title: The pharmacokinetics and pharmacodynamics of danirixin (GSK1325756)--a selective CXCR2 antagonist --in healthy adult subjects.
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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  ClinicalTrials.gov identifiers: NCT01209052 and NCT01209104.
authors.affiliation: Clinical Discovery, Respiratory Therapy Area Unit, GlaxoSmithKline R&D, 709 Swedeland Road, King of Prussia, PA, 19406, USA. bruce.e.miller@gsk.com.
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Miller
authors.affiliation: Clinical Statistics, GlaxoSmithKline R&D, Stockley Park West, Uxbridge, Middlesex, UB11 1BT, UK. sunil.j.mistry@gsk.com.
authors.forename: Sunil
authors.initials: S
authors.lastname: Mistry
authors.affiliation: Clinical Pharmacology Modeling and Simulation, GlaxoSmithKline, London, UK. kevinasmart1@gmail.com.|Roche Pharmaceuticals, Welwyn Garden City, UK. kevinasmart1@gmail.com.
authors.forename: Kevin
authors.initials: K
authors.lastname: Smart
authors.affiliation: Product Development, Platform Technology and Science, GlaxoSmithKline R&D, Park Road, Ware, Hertfordshire, SG 12 0DP, UK. paul.c.connolly@gsk.com.
authors.forename: Paul
authors.initials: P
authors.lastname: Connolly
authors.affiliation: Respiratory Therapy Area Unit, GlaxoSmithKline R&D, 709 Swedeland Road, King of Prussia, PA, 19406, USA. donald.c.carpenter@gsk.com.
authors.forename: Donald C
authors.initials: DC
authors.lastname: Carpenter
authors.affiliation: Clinical Pharmacology Sciences and Study Operations, GlaxoSmithKline, London, UK. hiran_CC@hotmail.com.|Global Development, Amgen Inc., Horsham, West Sussex, UK. hiran_CC@hotmail.com.
authors.forename: Hiran
authors.initials: H
authors.lastname: Cooray
authors.affiliation: Drug Metabolism and Pharmacokinetics, GlaxoSmithKline R&D, Park Road, Ware, Hertfordshire, SG 12 0DP, UK. jackie.c.bloomer@gsk.com.
authors.forename: Jackie C
authors.initials: JC
authors.lastname: Bloomer
authors.affiliation: Clinical Discovery, Respiratory Therapy Area Unit, GlaxoSmithKline R&D, 709 Swedeland Road, King of Prussia, PA, 19406, USA. ruth.m.tal-singer@gsk.com.
authors.forename: Ruth
authors.initials: R
authors.lastname: Tal-Singer
authors.affiliation: Discovery Medicine, Respiratory Therapy Area Unit, GlaxoSmithKline R&D, 709 Swedeland Road, King of Prussia, PA, 19406, USA. aili.l.lazaar@gsk.com.
authors.forename: Aili L
authors.initials: AL
authors.lastname: Lazaar
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D039481:CD11b Antigen / Q000097:blood; D054360:Chemokine CXCL1 / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005502:Food / Q000009:adverse effects; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D009853:Omeprazole / Q000494:pharmacology; D010880:Piperidines / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D023063:Receptors, Interleukin-8B / Q000037:antagonists & inhibitors*; D013450:Sulfones / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D055815:Young Adult
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D039481:CD11b Antigen; D054360:Chemokine CXCL1; C509295:ITGAM protein, human; D010880:Piperidines; D023063:Receptors, Interleukin-8B; D013450:Sulfones; D009853:Omeprazole; C581951:danirixin