Effect of Methylnaltrexone on the PK/PD Profiles of Ticagrelor in Patients Treated With Morphine
Condition: Coronary Artery Disease
MeSH terms: Coronary Artery Disease
Study type: Interventional
Phase: Phase 4

Summary: 
      Ticagrelor is associated with more prompt and potent antiplatelet effects compared with
      clopidogrel, leading to better clinical outcomes, including reduced cardiovascular mortality,
      across the spectrum of patients with acute coronary syndrome, including those with
      ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary
      intervention (PCI). However, in this latter setting a delay in the onset of its antiplatelet
      effects has been shown. Morphine has been identified as a cause of delayed P2Y12 inhibition
      in patients with STEMI. Methylnaltrexone is a parenteral peripheral opioid receptor
      antagonist which has the potential to prevent or reverse opioid-induced peripherally mediated
      side effects without affecting analgesia. However, whether the use of intravenous
      methylnaltrexone may overcome the effects of morphine administration on the pharmacokinetic
      (PK) and pharmacodynamics (PD) profiles of ticagrelor has not been investigated yet. The
      proposed investigation will include patients with coronary artery disease and will have a
      prospective, randomized, cross-over design.
    

Detailed description: 
      Ticagrelor is associated with more prompt and potent antiplatelet effects compared with
      clopidogrel, leading to better clinical outcomes, including reduced cardiovascular mortality,
      across the spectrum of patients with acute coronary syndrome, including those with
      ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary
      intervention (PCI). However, in this latter setting a delay in the onset of its antiplatelet
      effects has been shown. Morphine has been identified as a cause of delayed P2Y12 inhibition
      in patients with STEMI. In fact, opiates are known to inhibit gastric emptying, leading to
      delayed absorption and potentially decreasing peak plasma levels of orally administered
      drugs. Methylnaltrexone is a parenteral peripheral opioid receptor antagonist which has the
      potential to prevent or reverse opioid-induced peripherally mediated side effects (i.e.
      gastric emptying inhibition) without affecting analgesia. Studies have shown that
      methylnaltrexone effectively prevented morphine-induced gut motility change. However, whether
      the use of intravenous methylnaltrexone may overcome the effects of morphine administration
      on the pharmacokinetic (PK) and pharmacodynamics (PD) profiles of ticagrelor has not been
      investigated yet. The proposed investigation will include patients with coronary artery
      disease and will have a prospective, randomized, cross-over design. Patients will be
      randomized to receive either intravenous methylnaltrexone or placebo. Immediately after
      methylnaltrexone administration, patients will receive intravenous morphine and then will
      receive a 180-mg ticagrelor loading dose 15 minutes after morphine administration. After a 7
      ± 2 days wash-out period, patients will cross-over to the alternate study-treatment arm. At
      each visit, blood samples for PK and PD assessments will be collected at several time points.
      This study will provide insights on a possible treatment strategy to overcome the impaired
      P2Y12 inhibition induced by morphine.
    

Intervention name(s): Methylnaltrexone; Placebo; Morphine; Ticagrelor
Intervention type(s): Drug; Other; Drug; Drug
Intervention description(s): Methylnaltrexone will be administered diluted with 5 ml of normal saline as a single iv bolus; Placebo will be administered as a 0.9% sodium chloride iv injection; After methylnaltrexone, patients will receive 5-mg intravenous morphine; After morphine administration, patients will receive a 180-mg ticagrelor loading dose
Other intervention name(s): Relistor; Morphine sulfate; Brilinta
Intervention MeSH terms: Morphine; Methylnaltrexone; Ticagrelor
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment