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

Coronary Artery Disease Clinical Trial

Official title:

Effect of the Peripheral Opioid Receptor Antagonist Methylnaltrexone on the Pharmacokinetic and Pharmacodynamic Profiles of Ticagrelor in Patients Receiving Morphine: a Prospective, Randomized Placebo-controlled Trial

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02403830
• Other study ID #: AZ 10583 IISR
• Status: Completed
• Phase: Phase 4
• First received: February 17, 2015
• Last updated: April 25, 2017
• Start date: August 2015
• Est. completion date: May 2016

Study information

• Verified date: April 2017
• Source: University of Florida
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 30
• Est. completion date: May 2016
• Est. primary completion date: May 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

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.

Related Conditions & MeSH terms

• Coronary Artery Disease
• Coronary Disease
• Myocardial Ischemia

Intervention

Drug:
• Methylnaltrexone
Methylnaltrexone will be administered diluted with 5 ml of normal saline as a single iv bolus

Other:
• Placebo
Placebo will be administered as a 0.9% sodium chloride iv injection

Drug:
• Morphine
After methylnaltrexone, patients will receive 5-mg intravenous morphine
• Ticagrelor
After morphine administration, patients will receive a 180-mg ticagrelor loading dose

Locations

Country	Name	City	State
United States	University of Florida	Jacksonville	Florida

Sponsors (1)

Lead Sponsor	Collaborator
University of Florida

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Platelet Reactivity Measured by VerifyNow P2Y12	Platelet reactivity measured by VerifyNow P2Y12 2 hours after ticagrelor loading dose and reported as P2Y12 reaction units (PRU)	2 hours
Secondary	Platelet Reactivity Measured by VASP	Platelet reactivity measured by VASP 2 hours after ticagrelor loading dose and reported as platelet reactivity index (PRI)	2 hours
Secondary	AUC of Ticagrelor Plasma Levels	The area under the plasma concentration vs. time curve from time 0 to the last measurable concentration (AUC) was calculated based on ticagrelor plasma levels	6 hours