title: Effect of darapladib on plasma lipoprotein-associated phospholipase A2 activity in Japanese dyslipidemic patients, with exploratory analysis of a PLA2G7 gene polymorphism of Val279Phe.
abstract: BACKGROUND
  Lipoprotein-associated phospholipase A2 (Lp-PLA2) is being evaluated as a therapeutic target for treatment of atherosclerosis. This is the first study to examine the effects of darapladib, a novel selective Lp-PLA2 inhibitor, on Lp-PLA2 activity in Japanese dyslipidemic patients with/without the Val279Phe (V279F) single-nucleotide polymorphism (SNP) of the PLA2G7 gene. Exploratory analysis to examine the effects of V279F on Lp-PLA2 inhibition of darapladib was also performed.
  
  
  RESULTS
  This was a 4-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging trial of darapladib in 107 Japanese patients with dyslipidemia receiving statins. Patients were randomized to placebo (n=25), darapladib 40 mg (n=28), 80 mg (n=28), or 16 0mg (n=26). All darapladib doses produced sustained dose-dependent inhibition of Lp-PLA2 activity of approximately 49%, 58%, and 67%, respectively (P<0.001 for all comparisons). The inhibitory effect achieved a plateau by 1 week. Patients with the V279F homogenous mutation who have no circulating levels of Lp-PLA2, were excluded from the study. The Lp-PLA2 activity was inhibited in both homozygous wild-type and heterozygote genotypes of the V279F polymorphism subjects to a similar extent, although the heterogeneous mutation has almost half the level of Lp-PLA2 activity compared with that of wild-type in Japanese people. The most common adverse events were odor related. No major safety concerns were noted.
  
  
  CONCLUSIONS
  Darapladib produced sustained inhibition of Lp-PLA2 activity in Japanese dyslipidemic patients with/without the V279F SNP of Lp-PLA2.
authors: Department of Cardiovascular Medicine, Juntendo University School of Medicine, Tokyo 113-8421, Japan. daida@juntendo.ac.jp
authors: Hiroyuki
authors: H
authors: Daida
authors: Takayuki
authors: T
authors: Iwase
authors: Shigeru
authors: S
authors: Yagi
authors: Hidekazu
authors: H
authors: Ando
authors: Hiromu
authors: H
authors: Nakajima
mesh_terms: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D000328:Adult; D000369:Aged, 80 and over; D019943:Amino Acid Substitution; D044466:Asian People; D001547:Benzaldehydes / Q000008:administration & dosage* / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D050171:Dyslipidemias / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D007564:Japan; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010091:Oximes / Q000008:administration & dosage* / Q000009:adverse effects; D064801:Phospholipase A2 Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D054467:Phospholipases A2 / Q000097:blood / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D001713:Biphenyl Compounds; D004048:Diethylamines; D011744:Pyrimidinones; D013440:Sulfides
chemical_list: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D001547:Benzaldehydes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D010091:Oximes; D064801:Phospholipase A2 Inhibitors; D054467:Phospholipases A2; C526684:PLA2G7 protein, human; C529040:darapladib; D001713:Biphenyl Compounds; D004048:Diethylamines; D011744:Pyrimidinones; D013440:Sulfides