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Effects of genetic variation in the P2RX7 gene on pharmacodynamics of a P2X(7) receptor antagonist: a prospective genotyping approach.

ABSTRACT: AIMS:To investigate the effects of two single nucleotide polymorphisms (SNPs) in the human P2X? receptor gene (P2RX7)--1068G>A (A348T) and 1513A>C (E496A)--on P2X? receptor function, using a specific receptor antagonist (GSK1370319A) and prospective genetic stratification. METHODS:Lipopolysaccharide- and ATP-stimulated interleukin-1? production was determined in the presence or absence of GSK1370319A in blood culture from 32 prospectively genotyped subjects. RESULTS:There was approximately 6.7-fold difference (P < 0.0001) in IC?? for inhibition of ATP-stimulated interleukin-1? release by GSK1370319A between individuals with the homozygous gain--(1068A) and loss-of-function (1513C) genotypes (expressing the 348T, 496E and 348A, 496A alleles, respectively). CONCLUSIONS:Leukocyte P2X? receptors had significantly altered pharmacodynamic responses to a specific antagonist (GSK1370319A), directly related to SNP genotype.

SUBMITTER: McHugh SM

PROVIDER: S-EPMC3630758 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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Effects of genetic variation in the P2RX7 gene on pharmacodynamics of a P2X(7) receptor antagonist: a prospective genotyping approach.

McHugh Simon M SM Roman Shilina S Davis Bill B Koch Annelize A Pickett Alison M AM Richardson Jill C JC Miller Sam R SR Wetten Sally S Cox Charles J CJ Karpe Fredrik F Todd John A JA Bullmore Edward T ET

British journal of clinical pharmacology 20120801 2

<h4>Aims</h4>To investigate the effects of two single nucleotide polymorphisms (SNPs) in the human P2X₇ receptor gene (P2RX7)--1068G>A (A348T) and 1513A>C (E496A)--on P2X₇ receptor function, using a specific receptor antagonist (GSK1370319A) and prospective genetic stratification.<h4>Methods</h4>Lipopolysaccharide- and ATP-stimulated interleukin-1β production was determined in the presence or absence of GSK1370319A in blood culture from 32 prospectively genotyped subjects.<h4>Results</h4>There w ...[more]

PMID: 22295949

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Project description:Background and objectiveThere is no licensed treatment for refractory chronic cough; off-label therapies have limited efficacy and can produce adverse effects. Excessive adenosine triphosphate signaling via P2X3 receptors is implicated in refractory chronic cough, and selective P2X3 receptor antagonists such as eliapixant (BAY 1817080) are under investigation. The objective of the study was to investigate the safety and tolerability of ascending repeated oral doses of eliapixant in healthy volunteers.MethodsWe conducted a repeated-dose, double-blind, randomized, placebo-controlled study in 47 healthy male individuals. Subjects received repeated twice-daily ascending oral doses of eliapixant (10, 50, 200, and 750 mg) or placebo for 2 weeks. The primary outcome was frequency and severity of adverse events. Other outcomes included pharmacokinetics and evaluation of taste disturbances, which have occurred with the less selective P2X3 receptor antagonist gefapixant.ResultsPeak plasma concentrations of eliapixant were reached 3-4 h after administration of the first and subsequent doses. With multiple dosing, steady-state plasma concentrations were reached after ~ 6 days, and plasma concentrations predicted to achieve ≥ 80% P2X3 receptor occupancy (the level required for efficacy) were reached at 200 and 750 mg. Increases in plasma concentrations with increasing doses were less than dose proportional. After multiple dosing, mean plasma concentrations of eliapixant showed low peak-trough fluctuations and were similar for 200- and 750-mg doses. Eliapixant was well tolerated with a low incidence of taste-related adverse events.ConclusionsEliapixant (200 and 750 mg) produced plasma concentrations that cover the predicted therapeutic threshold over 24 h, with good safety and tolerability. These results enabled eliapixant to progress to clinical trials in patients with refractory chronic cough.Clinical trial registrationClinicaltrials.gov: NCT03310645 (initial registration: 16 October, 2017).

Dataset Information

Effects of genetic variation in the P2RX7 gene on pharmacodynamics of a P2X(7) receptor antagonist: a prospective genotyping approach.

Publications

Effects of genetic variation in the P2RX7 gene on pharmacodynamics of a P2X(7) receptor antagonist: a prospective genotyping approach.

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