Effect of Methylnaltrexone on the PK/PD Profiles of Ticagrelor in Patients Treated With Morphine

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.

Inclusion criteria:

- Patients with angiographically documented CAD.

- On treatment with low-dose aspirin (81 mg) for at least 30 days, as per standard of
care.

- Age between 18 and 80 years old.

Exclusion criteria:

- History of prior intracranial bleeding.

- On treatment with a P2Y12 receptor antagonist (ticlopidine, clopidogrel, prasugrel,
ticagrelor) or with vorapaxar in past 30 days.

- Known allergies to ticagrelor.

- On treatment with any oral anticoagulant (vitamin K antagonists, dabigatran,
rivaroxaban, apixaban).

- Treatment with glycoprotein IIb/IIIa inhibitors in past 7 days.

- Known blood dyscrasia or bleeding diathesis.

- Platelet count <80x106/mL.

- Hemoglobin <10 g/dL.

- Active bleeding.

- Hemodynamic instability.

- Creatinine clearance <30 mL/minute (as estimated by Cockcroft-Gault formula).

- Severe hepatic dysfunction.

- Acute or severe bronchial asthma or upper airway obstruction.

- Known or suspected mechanical gastrointestinal obstruction.

- Patients with sick sinus syndrome (SSS) or high degree AV block without pacemaker
protection.

- Current treatment with any drug interfering with morphine: central nervous system
depressants (other narcotic analgesics, general anesthetics, phenothiazines,
tricyclic antidepressants, tranquilizers, sedatives, hypnotics, antiemetics, and
alcohol), muscle relaxants, mixed agonist/antagonist analgesics (i.e., pentazocine,
nalbuphine, and butorphanol), cimetidine, monoamine oxidase inhibitors (MAOIs),
anticholinergics.

- Current treatment with drugs interfering with CYP3A4 metabolism (to avoid interaction
with ticagrelor): Ketoconazole, itraconazole, voriconazole, clarithromycin,
nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, atazanavir, and
telithromizycin.

- Pregnant females*. *Women of childbearing age must use reliable birth control (i.e.
oral contraceptives) while participating in the study.