title: The pharmacokinetics and safety of darapladib in subjects with severe renal impairment.
abstract: OBJECTIVE
  Darapladib is a potent and reversible orally active inhibitor of lipoprotein-associated phospholipase A2 (Lp-PLA2 ). The aim of the study was to assess the effects of severe renal impairment on the pharmacokinetics and safety/tolerability of darapladib compared with normal renal function.
  
  
  METHODS
  This was an open label, parallel group study of darapladib following 10 day once daily 160 mg oral dosing in subjects with normal (n = 8) and severe renal impairment (estimated glomerular filtration rate <30 ml min(-1) 1.73 m(-2) , n = 8). Plasma concentrations of total and unbound darapladib as well as total darapladib metabolites were determined in samples obtained over 24 h on day 10.
  
  
  RESULTS
  Plasma concentrations of total and unbound darapladib as well as all three metabolites were higher in subjects with severe renal impairment. Area under the plasma concentration vs. time curve between time zero and 24 h (AUC(0,24 h) and maximum plasma concentration (Cmax ) of total darapladib in severely renally impaired subjects were 52% and 59% higher than those in the matched healthy subjects, respectively. Similar results were found with the darapladib metabolites. Darapladib was highly plasma protein bound with 0.047% and 0.034% unbound circulating in plasma in severely renally impaired and healthy subjects, respectively. Unbound plasma darapladib exposures were more than two-fold higher in severely renally impaired subjects than in healthy controls. Adverse events (AE) were reported in 38% of healthy subjects and 75% of severely renally impaired subjects, most of which were mild or moderate in intensity.
  
  
  CONCLUSIONS
  The results of this study showed that darapladib exposure was increased in subjects with severe renal impairment compared with healthy controls. However, darapladib was generally well tolerated in both groups.
authors.affiliation: Clinical Pharmacology Modeling and Simulation, GlaxoSmithKline, King of Prussia, PA.
authors.forename: Mindy He
authors.initials: MH
authors.lastname: Magee
authors.affiliation: Metabolic Pathways and Cardiovascular Therapeutic Area, GlaxoSmithKline, King of Prussia, PA.
authors.forename: Bonnie
authors.initials: B
authors.lastname: Shaddinger
authors.affiliation: Clinical Statistics, GlaxoSmithKline, Research Triangle Park, NC.
authors.forename: David
authors.initials: D
authors.lastname: Collins
authors.affiliation: Clincal Pharmacology Sciences and Study Operations, GlaxoSmithKline, King of Prussia, PA, USA.
authors.forename: Shabana
authors.initials: S
authors.lastname: Siddiqi
authors.affiliation: Metabolic Pathways and Cardiovascular Therapeutic Area, GlaxoSmithKline, King of Prussia, PA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Soffer
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001547:Benzaldehydes / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010091:Oximes / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics*; D064801:Phospholipase A2 Inhibitors / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D051437:Renal Insufficiency / Q000378:metabolism*; D055815:Young Adult; D001713:Biphenyl Compounds; D004048:Diethylamines; D011744:Pyrimidinones; D013440:Sulfides
chemical_list: D001547:Benzaldehydes; D010091:Oximes; D064801:Phospholipase A2 Inhibitors; C529040:darapladib; D001713:Biphenyl Compounds; D004048:Diethylamines; D011744:Pyrimidinones; D013440:Sulfides
keywords: atherosclerosis; darapladib; pharmacokinetics; phospholipase A2; renal impairment