Pharmacokinetic and pharmacodynamic profiling of a P2X7 receptor allosteric modulator GSK1482160 in healthy human subjects.

British Journal of Clinical Pharmacology
Zahid AliChao Chen

Abstract

This paper describes findings from the first-in-human study for GSK1482160, an orally available allosteric P2X7 receptor modulator. The study aimed to assess the pharmacokinetics (PK), pharmacodynamics (PD), safety and tolerability of the compound in healthy subjects. Escalating single doses of up to 1 g were administered to healthy subjects in a single-blind and placebo-controlled fashion. Safety, tolerability, blood drug concentrations and ex vivo Il-1β production in blood were evaluated. Drug concentration peaked within 3.5 h of dosing under fasting conditions and declined thereafter with a relatively short half-life of less than 4.5 h. Exposure was proportional to dose with between subject variability of less than 60%. A PK/PD model quantified Il-1β as a function of drug exposure. The model allowed simulation of in vivo pharmacology for various untested dose levels and regimens. Furthermore, the mechanistic model supported the hypothesis that the compound reduces the efficacy of ATP at the P2X7 receptor without affecting its affinity. No major safety or tolerability concerns were identified in this small study (n = 29), except for one case of asymptomatic accelerated idioventricular rhythm at the top dose. The model-based a...Continue Reading

References

Nov 19, 1997·Neuropharmacology·G ColloG Buell
Jan 21, 2001·The Journal of Biological Chemistry·B J GuJ S Wiley
Sep 25, 2002·Physiological Reviews·R Alan North
Mar 9, 2004·The Journal of Immunology : Official Journal of the American Association of Immunologists·Ronald SluyterJames S Wiley
Jul 16, 2004·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Joan A SimAnnmarie Surprenant
Mar 21, 2006·The Journal of Immunology : Official Journal of the American Association of Immunologists·Davide FerrariFrancesco Di Virgilio
Jul 11, 2006·Human Molecular Genetics·Susanne LucaeBertram Müller-Myhsok
Jan 1, 2009·Nature Reviews. Drug Discovery·P Jeffrey ConnCraig W Lindsley
Oct 10, 2009·British Journal of Pharmacology·S RomanA D Michel
May 17, 2011·Current Opinion in Pharmacology·Paul M MatthewsRoger Gunn
Nov 9, 2011·British Journal of Pharmacology·Stephen P H AlexanderJohn A Peters
Dec 27, 2011·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Tobias EngelMiguel Diaz-Hernandez

❮ Previous
Next ❯

Citations

Aug 2, 2012·Nature Reviews. Drug Discovery·Charles A DinarelloJos W M van der Meer
Oct 3, 2014·BioMed Research International·Giulia Magni, Stefania Ceruti
Sep 17, 2014·Trends in Pharmacological Sciences·Beáta Sperlágh, Peter Illes
Dec 5, 2015·Nature Reviews. Drug Discovery·Knut BiberMarco Prinz
May 7, 2014·Chest·Guy G BrusselleMohamed Lamkanfi
Dec 5, 2015·Frontiers in Immunology·Talia H SwartzBenjamin K Chen
Oct 20, 2015·Ageing Research Reviews·Manju Tewari, Pankaj Seth
Jan 24, 2014·British Journal of Clinical Pharmacology·Albert FerroJames M Ritter
Oct 1, 2015·Journal of Medicinal Chemistry·Alex G BaldwinSally Freeman
Oct 10, 2013·Ageing Research Reviews·David Yang-Wei FannThiruma V Arumugam
Feb 1, 2015·Trends in Molecular Medicine·Davide FerrariAndrea la Sala
May 25, 2016·Glia·Anindya Bhattacharya, Knut Biber
Oct 19, 2016·Journal of Ocular Pharmacology and Therapeutics : the Official Journal of the Association for Ocular Pharmacology and Therapeutics·Kenneth A Jacobson, Mortimer M Civan
Oct 27, 2016·Kidney International·Robert I MenziesMatthew A Bailey
Aug 15, 2014·Science Translational Medicine·Sulayman D Dib-Hajj, Stephen G Waxman
Nov 1, 2016·Expert Opinion on Therapeutic Patents·Jin-Hee Park, Yong-Chul Kim
Apr 12, 2017·International Journal of Molecular Sciences·Claire TronelNicolas Arlicot
May 27, 2014·Inflammatory Bowel Diseases·Fernando Ochoa-CortesFievos L Christofi
Aug 12, 2018·British Journal of Pharmacology·Ben J Gu, James S Wiley
Mar 6, 2019·Clinical and Experimental Pharmacology & Physiology·Camila Guerra Martinez
Oct 2, 2020·Arteriosclerosis, Thrombosis, and Vascular Biology·Brandon G ShokoplesErnesto L Schiffrin
Aug 28, 2020·Frontiers in Molecular Neuroscience·Roberta AndrejewHenning Ulrich
Jun 12, 2018·Contrast Media & Molecular Imaging·Anne-Claire DupontNicolas Arlicot
Oct 12, 2017·Scientific Reports·Guillaume ArguinFernand-Pierre Gendron
Feb 23, 2018·Frontiers in Pharmacology·Luiz E B SavioRobson Coutinho-Silva
May 3, 2020·Chemistry : a European Journal·Haibo MeiVadim A Soloshonok
Aug 20, 2020·Molecular Neurodegeneration·Zhi RuanTsuneya Ikezu
Jun 17, 2020·Molecular Imaging·Hamideh Zarrinmayeh, Paul R Territo
Dec 10, 2016·European Journal of Nuclear Medicine and Molecular Imaging·Stefanie M A WillekensKoen Van Laere
Sep 24, 2020·ChemMedChem·Dimitra T PournaraMaria Koufaki
Nov 22, 2020·European Journal of Pharmacology·Guilherme Pegas Teixeira, Robson Xavier Faria
Mar 18, 2021·Purinergic Signalling·Matthew DrillMastura Monif
Apr 24, 2021·Frontiers in Cellular Neuroscience·Paul R Territo, Hamideh Zarrinmayeh
Oct 22, 2016·Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine·Paul R TerritoGary D Hutchins
Jun 20, 2021·Environmental Science and Pollution Research International·Aayush SehgalLotfi Aleya
Feb 6, 2019·Journal of Medicinal Chemistry·Quinn CoughlinDario Doller

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.