Platelet Aggregation Unchanged by Lipoprotein-Associated Phospholipase A2 Inhibition: Results from an In Vitro Study and Two Randomized Phase I Trials

Background

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.

Methods and Results

Full 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.

Conclusions

Lp-PLA₂ inhibition does not enhance platelet aggregation.

Trial Registration

1) Study 1: ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01745458","term_id":"NCT01745458"}}NCT01745458 2) Study 2: ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00387257","term_id":"NCT00387257"}}NCT00387257