Abstract
Background
Ticagrelor is widely used in patients with stable and acute coronary artery disease. Understanding the factors that influence its pharmacokinetics (PK) and pharmacodynamics (PD) could improve therapeutic outcomes. We therefore performed a pooled population PK/PD analysis using individual patient data from two studies. We focused on the impact of morphine administration and ST-segment elevation myocardial infarction (STEMI) on the risk of high platelet reactivity (HPR) and dyspnea.
Methods
A parent-metabolite population PK/PD model was developed based on data from 63 STEMI, 50 non-STEMI, and 25 chronic coronary syndrome (CCS) patients. Simulations were then run to evaluate the risk of non-response and adverse events associated with the identified variability factors.
Results
The final PK model consisted of first-order absorption with transit compartments, distribution with two compartments for ticagrelor and one compartment for AR-C124910XX (active metabolite of ticagrelor), and linear elimination for both drugs. The final PK/PD model was an indirect turnover model with production inhibition. Morphine dose and STEMI, independently, had a significant negative effect on the absorption rate (reduction of log(\({k}_{a}\)) by 0.21×morphine dose (mg) and by 2.37 in STEMI patients, both p < 0.001), and the presence of STEMI significantly impacted both efficacy and potency (both p < 0.001). The simulations run with the validated model showed a high rate of non-response in patients with those covariates (RR 1.19 for morphine, 4.11 for STEMI and 5.73 for morphine and STEMI, all three p < 0.001). By increasing ticagrelor dosage, the negative morphine effect was reversible in patients without STEMI and just limited in patients with STEMI.
Conclusion
The developed population PK/PD model confirmed the negative impact of morphine administration and presence of STEMI on ticagrelor PK and antiplatelet effect. Increasing ticagrelor doses seems effective in morphine users without STEMI, whereas the STEMI effect is not entirely reversible.
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References
Valgimigli M, Bueno H, Byrne RA, Collet J-P, Costa F, Jeppsson A, et al. 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS. Eur Heart J. 2018;39:213–60.
Dobesh PP, Oestreich JH. Ticagrelor: pharmacokinetics, pharmacodynamics, clinical efficacy, and safety. Pharmacotherapy. 2014;34:1077–90.
Teng R, Oliver S, Hayes MA, Butler K. Absorption, distribution, metabolism, and excretion of ticagrelor in healthy subjects. Drug Metab Dispos. 2010;38:1514–21.
Holm M, Tornvall P, Westerberg J, Rihan Hye S, van der Linden J. Ticagrelor pharmacokinetics and pharmacodynamics in patients with NSTEMI after a 180-mg loading dose. Platelets. 2017;28:706–11.
Parodi G, Valenti R, Bellandi B, Migliorini A, Marcucci R, Comito V, et al. Comparison of prasugrel and ticagrelor loading doses in ST-segment elevation myocardial infarction patients. J Am Coll Cardiol. 2013;61:1601–6.
Alexopoulos D, Xanthopoulou I, Gkizas V, Kassimis G, Theodoropoulos KC, Makris G, et al. Randomized assessment of ticagrelor versus prasugrel antiplatelet effects in patients with ST-segment-elevation myocardial infarction. Circ Cardiovasc Interv. 2012;5:797–804.
Silvain J, Storey RF, Cayla G, Esteve J-B, Dillinger J-G, Rousseau H, et al. P2Y12 receptor inhibition and effect of morphine in patients undergoing primary PCI for ST-segment elevation myocardial infarction: The PRIVATE-ATLANTIC study. Thromb Haemost. 2016;116:369–78.
Kubica J, Adamski P, Ostrowska M, Sikora J, Kubica JM, Sroka WD, et al. Morphine delays and attenuates ticagrelor exposure and action in patients with myocardial infarction: the randomized, double-blind, placebo-controlled IMPRESSION trial. Eur Heart J. 2016;37:245–52.
Liu S, Xue L, Shi X, Sun Z, Zhu Z, Zhang X, et al. Population pharmacokinetics and pharmacodynamics of ticagrelor and AR-C124910XX in Chinese healthy male subjects. Eur J Clin Pharmacol. 2018;74:745–54.
Amilon C, Niazi M, Berggren A, Åstrand M, Hamrén B. Population pharmacokinetics/pharmacodynamics of ticagrelor in children with sickle cell disease. Clin Pharmacokinet. 2019;58:1295–307.
Åstrand M, Amilon C, Röshammar D, Himmelmann A, Angiolillo DJ, Storey RF, et al. Pharmacokinetic–pharmacodynamic modelling of platelet response to ticagrelor in stable coronary artery disease and prior myocardial infarction patients. Br J Clin Pharmacol. 2019;85:413–21.
Röshammar D, Bergstrand M, Andersson T, Storey RF, Hamrén B. Population pharmacokinetics of ticagrelor and AR-C124910XX in patients with prior myocardial infarction. Int J Clin Pharmacol Ther. 2017;55:416–24.
Li J, Tang W, Storey RF, Husted S, Teng R. Population pharmacokinetics of ticagrelor in patients with acute coronary syndromes. Int J Clin Pharmacol Ther. 2016;54:666–74.
Zhang M, You X, Ke M, Jiao Z, Wu H, Huang P, et al. Prediction of ticagrelor and its active metabolite in liver cirrhosis populations using a physiologically based pharmacokinetic model involving pharmacodynamics. J Pharm Sci. 2019;108:2781–90.
Holm M, Tornvall P, Henareh L, Jensen U, Golster N, Alström P, et al. The MOVEMENT trial. J Am Heart Assoc. 2019;8 [cited 2 Mar 2022]. https://doi.org/10.1161/JAHA.118.010152.
Zhang L, Beal SL, Sheiner LB. Simultaneous vs. sequential analysis for population PK/PD data I: best-case performance. J Pharmacokinet Pharmacodyn. 2003;30:387–404.
Savic RM, Jonker DM, Kerbusch T, Karlsson MO. Implementation of a transit compartment model for describing drug absorption in pharmacokinetic studies. J Pharmacokinet Pharmacodyn. 2007;34:711–26.
Delattre M, Lavielle M, Poursat M-A. A note on BIC in mixed-effects models. Electron J Statist. 2014;8 [cited 27 July 2022]. https://projecteuclid.org/journals/electronic-journal-of-statistics/volume-8/issue-1/A-note-on-BIC-in-mixed-effects-models/https://doi.org/10.1214/14-EJS890.full.
Lavielle M, Chauvin J. Rsmlx: R Speaks “Monolix”; Antony, France: Lixoft; 2019.
Cannon CP, Husted S, Harrington RA, Scirica BM, Emanuelsson H, Peters G, et al. Safety, tolerability, and initial efficacy of AZD6140, the first reversible oral adenosine diphosphate receptor antagonist, compared with clopidogrel, in patients with non-ST-segment elevation acute coronary syndrome. J Am Coll Cardiol. 2007;50:1844–51.
Tantry US, Bonello L, Aradi D, Price MJ, Jeong Y-H, Angiolillo DJ, et al. Consensus and update on the definition of on-treatment platelet reactivity to adenosine diphosphate associated with ischemia and bleeding. J Am Coll Cardiol. 2013;62:2261–73.
Aradi D, Kirtane A, Bonello L, Gurbel PA, Tantry US, Huber K, et al. Bleeding and stent thrombosis on P2Y12-inhibitors: collaborative analysis on the role of platelet reactivity for risk stratification after percutaneous coronary intervention. Eur Heart J. 2015;36:1762–71.
Ortega-Paz L, Brugaletta S, Ariotti S, Akkerhuis KM, Karagiannis A, Windecker S, et al. Adenosine and ticagrelor plasma levels in patients with and without ticagrelor-related dyspnea. Circulation. 2018;138:646–8.
Djerada Z, Feliu C, Cazaubon Y, Smati F, Gomis P, Guerrot D, et al. Population pharmacokinetic–pharmacodynamic modeling of ropivacaine in spinal anesthesia. Clin Pharmacokinet. 2018;57:1135–47.
Allard Q, Djerada Z, Pouplard C, Repessé Y, Desprez D, Galinat H, et al. Real life population pharmacokinetics modelling of eight factors VIII in patients with severe haemophilia A: is it always relevant to switch to an extended half-life? Pharmaceutics. 2020;12:380.
Wils J, Djerada Z, Roca F, Duflot T, Iacob M, Remy-Jouet I, et al. Alteration in the availability of epoxyeicosatrienoic acids contributes with NO to the development of endothelial dysfunction in conduit arteries during aging. Atherosclerosis. 2018;275:239–45.
Zhang Y, Wang N, Gu Q. Effects of morphine on P2Y12 platelet inhibitors in patients with acute myocardial infarction: a meta-analysis. Am J Emerg Med. 2021;41:219–28.
Vaidya GN, Khan A, Ghafghazi S. Effect of morphine use on oral P2Y12 platelet inhibitors in acute myocardial infarction: meta-analysis. Indian Heart J. 2019;71:126–35.
Duarte GS, Nunes-Ferreira A, Rodrigues FB, Pinto FJ, Ferreira JJ, Costa J, et al. Morphine in acute coronary syndrome: systematic review and meta-analysis. BMJ Open. 2019;9: e025232.
Gue YX, Spinthakis N, Farag M, Kubica J, Siller-Matula JM, Srinivasan M, et al. Impact of preadmission morphine on reinfarction in patients with ST-elevation myocardial infarction treated with percutaneous coronary intervention: a meta-analysis. Clin Pharmacol Ther. 2020;108:54–62.
Radu RI, Ben Gal T, Abdelhamid M, Antohi E-L, Adamo M, Ambrosy AP, et al. Antithrombotic and anticoagulation therapies in cardiogenic shock: a critical review of the published literature. ESC Heart Fail. 2021;8:4717–36.
Harjola V-P, Parissis J, Bauersachs J, Brunner-La Rocca H-P, Bueno H, Čelutkienė J, et al. Acute coronary syndromes and acute heart failure: a diagnostic dilemma and high-risk combination. A statement from the Acute Heart Failure Committee of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail. 2020;22:1298–314.
Hobl E-L, Reiter B, Schoergenhofer C, Schwameis M, Derhaschnig U, Kubica J, et al. Morphine decreases ticagrelor concentrations but not its antiplatelet effects: a randomized trial in healthy volunteers. Eur J Clin Invest. 2016;46:7–14.
Adamski P, Sikora J, Laskowska E, Buszko K, Ostrowska M, Umińska JM, et al. Comparison of bioavailability and antiplatelet action of ticagrelor in patients with ST-elevation myocardial infarction and non-ST-elevation myocardial infarction: a prospective, observational, single-centre study. PLoS ONE. 2017;12: e0186013.
Parodi G, Bellandi B, Xanthopoulou I, Capranzano P, Capodanno D, Valenti R, et al. Morphine is associated with a delayed activity of oral antiplatelet agents in patients with ST-elevation acute myocardial infarction undergoing primary percutaneous coronary intervention. Circ Cardiovasc Interv. 2015;8:e001593.
Buszko K, Kubica K, Hobl E-L, Adamski P, Wnuk K, Jilma B, et al. Pharmacokinetic modeling of morphine’s effect on plasma concentrations of ticagrelor and its metabolite in healthy volunteers. Front Physiol. 2021;12: 663170.
Holm M, Tornvall P, Beck O, Fux T, van der Linden J. Impact of morphine dose on ticagrelor uptake and platelet inhibition in patients with ST-segment elevation myocardial infarction—a substudy from the prospective randomized MOVEMENT trial. Thrombosis Update. 2021;5: 100071.
Adamski P, Buszko K, Sikora J, Niezgoda P, Fabiszak T, Ostrowska M, et al. Determinants of high platelet reactivity in patients with acute coronary syndromes treated with ticagrelor. Sci Rep. 2019;9:3924.
Franchi F, Rollini F, Cho JR, Bhatti M, DeGroat C, Ferrante E, et al. Impact of escalating loading dose regimens of ticagrelor in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention. JACC Cardiovasc Interv. 2015;8:1457–67.
Nimmo WS, Heading RC, Wilson J, Tothill P, Prescott LF. Inhibition of gastric emptying and drug absorption by narcotic analgesics. Br J Clin Pharmacol. 1975;2:509–13.
Holzer P. Opioid receptors in the gastrointestinal tract. Regul Pept. 2009;155:11–7.
Batchelor R, Liu DH, Bloom J, Noaman S, Chan W. Association of periprocedural intravenous morphine use on clinical outcomes in ST-elevation myocardial infarction (STEMI) treated by primary percutaneous coronary intervention: systematic review and meta-analysis. Catheter Cardiovasc Interv. 2020;96:76–88.
Heestermans AACM, van Werkum JW, Taubert D, Seesing TH, von Beckerath N, Hackeng CM, et al. Impaired bioavailability of clopidogrel in patients with a ST-segment elevation myocardial infarction. Thromb Res. 2008;122:776–81.
Scalone G, Coviello I, Barone L, Battipaglia I, Aurigemma C, Careri G, et al. Evidence of increased platelet reactivity in the first six months after acute ST segment elevation myocardial infarction. Thromb Res. 2011;128:174–8.
Schoergenhofer C, Hobl E-L, Staudinger T, Speidl WS, Heinz G, Siller-Matula J, et al. Prasugrel in critically ill patients. Thromb Haemost. 2017;117:1582–7.
Bliden KP, Tantry US, Storey RF, Jeong Y-H, Gesheff M, Wei C, et al. The effect of ticagrelor versus clopidogrel on high on-treatment platelet reactivity: combined analysis of the ONSET/OFFSET and RESPOND studies. Am Heart J. 2011;162:160–5.
Franchi F, Rollini F, Park Y, Hu J, Kureti M, Rivas Rios J, et al. Effects of methylnaltrexone on ticagrelor-induced antiplatelet effects in coronary artery disease patients treated with morphine. JACC Cardiovasc Interv. 2019;12:1538–49.
Kubica J. Opioids and oral P2Y12 receptor inhibitors: a drug–drug interaction. Cardiol J. 2022;29:727–9.
Haghbayan H, Deif B, Coomes EA. Chewed or crushed administration of adenosine diphosphate receptor inhibitors in acute coronary syndromes: a systematic review and meta-analysis of randomized controlled trials. Cardiovasc Drugs Ther. 2020;34:139–42.
Sikora J, Niezgoda P, Barańska M, Buszko K, Skibińska N, Sroka W, et al. METoclopramide administration as a strategy to overcome MORPHine-ticagrelOr Interaction in PatientS with Unstable Angina PectorIS—the METAMORPHOSIS trial. Thromb Haemost. 2018;118:2126–33.
Niezgoda P, Barańska MA, Sikora J, Sobczak P, Buszko K, Sikora A, et al. Oral NAloxone to overcome the moRphine effect in acute COronary syndrome patients treated with TICagrelor—NARCOTIC trial. Cardiol J. 2022;29:432–40.
Lavielle M. Mixed effects models for the population approach: models, tasks, methods and tools. 2015 [cited 3 Dec 2019]. http://www.crcnetbase.com/isbn/9781482226515. Accessed 1 Dec 2021.
Gruba SM, Francis DH, Meyer AF, Spanolios E, He J, Meyer BM, et al. Characterization of the presence and function of platelet opioid receptors. ACS Meas Au. 2022;2:4–13.
Bartko J, Schoergenhofer C, Schwameis M, Wadowski P, Kubica J, Jilma B, et al. Morphine interaction with aspirin: a double-blind, crossover trial in healthy volunteers. J Pharmacol Exp Ther. 2018;365:430–6.
Dillinger J-G, Manzo Silberman S, Bal ditSollier C, Amsallem M, Sideris G, Voicu S, et al. Ticagrelor effectiveness overestimated by VASP index. Int J Cardiol. 2014;176:557–9.
Lavielle M, Ribba B. Enhanced method for diagnosing pharmacometric models: random sampling from conditional distributions. Pharm Res. 2016;33:2979–88.
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The original studies were funded by a non-restricted research grant from Astra Zeneca (NSTEMI/CCS study) and a grant from the Swedish Heart and Lung foundation (MOVEMENT trial); however, the present study received no funding.
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Celine Konecki, Manne Holm, and Zoubir Djerada have no conflicts to disclose.
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The studies were conducted in accordance with the Declaration of Helsinki and were approved by the regional ethical review board in Stockholm.
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Written informed consent was obtained from all subjects in both studies.
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The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.
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CK, MH and ZD wrote the manuscript, performed the research, analyzed the data, and validated the manuscript. MH and ZD designed the research.
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Konecki, C., Holm, M. & Djerada, Z. Negative Impact of ST-Segment Elevation Myocardial Infarction and Morphine Dose on Ticagrelor Uptake and Pharmacodynamics: A Population PK/PD Analysis of Pooled Individual Participant Data. Clin Pharmacokinet 62, 905–920 (2023). https://doi.org/10.1007/s40262-023-01243-5
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DOI: https://doi.org/10.1007/s40262-023-01243-5