Advertisement

Topics

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

2014-08-27 03:12:31 | BioPortfolio

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.

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.

Study Design

Observational Model: Case Control, Time Perspective: Prospective

Conditions

Depressive Disorder

Intervention

GSK1360707 is a potent re-uptake inhibitor of the neurotransmitters dopamine, norepinephrine and serotonin

Location

GSK Investigational Site
Harrow
Middlesex
United Kingdom
HA1 3UJ

Status

Completed

Source

GlaxoSmithKline

Results (where available)

View Results

Links

Published on BioPortfolio: 2014-08-27T03:12:31-0400

Clinical Trials [1103 Associated Clinical Trials listed on BioPortfolio]

Antidepressant Safety in Kids Study

This study will evaluate the risks and benefits of treatment with a selective serotonin reuptake inhibitor or serotonin-norepinephrine reuptake inhibitor in children and adolescents with a...

Pilot Study of Atomoxetine To Enhance COgnition In Patients With Schizophrenia

Relationships between altered prefrontal cortical dopamine, norepinephrine and some cognitive impairments of schizophrenia supports and approach for pharmacological remediation of cognitiv...

12 Week Safety Trial of Flibanserin in Depressed Women Taking a Selective Serotonin Reuptake Inhibitor or Norepinephrine Serotonin Reuptake Inhibitor With Decreased Sexual Desire and Distress

The current trial will explore the safety of flibanserin in combination with Selective Serotonin Reuptake Inhibitors or Norepinephrine Serotonin Reuptake Inhibitors in a representative pop...

Dopamine and Norepinephrine in Shock Patients

The purpose of this study is to compare the efficacy of dopamine and norepinephrine, two commonly used vasopressor agents, in the treatment of shock.

Study of Milnacipran for the Treatment of Fibromyalgia

Antidepressants of all varieties represent a common form of therapy for many chronic states including fibromyalgia. The majority of antidepressants increase the levels of serotonin or nore...

PubMed Articles [8762 Associated PubMed Articles listed on BioPortfolio]

Association of Coprescription of Triptan Antimigraine Drugs and Selective Serotonin Reuptake Inhibitor or Selective Norepinephrine Reuptake Inhibitor Antidepressants With Serotonin Syndrome.

In 2006, the US Food and Drug Administration (FDA) issued an advisory warning on the risk of serotonin syndrome with concomitant use of triptans and selective serotonin reuptake inhibitor (SSRI) or se...

Association analysis of norepinephrine transporter polymorphisms and methylphenidate response in ADHD patients.

Methylphenidate (MPH) is the most frequently prescribed drug in Attention Deficit Hyperactivity Disorder (ADHD). Hitherto mostly the dopamine transporter gene has been studied in MPH-response and only...

Sulfation of Catecholamines and Serotonin by SULT1A3 Allozymes.

Previous studies have demonstrated the involvement of sulfoconjugation in the metabolism of catecholamines and serotonin. The current study aimed to clarify the effects of single nucleotide polymorphi...

In Vitro Assays for the Functional Characterization of the Dopamine Transporter (DAT).

Detailed in this unit are protocols for studying the in vitro uptake of dopamine (DA) as a means for defining the functional characteristics of dopamine transporters. All assays are performed using co...

Multi-metal, multi-wavelength surface-enhanced Raman spectroscopy detection of neurotransmitters.

The development of a sensor for the rapid and sensitive detection of neurotransmitters could provide a pathway for the diagnosis of neurological diseases, leading to the discovery of more effective tr...

Medical and Biotech [MESH] Definitions

One of the catecholamine NEUROTRANSMITTERS in the brain. It is derived from TYROSINE and is the precursor to NOREPINEPHRINE and EPINEPHRINE. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement. A family of receptors (RECEPTORS, DOPAMINE) mediate its action.

Tricyclic antidepressant with anticholinergic and sedative properties. It appears to prevent the re-uptake of norepinephrine and serotonin at nerve terminals, thus potentiating the action of these neurotransmitters. Amitriptyline also appears to antagonize cholinergic and alpha-1 adrenergic responses to bioactive amines.

Compounds that specifically inhibit the reuptake of serotonin in the brain. This increases the serotonin concentration in the synaptic cleft which then activates serotonin receptors to a greater extent. These agents have been used in treatment of depression, panic disorder, obsessive-compulsive behavior, and alcoholism, as analgesics, and to treat obesity and bulimia. Many of the ADRENERGIC UPTAKE INHIBITORS also inhibit serotonin uptake; they are not included here.

Drugs that block the transport of DOPAMINE into axon terminals or into storage vesicles within terminals. Most of the ADRENERGIC UPTAKE INHIBITORS also inhibit dopamine uptake.

A benzofuran, indole, and piperazine derivative that functions as a SEROTONIN UPTAKE INHIBITOR and partial SEROTONIN 5-HT1 RECEPTOR AGONIST. It is used as an ANTIDEPRESSIVE AGENT.

More From BioPortfolio on "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"

Advertisement
Quick Search
Advertisement
Advertisement

 

Relevant Topics

Nutrition
Within medicine, nutrition (the study of food and the effect of its components on the body) has many different roles. Appropriate nutrition can help prevent certain diseases, or treat others. In critically ill patients, artificial feeding by tubes need t...

Blood
Blood is a specialized bodily fluid that delivers necessary substances to the body's cells (in animals) – such as nutrients and oxygen – and transports waste products away from those same cells.  In vertebrates, it is composed of blo...

Diagnostics
A diagnostic test is any kind of medical test performed to aid in the diagnosis or detection of disease. For example: to diagnose diseases to measure the progress or recovery from disease to confirm that a person is free from disease Clin...


Searches Linking to this Trial