title: Evaluation of the safety, pharmacokinetics, pharmacodynamics, and drug-drug interaction potential of a selective Lp-PLA2 inhibitor (GSK2647544) in healthy volunteers .
abstract: OBJECTIVE
  To evaluate in healthy volunteers the safety, pharmacokinetics (PK), pharmacodynamics (PD), and drug-drug interaction (DDI) potential of GSK2647544, (a selective lipoprotein-associated phospholipase A2 (Lp-PLA2) inhibitor).
  
  
  METHODS
  Study 1 was a single-blind, randomized, placebo-controlled, crossover study with healthy male volunteers randomized to receive single escalating oral doses (0.5 - 750 mg) of GSK2647544. Study 2 was a single-blind, randomized, placebo-controlled study with healthy volunteers randomized to receive repeat doses (80 mg) of GSK2647544. The drug-drug interaction of GSK2647544 with simvastatin was also evaluated in study 2.
  
  
  RESULTS
  Across both studies GSK2647544 doses were generally well tolerated with no GSK2647544-related clinically significant findings. GSK2647544 was readily absorbed and its plasma concentration declined bi-exponentially with a terminal half-life ranging from 8 to 16 hours. Plasma exposure of GSK2647544 increased approximately dose-proportionally. There was GSK2647544 dose-dependent inhibition of plasma Lp-PLA2 activity, with a trough inhibition (12 hours after dose) of 85.6% after 7-day twice daily dosing. The administration of simvastatin concomitantly with GSK2647544 increased the overall exposure (area under the plasma concentration-time curve and maximum plasma concentration) of simvastatin and simvastatin acid by 3.6- to 4.3-fold and 1.5- to 3.1-fold, respectively.
  
  
  CONCLUSIONS
  GSK2647544 was generally well tolerated and had a reasonable PK-PD profile. The clinically significant drug-drug interaction led to an early termination of study 2. .
authors.forename: Kai
authors.initials: K
authors.lastname: Wu
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Xu
authors.forename: Regan
authors.initials: R
authors.lastname: Fong
authors.forename: Xiaozhou
authors.initials: X
authors.lastname: Yao
authors.forename: Yanmei
authors.initials: Y
authors.lastname: Xu
authors.forename: William
authors.initials: W
authors.lastname: Guiney
authors.forename: Frank
authors.initials: F
authors.lastname: Gray
authors.forename: Andrew
authors.initials: A
authors.lastname: Lockhart
mesh_terms: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000037:antagonists & inhibitors*; D000328:Adult; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D010647:Phenyl Ethers / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000494:pharmacology; D011744:Pyrimidinones / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000494:pharmacology; D019821:Simvastatin / Q000494:pharmacology; D016037:Single-Blind Method
chemical_list: D065692:Cytochrome P-450 CYP3A Inhibitors; C000615596:GSK2647544; D010647:Phenyl Ethers; D011744:Pyrimidinones; D019821:Simvastatin; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase