emerging PET occupancy data.
Subsequent doses, if any, will be chosen based on the observed scan results. No single dose, or total dose split over 2 dosing sessions, will exceed the maximum dose in the FTIH study.
Intervention MeSH terms: Dopamine; Norepinephrine; Serotonin; Neurotransmitter Agents
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Positron Emission Tomography; serotonin; inhibitor of the neurotransmitters; safety of single oral doses; norepinephrine; dopamine