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The pharmacokinetics and pharmacodynamics of danirixin (GSK1325756) − a selective CXCR2 antagonist − in healthy adult subjects

Overview of attention for article published in BMC Pharmacology and Toxicology, June 2015
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Title
The pharmacokinetics and pharmacodynamics of danirixin (GSK1325756) − a selective CXCR2 antagonist − in healthy adult subjects
Published in
BMC Pharmacology and Toxicology, June 2015
DOI 10.1186/s40360-015-0017-x
Pubmed ID
Authors

Bruce E. Miller, Sunil Mistry, Kevin Smart, Paul Connolly, Donald C. Carpenter, Hiran Cooray, Jackie C. Bloomer, Ruth Tal-Singer, Aili L. Lazaar

Abstract

Excessive neutrophil presence and activation is important in a number of acute and chronic inflammatory diseases. The CXCR2 chemokine receptor is important in controlling the extravasation and activation of neutrophils. Selective antagonism of the CXCR2 receptor is a potential approach to reducing neutrophil migration and activation. Danirixin, is a small molecule, CXCR2 antagonist being evaluated as a potential anti-inflammatory medicine. (1) First time in human (FTIH) double-blind, placebo-controlled study to evaluate the safety, pharmacokinetics, and pharmacodynamics of single ascending and repeat oral doses of danirixin in healthy male subjects; (2) single-dose study of age, gender, food, and proton-pump inhibitor effects on the pharmacokinetics of danirixin in healthy adult subjects; and placebo-controlled study of the pharmacokinetics of danirixin in healthy elderly subjects. There were no serious adverse events and no adverse events considered to be of clinical relevance. There were no withdrawals due to adverse events. Systemic exposure following single doses of danirixin 10 mg, 25 mg, 50 mg, 100 mg, and 200 mg increased with increasing dose. Engagement of pharmacology was demonstrated as inhibition of ex-vivo CXCL1-induced CD11b expression on peripheral blood neutrophils when compared to placebo (approximately 50 % for 50 mg and 100 mg danirixin, and 72 % at 200 mg). There was a 37 % decrease in Cmax and a 16 % decrease in AUC (0-∞) following administration of danirixin in the presence of food. Cmax also decreased by 65 % when danirixin 100 mg was administered following omeprazole 40 mg once daily for 5 days. The AUC (0-∞) and Cmax were 50 % lower in elderly subjects compared with younger subjects. The dose-dependent inhibition of agonist-induced neutrophil activation following single and repeated once daily oral administration of danirixin suggests that this CXCR2 antagonist may have benefit in neutrophil-predominant inflammatory diseases. Co-administration with food, gastric acid reducing agents, and variable exposure in the elderly have important clinical implications that need to be taken into consideration in subsequent clinical evaluations. ClinicalTrials.gov identifiers: NCT01209052 and NCT01209104.

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Mendeley readers

The data shown below were compiled from readership statistics for 59 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
United Kingdom 1 2%
Unknown 58 98%

Demographic breakdown

Readers by professional status Count As %
Researcher 14 24%
Student > Master 6 10%
Other 4 7%
Student > Doctoral Student 4 7%
Student > Bachelor 4 7%
Other 10 17%
Unknown 17 29%
Readers by discipline Count As %
Medicine and Dentistry 15 25%
Pharmacology, Toxicology and Pharmaceutical Science 5 8%
Immunology and Microbiology 5 8%
Biochemistry, Genetics and Molecular Biology 4 7%
Agricultural and Biological Sciences 3 5%
Other 9 15%
Unknown 18 31%

Attention Score in Context

This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 21 June 2015.
All research outputs
#4,377,839
of 5,258,644 outputs
Outputs from BMC Pharmacology and Toxicology
#133
of 150 outputs
Outputs of similar age
#149,994
of 185,357 outputs
Outputs of similar age from BMC Pharmacology and Toxicology
#5
of 5 outputs
Altmetric has tracked 5,258,644 research outputs across all sources so far. This one is in the 1st percentile – i.e., 1% of other outputs scored the same or lower than it.
So far Altmetric has tracked 150 research outputs from this source. They receive a mean Attention Score of 4.3. This one is in the 1st percentile – i.e., 1% of its peers scored the same or lower than it.
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