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.


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.


BACKGROUND
1) Study 1: ClinicalTrials.gov NCT01745458 2) Study 2: ClinicalTrials.gov NCT00387257.
Discovery Medicine, Heart Failure Discovery Performance Unit, Metabolic Pathways and Cardiovascular Therapeutic Area, GlaxoSmithKline, King of Prussia, Pennsylvania, United States of America.
Bonnie C
BC
Shaddinger
Discovery Biometrics, GlaxoSmithKline, King of Prussia, Pennsylvania, United States of America.
Yanmei
Y
Xu
Research Statistics Unit, GlaxoSmithKline, Stockley Park, United Kingdom.
James H
JH
Roger
Discovery Medicine, Heart Failure Discovery Performance Unit, Metabolic Pathways and Cardiovascular Therapeutic Area, GlaxoSmithKline, King of Prussia, Pennsylvania, United States of America.
Colin H
CH
Macphee
Janssen-Cilag Pty Ltd, Macquarie Park, New South Wales, Australia.
Malcolm
M
Handel
Discovery Biometrics, GlaxoSmithKline, King of Prussia, Pennsylvania, United States of America.
Charlotte A
CA
Baidoo
Discovery Medicine, Heart Failure Discovery Performance Unit, Metabolic Pathways and Cardiovascular Therapeutic Area, GlaxoSmithKline, King of Prussia, Pennsylvania, United States of America.
Mindy
M
Magee
Discovery Medicine, Heart Failure Discovery Performance Unit, Metabolic Pathways and Cardiovascular Therapeutic Area, GlaxoSmithKline, King of Prussia, Pennsylvania, United States of America.
John J
JJ
Lepore
Discovery Medicine, Heart Failure Discovery Performance Unit, Metabolic Pathways and Cardiovascular Therapeutic Area, GlaxoSmithKline, King of Prussia, Pennsylvania, United States of America.
Dennis L
DL
Sprecher
D000081:Acetamides / Q000494:pharmacology; D000328:Adult; D000704:Analysis of Variance; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008074:Lipoproteins / Q000378:metabolism*; D008297:Male; D008954:Models, Biological; D009517:New South Wales; D064801:Phospholipase A2 Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects* / Q000502:physiology; D015363:Quinolones / Q000494:pharmacology; D010880:Piperidines
D000081:Acetamides; D008074:Lipoproteins; D064801:Phospholipase A2 Inhibitors; D015363:Quinolones; C000592856:rilapladib; D010880:Piperidines