1. Academic Validation
  2. The pharmacokinetics and pharmacodynamics of danirixin (GSK1325756)--a selective CXCR2 antagonist --in healthy adult subjects

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

  • BMC Pharmacol Toxicol. 2015 Jun 20;16:18. doi: 10.1186/s40360-015-0017-x.
Bruce E Miller 1 Sunil Mistry 2 Kevin Smart 3 4 Paul Connolly 5 Donald C Carpenter 6 Hiran Cooray 7 8 Jackie C Bloomer 9 Ruth Tal-Singer 10 Aili L Lazaar 11
Affiliations

Affiliations

  • 1 Clinical Discovery, Respiratory Therapy Area Unit, GlaxoSmithKline R&D, 709 Swedeland Road, King of Prussia, PA, 19406, USA. bruce.e.miller@gsk.com.
  • 2 Clinical Statistics, GlaxoSmithKline R&D, Stockley Park West, Uxbridge, Middlesex, UB11 1BT, UK. sunil.j.mistry@gsk.com.
  • 3 Clinical Pharmacology Modeling and Simulation, GlaxoSmithKline, London, UK. kevinasmart1@gmail.com.
  • 4 Roche Pharmaceuticals, Welwyn Garden City, UK. kevinasmart1@gmail.com.
  • 5 Product Development, Platform Technology and Science, GlaxoSmithKline R&D, Park Road, Ware, Hertfordshire, SG 12 0DP, UK. paul.c.connolly@gsk.com.
  • 6 Respiratory Therapy Area Unit, GlaxoSmithKline R&D, 709 Swedeland Road, King of Prussia, PA, 19406, USA. donald.c.carpenter@gsk.com.
  • 7 Clinical Pharmacology Sciences and Study Operations, GlaxoSmithKline, London, UK. hiran_CC@hotmail.com.
  • 8 Global Development, Amgen Inc., Horsham, West Sussex, UK. hiran_CC@hotmail.com.
  • 9 Drug Metabolism and Pharmacokinetics, GlaxoSmithKline R&D, Park Road, Ware, Hertfordshire, SG 12 0DP, UK. jackie.c.bloomer@gsk.com.
  • 10 Clinical Discovery, Respiratory Therapy Area Unit, GlaxoSmithKline R&D, 709 Swedeland Road, King of Prussia, PA, 19406, USA. ruth.m.tal-singer@gsk.com.
  • 11 Discovery Medicine, Respiratory Therapy Area Unit, GlaxoSmithKline R&D, 709 Swedeland Road, King of Prussia, PA, 19406, USA. aili.l.lazaar@gsk.com.
Abstract

Background: 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.

Methods: (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.

Results: 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.

Conclusion: 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.

Trial registration: ClinicalTrials.gov identifiers: NCT01209052 and NCT01209104.

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