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
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 入组人数
- 30
- 试验地点
- 1
- 主要终点
- Platelet Reactivity Measured by VerifyNow P2Y12
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Methylnaltrexone
Patients will be randomly assigned in a 1:1 fashion to receive either i.v methylnaltrexone or placebo (0.9% sodium chloride iv injection). Methylnaltrexone, at a dose of 0.3 mg/Kg, will be administered diluted with 5 ml of normal saline as a single i.v. bolus over 1 minute followed by morphine (5-mg intravenous bolus). Then patients will receive iv morphine and a loading dose of ticagrelor.
干预措施: Methylnaltrexone (Drug)
Methylnaltrexone
Patients will be randomly assigned in a 1:1 fashion to receive either i.v methylnaltrexone or placebo (0.9% sodium chloride iv injection). Methylnaltrexone, at a dose of 0.3 mg/Kg, will be administered diluted with 5 ml of normal saline as a single i.v. bolus over 1 minute followed by morphine (5-mg intravenous bolus). Then patients will receive iv morphine and a loading dose of ticagrelor.
干预措施: Morphine (Drug)
Methylnaltrexone
Patients will be randomly assigned in a 1:1 fashion to receive either i.v methylnaltrexone or placebo (0.9% sodium chloride iv injection). Methylnaltrexone, at a dose of 0.3 mg/Kg, will be administered diluted with 5 ml of normal saline as a single i.v. bolus over 1 minute followed by morphine (5-mg intravenous bolus). Then patients will receive iv morphine and a loading dose of ticagrelor.
干预措施: Ticagrelor (Drug)
Placebo
Patients will be randomly assigned in a 1:1 fashion to receive either i.v methylnaltrexone or placebo (0.9% sodium chloride iv injection). Methylnaltrexone, at a dose of 0.3 mg/Kg, will be administered diluted with 5 ml of normal saline as a single i.v. bolus over 1 minute followed by morphine (5-mg intravenous bolus). Then patients will receive iv morphine and a loading dose of ticagrelor.
干预措施: Placebo (Other)
Placebo
Patients will be randomly assigned in a 1:1 fashion to receive either i.v methylnaltrexone or placebo (0.9% sodium chloride iv injection). Methylnaltrexone, at a dose of 0.3 mg/Kg, will be administered diluted with 5 ml of normal saline as a single i.v. bolus over 1 minute followed by morphine (5-mg intravenous bolus). Then patients will receive iv morphine and a loading dose of ticagrelor.
干预措施: Morphine (Drug)
Placebo
Patients will be randomly assigned in a 1:1 fashion to receive either i.v methylnaltrexone or placebo (0.9% sodium chloride iv injection). Methylnaltrexone, at a dose of 0.3 mg/Kg, will be administered diluted with 5 ml of normal saline as a single i.v. bolus over 1 minute followed by morphine (5-mg intravenous bolus). Then patients will receive iv morphine and a loading dose of ticagrelor.
干预措施: Ticagrelor (Drug)
结局指标
主要结局
Platelet Reactivity Measured by VerifyNow P2Y12
时间窗: 2 hours
Platelet reactivity measured by VerifyNow P2Y12 2 hours after ticagrelor loading dose and reported as P2Y12 reaction units (PRU)
次要结局
- Platelet Reactivity Measured by VASP(2 hours)
- AUC of Ticagrelor Plasma Levels(6 hours)