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

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.