title: An effect of moderate hepatic impairment on the pharmacokinetics and safety of darapladib.
abstract: OBJECTIVE
  This was a phase 1, open label, non-randomized study designed to assess the pharmacokinetics and safety/tolerability of 10 consecutive once daily 40 mg oral doses of darapladib in subjects with moderate hepatic impairment (n = 12) compared with matched healthy volunteers (n = 12).
  
  
  RESULTS
  For total darapladib, a small increase in total and peak exposure was observed in the subjects with moderate hepatic impairment compared with the subjects with normal hepatic function. The area under the plasma concentration-time curve during a dosing interval of duration τ (AUC(0,τ), geometric mean 223 ng ml(-1)  h [90% CI 158, 316 ng ml(-1 ) h], in moderate hepatic impaired subjects, vs. geometric mean 186 ng ml(-1 ) h [90% CI 159, 217 ng ml(-1 ) h], in healthy subjects) and maximum concentration (Cmax ) were 20% and 7% higher, respectively, in the subjects with moderate hepatic impairment than in the healthy control subjects and there was no change in time to maximum concentration (tmax ). Protein binding was performed to measure the amount of unbound drug vs. bound. Steady-state was achieved by day 10 for darapladib and its metabolites (M4, M3 and M10). Darapladib was generally well tolerated, with adverse events (AEs) reported by seven subjects in the hepatic impairment group and three subjects in the healthy matched group (five and one of which were drug-related AEs, respectively). The most common AEs were gastrointestinal. These AEs were mostly mild to moderate and there were no deaths, serious AEs or withdrawals due to AEs.
  
  
  CONCLUSIONS
  The results of this phase 1 study show that darapladib (40 mg) is well tolerated and its pharmacokinetics remain relatively unchanged in patients with moderate hepatic impairment.
authors.affiliation: Clinical Pharmacology Modeling and Simulation, GlaxoSmithKline, King of Prussia, PA, USA.
authors.forename: Mindy He
authors.initials: MH
authors.lastname: Magee
authors.forename: Shawn
authors.initials: S
authors.lastname: Shearn
authors.forename: Bonnie
authors.initials: B
authors.lastname: Shaddinger
authors.forename: Zixing
authors.initials: Z
authors.lastname: Fang
authors.forename: Ruchira
authors.initials: R
authors.lastname: Glaser
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D019540:Area Under Curve; D001547:Benzaldehydes / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008107:Liver Diseases / Q000097:blood / Q000175:diagnosis / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D010091:Oximes / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics*; D064801:Phospholipase A2 Inhibitors / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics*; D012720:Severity of Illness Index; 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; hepatic impairment; pharmacokinetics; phospholipase A2