Morphine interaction with prasugrel: a double-blind, cross-over trial in healthy volunteers.
BACKGROUND
Morphine decreases the concentrations and effects of clopidogrel, which could lead to treatment failure in myocardial infarction.


OBJECTIVE
To clarify whether more potent P2Y12-inhibitors may provide an effective alternative, we examined drug-drug interactions between morphine and prasugrel.


METHODS
Twelve healthy volunteers received 60 mg prasugrel with placebo or 5 mg morphine intravenously in a randomized, double-blind, placebo-controlled, cross-over trial. Pharmacokinetics were determined by liquid chromatography tandem mass spectrometry, and prasugrel effects were measured by platelet function tests.


RESULTS
Morphine neither diminished total drug exposure (AUC), which was the primary endpoint, nor significantly delayed drug absorption of prasugrel. However, morphine reduced maximal plasma concentrations (C max) of prasugrel active metabolite by 31 % (p = 0.019). Morphine slightly, but not significantly, delayed the onset of maximal inhibition of platelet plug formation under high shear rates (30 vs. 20 min). Whole blood aggregation was not influenced.


CONCLUSIONS
Although morphine significantly decreases the maximal plasma concentrations of prasugrel active metabolite, it does not diminish its effects on platelets to a clinically relevant degree in healthy volunteers. However, it should be considered that the observed decrease in C max of prasugrel active metabolite caused by morphine co-administration may gain relevance in STEMI patients.


BACKGROUND
NCT01369186, EUDRA-CT#: 2010-023761-22.
Department of Clinical Pharmacology, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria. eva-luise.hobl@meduniwien.ac.at.
Eva-Luise
EL
Hobl
Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, Vienna, Austria.
Birgit
B
Reiter
Department of Clinical Pharmacology, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.
Christian
C
Schoergenhofer
Department of Clinical Pharmacology, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.
Michael
M
Schwameis
Department of Clinical Pharmacology, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.
Ulla
U
Derhaschnig
Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Vienna, Austria.
Irene Marthe
IM
Lang
Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, Vienna, Austria.
Thomas
T
Stimpfl
Department of Clinical Pharmacology, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria. bernd.jilma@meduniwien.ac.at.
Bernd
B
Jilma
D000328:Adult; D000701:Analgesics, Opioid / Q000008:administration & dosage* / Q000009:adverse effects; D001317:Austria; D001711:Biotransformation; D002853:Chromatography, Liquid; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004347:Drug Interactions; D016903:Drug Monitoring / Q000379:methods; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D009020:Morphine / Q000008:administration & dosage* / Q000009:adverse effects; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D010979:Platelet Function Tests; D000068799:Prasugrel Hydrochloride / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D058921:Purinergic P2Y Receptor Antagonists / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D018570:Risk Assessment; D053719:Tandem Mass Spectrometry; D055815:Young Adult
D000701:Analgesics, Opioid; D010975:Platelet Aggregation Inhibitors; D058921:Purinergic P2Y Receptor Antagonists; D009020:Morphine; D000068799:Prasugrel Hydrochloride
Drug interactions; Morphine; Platelet function tests; Prasugrel; Vasodilator-stimulated phosphoprotein