title: Safety, tolerability, pharmacokinetics and pharmacodynamics of GSK2239633, a CC-chemokine receptor 4 antagonist, in healthy male subjects: results from an open-label and from a randomised study.
abstract: BACKGROUND
  The CC-chemokine receptor 4 (CCR4) is thought potentially to play a critical role in asthma pathogenesis due to its ability to recruit type 2 T-helper lymphocytes to the inflamed airways. Therefore, CCR4 provides an excellent target for anti-inflammatory therapy.
  
  
  METHODS
  The safety, tolerability, pharmacokinetics and pharmacodynamics of the CCR4 antagonist GSK2239633, N-(3-((3-(5-chlorothiophene-2-sulfonamido)-4-methoxy-1H-indazol-1-yl)methyl)benzyl)-2-hydroxy-2-methylpropanamide, were examined in healthy males. Two studies were performed: 1) an open-label, study in which six subjects received a single intravenous infusion of [14C]-GSK2239633 100 μg (10 kBq) (NCT01086462), and 2) a randomised, double-blind, placebo-controlled, cross-over, ascending dose study in which 24 subjects received single oral doses of GSK2239633 150-1500 mg (NCT01371812).
  
  
  RESULTS
  Following intravenous dosing, plasma GSK2239633 displayed rapid, bi-phasic distribution and slow terminal elimination (t½: 13.5 hours), suggesting that GSK2239633 was a low to moderate clearance drug. Following oral dosing, blood levels of GSK2239633 reached Cmax rapidly (median tmax: 1.0-1.5 hours). Estimated GSK2239633 bioavailability was low with a maximum value determined of only 16%. Food increased GSK2239633 systemic exposure (as assessed by AUC and Cmax). Increases in AUC and Cmax were less than dose proportional. Adverse events were reported by three subjects (50%) following intravenous administration, and by 19 subjects (79%) following oral administration; most (46/47; 98%) events were mild/moderate in intensity. GSK2239633 1500 mg inhibited thymus- and activation-regulated chemokine-induced (TARC) actin polymerisation reaching a mean CCR4 occupancy of 74%.
  
  
  CONCLUSIONS
  In conclusion, GSK2239633 was well-tolerated and capable of inhibiting TARC from activating the CCR4 receptor.
authors: Anthony
authors: A
authors: Cahn
authors: Simon
authors: S
authors: Hodgson
authors: Robert
authors: R
authors: Wilson
authors: Jonathan
authors: J
authors: Robertson
authors: Joanna
authors: J
authors: Watson
authors: Misba
authors: M
authors: Beerahee
authors: Steve C
authors: SC
authors: Hughes
authors: Graeme
authors: G
authors: Young
authors: Rebecca
authors: R
authors: Graves
authors: David
authors: D
authors: Hall
authors: Sjoerd
authors: S
authors: van Marle
authors: Roberto
authors: R
authors: Solari
mesh_terms: D015746:Abdominal Pain / Q000139:chemically induced; D000284:Administration, Oral; D000328:Adult; D000368:Aged; D019540:Area Under Curve; D001682:Biological Availability; D003967:Diarrhea / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D006261:Headache / Q000139:chemically induced; D006801:Humans; D007191:Indazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D007262:Infusions, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D054398:Receptors, CCR4 / Q000037:antagonists & inhibitors*; D012220:Rhinitis / Q000139:chemically induced; D013449:Sulfonamides / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D007191:Indazoles; C581002:N-((3-((3-(((5-chloro-2-thienyl)sulfonyl)amino)-4-(methyloxy)-1H-indazol-1-yl)methyl)phenyl)methyl)-2-hydroxy-2-methylpropanamide; D054398:Receptors, CCR4; D013449:Sulfonamides