Trial reportBritish journal of clinical pharmacology2013
Pharmacokinetic and pharmacodynamic profiling of a P2X7 receptor allosteric modulator GSK1482160 in healthy human subjects.
Trial report in British journal of clinical pharmacology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers, 1 of them a synthesis that pooled it.
What it found
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
41 citing papers in PubMed, 1 synthesis or guideline pooled it.
- The role of convergent ion channel pathways in microglial phenotypes: a systematic review of the implications for neurological and psychiatric disorders.Translational psychiatry · 2018Pooled it
- Clemastine fumarate accelerates accumulation of disability in progressive multiple sclerosis by enhancing pyroptosis.The Journal of clinical investigation · 2025Trial
- P2X7 receptor: a potential therapeutic target for chronic respiratory diseases.Molecular and cellular biochemistry · 2026Review
- Understanding interspecies drug response variations between human and rodent P2X7 receptors.Nature communications · 2025Article
- On-Cell Saturation Transfer Difference NMR Spectroscopy on Ion Channels: Characterizing Negative Allosteric Modulator Binding Interactions of P2X7.Journal of the American Chemical Society · 2025Article
- Review
- Ionotropic purinergic receptor 7 (P2X7) channel structure and pharmacology provides insight regarding non-nucleotide agonism.Channels (Austin, Tex.) · 2024Review
- Involvement of microglial P2X7 receptor in pain modulation.CNS neuroscience & therapeutics · 2024Review
- Potential roles of enteric glial cells in Crohn's disease: A critical review.Cell proliferation · 2024Review
- Unlocking the therapeutic potential of P2X7 receptor: a comprehensive review of its role in neurodegenerative disorders.Frontiers in pharmacology · 2024Review
- Chronic cough relief by allosteric modulation of P2X3 without taste disturbance.Nature communications · 2023Article
- Leveraging the ATP-P2X7 receptor signalling axis to alleviate traumatic CNS damage and related complications.Medicinal research reviews · 2023Review
- Spotlight on P2X7 Receptor PET Imaging: A Bright Target or a Failing Star?International journal of molecular sciences · 2023Review
- Tumour immune escape via P2X7 receptor signalling.Frontiers in immunology · 2023Review
- P2 purinergic receptor dysregulation in urologic disease.Purinergic signalling · 2022Review
- P2X3-selective mechanism of Gefapixant, a drug candidate for the treatment of refractory chronic cough.Computational and structural biotechnology journal · 2022Article
- Targeting NLRP3 inflammasome as a chief instigator of obesity, contributing to local adipose tissue inflammation and insulin resistance.Environmental science and pollution research international · 2021Review
- Antagonism of the ATP-gated P2X7 receptor: a potential therapeutic strategy for cancer.Purinergic signalling · 2021Review
- P2X7 Receptors: An Untapped Target for the Management of Cardiovascular Disease.Arteriosclerosis, thrombosis, and vascular biology · 2021Review
- P2XFrontiers in cellular neuroscience · 2021Review
Corrections and comments
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Authors and funding
10 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
aimsThis 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.
methodsEscalating 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.
resultsDrug 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.
conclusionThe model-based approach maximized analysis power by integrating all biomarker data and revealed mechanistic insight into the pharmacology of P2X7 modulation by GSK1482160. Simulations by this model ultimately led to the discontinuation of the development of this compound. The therapeutic relevance of the P2X7 receptor remains to be tested in patients. The mechanistic-model-based approach can be applied widely to drug development.
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