Effect of Darapladib on Plasma Lipoprotein-Associated Phospholipase A2 Activity in Japanese Dyslipidemic Patients, With Exploratory Analysis of a PLA2G7 Gene Polymorphism of Val279Phe
スポンサーリンク
概要
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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. Methods and 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 40mg (n=28), 80mg (n=28), or 160mg (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.
著者
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Iwase Takayuki
Glaxo Smith Kline K.K.
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Daida Hiroyuki
Department Of Cardiology
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Yagi Shigeru
GlaxoSmithKline K.K.
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Ando Hidekazu
GlaxoSmithKline K.K.
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Nakajima Hiromu
GlaxoSmithKline K.K.
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