Summary of adverse experiences during treatment (14±4 days) in the carotid endarterectomy study.

<p>Summary of adverse experiences during treatment (14±4 days) in the carotid endarterectomy study.</p

Disposition of patients throughout the carotid endarterectomy study.

<p>Disposition of patients throughout the carotid endarterectomy study.</p

The influence of darapladib treatment (14±4 days) on plaque (A) caspase-3 activity and (B) caspase-8 activity (mean ± SEM).

<p><i>P</i> values represent comparisons of darapladib 80 mg with placebo. AU, activity units.</p

The influence of darapladib treatment (14±4 days) on the expression (mRNA) of several plaque biomarkers.

<p>Vertical bars represent 95% confidence intervals (CI). CD40L, CD40 ligand; MMP, matrix metalloproteinase; PAI, plasminogen activator inhibitor; ICAM, intercellular adhesion molecule; IL, interleukin; Lp-PLA, lipoprotein-associated phospholipase A₂.</p

Analysis of plaque lysophosphatidylcholine (lysoPC) content following treatment (14±4 days) with darapladib.

<p>Data represent mean ± standard deviation.</p

Effect of darapladib treatment (14±4 days) on plaque and plasma lipoprotein-associated phospholipase A₂ activity.

<p>Vertical bars for plaque and plasma data points represent 97.5% and 95% confidence intervals (CI), respectively. Baseline plasma Lp-PLA₂ activity levels are provided in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0089034#pone-0089034-t001" target="_blank">Table 1</a>. At Day 15, plasma Lp-PLA₂ activity levels (mean ± SD) for placebo, 40 mg darapladib, and 80 mg darapladib were 141.4±39.3, 63.4±28.3, and 27.0±11.4 nmol/min/ml, respectively. At Day 15, plaque Lp-PLA₂ activity levels (mean ± SEM) for placebo, 40 mg darapladib, and 80 mg darapladib were 0.94±0.14, 0.26±0.13, and 0.11±0.14 nmol/min/mg protein, respectively.</p

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

<div><p>Background</p><p>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.</p><p>Methods and Results</p><p>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.</p><p>Conclusions</p><p>Lp-PLA₂ inhibition does not enhance platelet aggregation.</p><p>Trial Registration</p><p>1) Study 1: ClinicalTrials.gov <a href="http://www.clinicaltrials.gov/ct2/show/NCT01745458?term=NCT01745458&rank=1andwww.clinicaltrials.gov/ct2/show/NCT01750827?term=NCT01750827&rank=1" target="_blank">NCT01745458</a> 2) Study 2: ClinicalTrials.gov <a href="http://www.clinicaltrials.gov/ct2/show/NCT00387257?term=NCT00387257&rank=1" target="_blank">NCT00387257</a></p></div

Comparison of the EC₅₀ for collagen-induced platelet aggregation (Study 2).

a<p>EC₅₀ rilapladib/EC₅₀ placebo.</p>b<p>Corresponding to the predose time during treatment.</p>c<p>Corresponding to the 6 hours postdose time during treatment.</p><p>EC₅₀, 50% maximal platelet aggregation; CI, confidence interval.</p