PMID- 24938621
OWN - NLM
STAT- MEDLINE
DCOM- 20150729
LR  - 20211021
IS  - 1365-2125 (Electronic)
IS  - 0306-5251 (Print)
IS  - 0306-5251 (Linking)
VI  - 78
IP  - 5
DP  - 2014 Nov
TI  - An effect of moderate hepatic impairment on the pharmacokinetics and safety of 
      darapladib.
PG  - 1014-21
LID - 10.1111/bcp.12436 [doi]
AB  - AIM/METHODS: 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 tau (AUC(0,tau), 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.
CI  - (c) 2014 The British Pharmacological Society.
FAU - Magee, Mindy He
AU  - Magee MH
AD  - Clinical Pharmacology Modeling and Simulation, GlaxoSmithKline, King of Prussia, 
      PA, USA.
FAU - Shearn, Shawn
AU  - Shearn S
FAU - Shaddinger, Bonnie
AU  - Shaddinger B
FAU - Fang, Zixing
AU  - Fang Z
FAU - Glaser, Ruchira
AU  - Glaser R
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Br J Clin Pharmacol
JT  - British journal of clinical pharmacology
JID - 7503323
RN  - 0 (Benzaldehydes)
RN  - 0 (Oximes)
RN  - 0 (Phospholipase A2 Inhibitors)
RN  - UI1U1MYH09 (darapladib)
SB  - IM
MH  - Administration, Oral
MH  - Adolescent
MH  - Adult
MH  - Aged
MH  - Area Under Curve
MH  - Benzaldehydes/administration & dosage/*adverse effects/blood/*pharmacokinetics
MH  - Dose-Response Relationship, Drug
MH  - Drug Administration Schedule
MH  - Female
MH  - Humans
MH  - Liver Diseases/blood/diagnosis/*metabolism
MH  - Male
MH  - Metabolic Clearance Rate
MH  - Middle Aged
MH  - Oximes/administration & dosage/*adverse effects/blood/*pharmacokinetics
MH  - Phospholipase A2 Inhibitors/administration & dosage/*adverse 
      effects/blood/*pharmacokinetics
MH  - Severity of Illness Index
MH  - Young Adult
PMC - PMC4243875
OTO - NOTNLM
OT  - atherosclerosis
OT  - darapladib
OT  - hepatic impairment
OT  - pharmacokinetics
OT  - phospholipase A2
EDAT- 2014/06/19 06:00
MHDA- 2015/07/30 06:00
PMCR- 2015/11/01
CRDT- 2014/06/19 06:00
PHST- 2012/12/27 00:00 [received]
PHST- 2014/05/31 00:00 [accepted]
PHST- 2014/06/19 06:00 [entrez]
PHST- 2014/06/19 06:00 [pubmed]
PHST- 2015/07/30 06:00 [medline]
PHST- 2015/11/01 00:00 [pmc-release]
AID - 10.1111/bcp.12436 [doi]
PST - ppublish
SO  - Br J Clin Pharmacol. 2014 Nov;78(5):1014-21. doi: 10.1111/bcp.12436.