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

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• P2X7 receptors are involved in the production of pro-inflammatory cytokines, such as Il-1b, by central and peripheral immune cells. Il-1b has been implicated as an important mediator of inflammation. Therefore, the P2X7 receptor is an attractive therapeutic target for inflammatory diseases. WHAT THIS STUDY ADDS• Findings in pharmacokinetics, pharmacodynamics, safety and tolerability of a P2X7 receptor modulator, GSK1482160, from the first human study for the molecule are described. A pharmacokinetic/ pharmacodynamic model for LPS-stimulated ATP-induced Il-1b production in blood allowed the integration of all relevant data and provided in vivo evidence of the nature of the drug-receptor interaction. The model has the potential to be used to simulate future trials. 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-1b 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-1b 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.

Characterization of 11C-GSK1482160 for Targeting the P2X7 Receptor as a Biomarker for Neuroinflammation

“…Moreover, in isolated perfused rodent livers no evidence of hydroxylation has been shown, and in nearly all animal species studied most of the GSK14822160 parent was recovered from the urine (32). This is supported by the pharmacokinetic determination of the GSK14822160 clearance and circulating half-life, which when modeled are in excess of 2,177 mL/h and 30.5 h, respectively, in humans (derived from (32)).…”

“…Although the aforementioned tracer kinetic modeling was performed on metabolite-uncorrected data, which have been shown to affect interpretation of many PET radiopharmaceuticals (31), work on GSK1482160 in liver microsomes, liver S9 fraction, and hepatocytes in multiple species has been shown to be metabolically stable (32). Moreover, in isolated perfused rodent livers no evidence of hydroxylation has been shown, and in nearly all animal species studied most of the GSK14822160 parent was recovered from the urine (32).…”

P2X-Selective Purinergic Antagonists Are Strong Inhibitors of HIV-1 Fusion during both Cell-to-Cell and Cell-Free Infection

“…The purinergic antagonists are being actively studied for their therapeutic potential and have been demonstrated to be safe in clinical trials testing P2X7 antagonists in the treatment of rheumatoid arthritis (including trials AZD9056, CE-224,535, and GSK1482160) (48)(49)(50)(51)(52). We postulate that the development of targeted therapies that block these signaling pathways may provide simultaneous treatment of HIV-1 infection, the chronic inflammation associated with HIV-1 infection, and, possibly, the associated long-term sequelae, including neurotoxic effects (53).…”

Ocular Purine Receptors as Drug Targets in the Eye

“…4,121 The trials for rheumatoid arthritis failed to show efficacy, but the trial of GSK1482160 95 showed a reduction of IL1b following exposure to LPS. 122 Antagonists of the P2X7R prevent neuronal apoptosis in the retina induced by ATP or by hypoxia. 118,[123][124][125][126]127,128 Such antagonists include Brilliant Blue G (BBG, structure not shown) and MRS 2540 91.…”