Abstract
BackgroundWe explored the theorized upregulation of platelet-activating factor (PAF)– mediated biologic responses following lipoprotein-associated phospholipase A2 (Lp-PLA2) inhibition using human platelet aggregation studies in an in vitro experiment and in 2 clinical trials.Methods and ResultsFull platelet aggregation concentration response curves were generated in vitro to several platelet agonists in human plasma samples pretreated with rilapladib (selective Lp-PLA2 inhibitor) or vehicle. This was followed by a randomized, double-blind crossover study in healthy adult men (n = 26) employing a single-agonist dose assay of platelet aggregation, after treatment of subjects with 250 mg oral rilapladib or placebo once daily for 14 days. This study was followed by a second randomized, double-blind parallel-group trial in healthy adult men (n = 58) also treated with 250 mg oral rilapladib or placebo once daily for 14 days using a full range of 10 collagen concentrations (0–10 µg/ml) for characterizing EC50 values for platelet aggregation for each subject. Both clinical studies were conducted at the GlaxoSmithKline Medicines Research Unit in the Prince of Wales Hospital, Sydney, Australia. EC50 values derived from multiple agonist concentrations were compared and no pro-aggregant signals were observed during exposure to rilapladib in any of these platelet studies, despite Lp-PLA2 inhibition exceeding 90%. An increase in collagen-mediated aggregation was observed 3 weeks post drug termination in the crossover study (15.4% vs baseline; 95% confidence interval [CI], 3.9–27.0), which was not observed during the treatment phase and was not observed in the parallel-group study employing a more robust EC50 examination.ConclusionsLp-PLA2 inhibition does not enhance platelet aggregation.Trial Registration1) Study 1: ClinicalTrials.gov NCT01745458 2) Study 2: ClinicalTrials.gov NCT00387257
Highlights
Potent, selective, and orally active lipoprotein-associated phospholipase A2 (Lp-PLA2) inhibitors are in clinical development to determine their effects on reducing the risk of atherothrombosis and associated clinical sequelae [1,2,3,4]
Lp-PLA2 was initially described as platelet-activating factor (PAF) acetylhydrolase (PAF-AH) because of its ability to hydrolyze PAF in vitro into biologically inactive lyso-PAF [5,6,7], when PAF in micromolar concentrations is added to isolated human plasma, [8]
LpPLA2 activity was measured in parallel using plasma samples that were derived from Platelet-rich plasma (PRP) that had been treated either with vehicle or rilapladib (100 nM) for 5 minutes using [3H]-PAF as the substrate as previously described [21]
Summary
Selective, and orally active lipoprotein-associated phospholipase A2 (Lp-PLA2) inhibitors are in clinical development to determine their effects on reducing the risk of atherothrombosis and associated clinical sequelae (eg, acute coronary syndromes, ischemic stroke, etc) [1,2,3,4]. Based on its role in platelet function, PAF accumulation could theoretically increase platelet aggregation, potentially contributing to adverse thrombotic events in the target population for which Lp-PLA2 inhibitors are being developed [9,10]. Published evidence to date offers mixed results regarding the role of Lp-PLA2 activity in influencing PAF-mediated biology. As a result, understanding the relationship between Lp-PLA2 and PAF-mediated responses has been a critical step for advancing the clinical development of Lp-PLA2 inhibitors (darapladib and rilapladib) and initiating large-scale cardiovascular outcomes trials [19,20]. We explored the theorized upregulation of platelet-activating factor (PAF)– mediated biologic responses following lipoprotein-associated phospholipase A2 (Lp-PLA2) inhibition using human platelet aggregation studies in an in vitro experiment and in 2 clinical trials
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