Author + information
- Received March 1, 2019
- Revision received May 17, 2019
- Accepted May 20, 2019
- Published online August 19, 2019.
- Francesco Franchi, MD,
- Fabiana Rollini, MD,
- Yongwhi Park, MD,
- Jenny Hu, MD,
- Megha Kureti, MD,
- Jose Rivas Rios, MD,
- Gabriel Faz, MD,
- Dmitry Yaranov, MD,
- Latonya Been, AAS,
- Andres M. Pineda, MD,
- Siva Suryadevara, MD,
- Daniel Soffer, MD,
- Martin M. Zenni, MD,
- Theodore A. Bass, MD and
- Dominick J. Angiolillo, MD, PhD∗ ()
- ↵∗Address for correspondence:
Dr. Dominick J. Angiolillo, University of Florida College of Medicine–Jacksonville, 655 West 8th Street, Jacksonville, Florida 32209.
Objectives 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.
Background Morphine delays the onset of action of oral P2Y12 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.
Methods 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 P2Y12, light transmittance aggregometry, and vasodilator-stimulated phosphoprotein.
Results 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 P2Y12 reaction units by VerifyNow P2Y12 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.
Conclusions 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)
The present study was investigator initiated and was funded by a grant from AstraZeneca. AstraZeneca had no role in study design, analysis, or decision to publish these results. Dr. Franchi has received consulting fees or honoraria from AstraZeneca and Sanofi. Dr. Rollini has received consulting fees or honoraria from Chiesi. Dr. Angiolillo has received consulting fees or honoraria from Amgen, Aralez, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, Daiichi Sankyo, Eli Lilly, Haemonetics, Janssen, Merck, PhaseBio, PLx Pharma, Pfizer, Sanofi, and The Medicines Company; has participated in review activities for CeloNova and St. Jude Medical; and has received institutional payments for grants from Amgen, AstraZeneca, Bayer, Biosensors, CeloNova, CSL Behring, Daiichi Sankyo, Eisai, Eli Lilly, Gilead, Idorsia, Janssen, Matsutani Chemical Industry, Merck, Novartis, Osprey Medical, and Renal Guard Solutions. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Received March 1, 2019.
- Revision received May 17, 2019.
- Accepted May 20, 2019.
- 2019 American College of Cardiology Foundation
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