title: Single and Multiple Dose Pharmacokinetics, Pharmacodynamics and Safety of the Novel Lipoprotein-Associated Phospholipase A2 Enzyme Inhibitor Darapladib in Healthy Chinese Subjects: An Open Label Phase-1 Clinical Trial.
abstract: OBJECTIVE
  Darapladib is a lipoprotein-associated phospholipase A2 (Lp-PLA2) inhibitor. This study evaluated the pharmacokinetics, pharmacodynamics and safety of darapladib in healthy Chinese subjects.
  
  
  METHODS
  Twenty-four subjects received darapladib 160 mg orally, approximately 1 hour after a standard breakfast, as a single dose and once daily for 28 days. Non-compartmental methods were used to determine the single and multiple dose pharmacokinetics of darapladib and its metabolite SB-553253. Repeat dose Lp-PLA2 activity and safety were evaluated.
  
  
  RESULTS
  Systemic exposure (AUC(0-T), Cmax geometric mean (CVb%)) of darapladib was higher after multiple-dosing (519 ng.h/mL (33.3%), 34.4 ng/mL (49.9%)) compared to single-dose administration (153 ng.h/mL (69.0%), 17.9 ng/mL (55.2%). The steady-state accumulation ratio was less than unity (Rs = 0.80), indicating time-dependent pharmacokinetics of darapladib. Darapladib steady-state was reached by Day 14 of once daily dosing. Systemic exposure to SB-553253 was lower than darapladib with median (SB-553253: darapladib) ratios for AUC(0-τ) of 0.0786 for single dose and 0.0532 for multiple dose administration. On Day 28, pre-dose and maximum inhibition of Lp-PLA2 activity was approximately 70% and 75% relative to the baseline value, respectively and was dependent of darapladib concentration. The most common adverse events (≥ 21% subjects) were abnormal faeces, abnormal urine odour, diarrhoea and nasopharyngitis.
  
  
  CONCLUSIONS
  Darapladib 160 mg single and repeat doses were profiled in healthy Chinese subjects. Single dose systemic exposure to darapladib in healthy Chinese subjects was consistent with that observed previously in Western subjects whereas steady-state systemic exposure was approximately 65% higher in Chinese than Western subjects. The Lp-PLA2 activity and adverse event profile were similar in healthy Chinese and previous reports in Western subjects. Ethnic-specific dose adjustment of darapladib is not considered necessary for the Chinese population.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT02000804.
authors.affiliation: Phase I Clinical Research Unit, Shanghai Xuhui Central Hospital, Shanghai, China.
authors.forename: Chaoying
authors.initials: C
authors.lastname: Hu
authors.affiliation: Clinical Pharmacology Modeling and Simulation, GSK Medicines Research Centre, Stevenage, United Kingdom.
authors.forename: Debra
authors.initials: D
authors.lastname: Tompson
authors.affiliation: Clinical Pharmacology Modeling and Simulation, GlaxoSmithKline, King of Prussia, Pennsylvania, United States of America.
authors.forename: Mindy
authors.initials: M
authors.lastname: Magee
authors.affiliation: Phase I Clinical Research Unit, Shanghai Xuhui Central Hospital, Shanghai, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Phase I Clinical Research Unit, Shanghai Xuhui Central Hospital, Shanghai, China.
authors.forename: Yan Mei
authors.initials: YM
authors.lastname: Liu
authors.affiliation: China Medicine Development, GlaxoSmithKline (China) R&D Company Limited, Shanghai, China.
authors.forename: Wenjing
authors.initials: W
authors.lastname: Zhu
authors.affiliation: China Medicine Development, GlaxoSmithKline (China) R&D Company Limited, Shanghai, China.
authors.forename: Hongxin
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Ethnopharmacology, GlaxoSmithKline, Sydney, Australia.
authors.forename: Annette S
authors.initials: AS
authors.lastname: Gross
authors.affiliation: Phase I Clinical Research Unit, Shanghai Xuhui Central Hospital, Shanghai, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Liu
mesh_terms: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000328:Adult; D044466:Asian People; D001547:Benzaldehydes / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D002681:China; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D010091:Oximes / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001713:Biphenyl Compounds; D004048:Diethylamines; D011744:Pyrimidinones; D013440:Sulfides
chemical_list: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D001547:Benzaldehydes; D004791:Enzyme Inhibitors; D010091:Oximes; C529040:darapladib; D001713:Biphenyl Compounds; D004048:Diethylamines; D011744:Pyrimidinones; D013440:Sulfides