University of Florida College of Medicine-Jacksonville, Jacksonville, Florida.
University of Florida College of Medicine-Jacksonville, Jacksonville, Florida.
JACC Cardiovasc Interv. 2019 Aug 26;12(16):1538-1549. doi: 10.1016/j.jcin.2019.05.028. Epub 2019 Jul 31.
The aim of this study was to assess if intravenous methylnaltrexone can counteract the effects of morphine on the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of ticagrelor.
Morphine delays the onset of action of oral P2Y receptor inhibitors, including ticagrelor, by inhibiting gastric emptying and leading to delayed drug absorption. Methylnaltrexone is a peripheral opioid receptor antagonist that has the potential to prevent opioid-induced peripherally mediated side effects (e.g., gastric emptying inhibition) without affecting analgesia.
In this prospective, randomized, double-blind, placebo-controlled, crossover study, aspirin-treated patients with stable coronary artery disease (n = 30) were randomized to receive methylnaltrexone (0.3 mg/kg intravenous) or matching placebo. After methylnaltrexone or placebo administration, all patients received morphine (5 mg intravenous). This was followed 15 min later by a 180-mg loading dose of ticagrelor. Patients crossed over to the alternative study treatment after 7 ± 2 days of washout. PK and PD assessments were performed at 12 time points (6 pre- and 6 post-crossover). PK analysis included measurement of plasma levels of ticagrelor and its major active metabolite (AR-C124910XX). PD assessments included VerifyNow P2Y, light transmittance aggregometry, and vasodilator-stimulated phosphoprotein.
Only marginal changes in plasma levels of ticagrelor (and its major active metabolite) were observed with ticagrelor: maximum plasma concentration and area under the plasma concentration versus time curve from time 0 to the last measurable concentration were 38% and 30% higher, respectively, in patients receiving methylnaltrexone compared with those receiving placebo, but no differences in time to maximum plasma concentration were observed. There were no differences in P2Y reaction units by VerifyNow P2Y between groups at each time point, including 2 h (the primary endpoint; p = 0.261). Similarly, there were no differences in PD markers assessed by light transmittance aggregometry and vasodilator-stimulated phosphoprotein.
In patients with coronary artery disease receiving morphine, intravenous administration of the peripheral opioid receptor antagonist methylnaltrexone leads to only marginal changes in plasma levels of ticagrelor and its major metabolite, without affecting levels of platelet reactivity. (Effect of Methylnaltrexone on the PK/PD Profiles of Ticagrelor in Patients Treated With Morphine; NCT02403830).
本研究旨在评估静脉给予甲基纳曲酮是否可以逆转吗啡对替格瑞洛药代动力学（PK）和药效动力学（PD）特征的影响。
吗啡通过抑制胃排空导致药物吸收延迟，从而延迟口服 P2Y 受体抑制剂（包括替格瑞洛）的起效时间。甲基纳曲酮是一种外周阿片受体拮抗剂，有可能预防阿片类药物引起的外周介导的副作用（如胃排空抑制），而不影响镇痛作用。
在这项前瞻性、随机、双盲、安慰剂对照、交叉研究中，接受阿司匹林治疗的稳定性冠状动脉疾病患者（n=30）被随机分为接受甲基纳曲酮（0.3mg/kg 静脉注射）或匹配安慰剂组。在给予甲基纳曲酮或安慰剂后，所有患者均接受吗啡（5mg 静脉注射）。15min 后，给予替格瑞洛 180mg 负荷剂量。在洗脱期 7±2 天后，患者交叉至替代研究治疗。PK 和 PD 评估在 12 个时间点进行（6 个交叉前和 6 个交叉后）。PK 分析包括测量替格瑞洛及其主要活性代谢物（AR-C124910XX）的血浆水平。PD 评估包括 VerifyNow P2Y、透光比浊法和血管扩张刺激磷蛋白。
替格瑞洛（及其主要活性代谢物）的血浆水平仅出现轻微变化：与接受安慰剂的患者相比，接受甲基纳曲酮的患者替格瑞洛的最大血浆浓度和从 0 到最后可测量浓度的血浆浓度-时间曲线下面积分别升高 38%和 30%，但最大血浆浓度时间无差异。在每个时间点，通过 VerifyNow P2Y 测定的 P2Y 反应单位在两组之间没有差异，包括 2h（主要终点；p=0.261）。同样，通过透光比浊法和血管扩张刺激磷蛋白测定的 PD 标志物也没有差异。
在接受吗啡治疗的冠状动脉疾病患者中，静脉给予外周阿片受体拮抗剂甲基纳曲酮仅导致替格瑞洛及其主要代谢物的血浆水平出现轻微变化，而不影响血小板反应性水平。（甲基纳曲酮对吗啡治疗患者替格瑞洛 PK/PD 特征的影响；NCT02403830）。
