Electrocardiographic safety of cangrelor, a new intravenous antiplatelet agent: a randomized, double-blind, placebo- and moxifloxacin-controlled thorough QT study.
Cangrelor is an intravenous P2Y12 inhibitor under investigation as an antiplatelet drug in the setting of acute coronary syndromes. To determine the electrophysiologic safety of parenteral cangrelor, cardiac repolarization effects were measured in 67 healthy volunteers (aged 18-45 years) in a randomized crossover design, including 4 treatment sequences of therapeutic cangrelor, supratherapeutic cangrelor, placebo, and moxifloxacin (positive control). Triplicate electrocardiogram measurements and pharmacokinetic samples were collected at baseline and 9 time points postdose on day 1. For both cangrelor and moxifloxacin, time-matched, placebo-adjusted change in QT from baseline was evaluated using an individual (QTcI) heart rate correction. After cangrelor dosing, change in QTcI was <5 ms at all times points and all corresponding upper 2-sided 90% confidence intervals (CIs) were <10 ms. Although moxifloxacin failed to show a lower CI >5 ms, expected time trends and lower CI >4.0 ms demonstrate assay sensitivity. QTcI was not affected by plasma concentrations of cangrelor metabolites, and cangrelor had no other adverse effects on electrocardiographic parameters. Clinically, cangrelor exposure was well tolerated. Thus, this thorough QT study demonstrated that therapeutic and supratherapeutic cangrelor doses do not adversely affect cardiac repolarization in normal volunteers (clinicaltrials.gov; identifier NCT00699504).
*Duke University Medical Center, Durham, NC; †Duke Clinical Research Institute, Durham, NC; ‡Thomas Jefferson University, Philadelphia, PA; and §The Medicines Company, Parsippany, NJ.
Cynthia L
CL
Green
David J
DJ
Whellan
Lindsay
L
Lambe
S E
SE
Bellibas
Peter
P
Wijngaard
Jayne
J
Prats
Mitchell W
MW
Krucoff
D000249:Adenosine Monophosphate / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000293:Adolescent; D000328:Adult; D001372:Aza Compounds / Q000009:adverse effects*; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004562:Electrocardiography; D005260:Female; D024841:Fluoroquinolones; D005500:Follow-Up Studies; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced*; D008297:Male; D008875:Middle Aged; D000077266:Moxifloxacin; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D058921:Purinergic P2Y Receptor Antagonists / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D011804:Quinolines / Q000009:adverse effects*; D013997:Time Factors; D055815:Young Adult
D001372:Aza Compounds; D024841:Fluoroquinolones; D010975:Platelet Aggregation Inhibitors; D058921:Purinergic P2Y Receptor Antagonists; D011804:Quinolines; D000249:Adenosine Monophosphate; C117446:cangrelor; D000077266:Moxifloxacin