PDF herunterladen
Hamostaseologie 2020; 40(05): 679-686
DOI: 10.1055/a-1120-4064
Original Article

Potential Drug Interactions between Recombinant Interleukin-2 and Direct Oral Anticoagulants: Indirect Evidence from In Vivo Animal Studies

Seyed Hamidreza Mahmoudpour
1   Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Mainz, Germany
2   Department of Biometry and Bioinformatics, Institute for Medical Biostatistics, Epidemiology, and Informatics (IMBEI), University Medical Center Mainz, Mainz, Germany
,
Luca Valerio
1   Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Mainz, Germany
,
Jonathan Douxfils
3   Department of Pharmacy, Namur Thrombosis and Hemostasis Center (NTHC), Namur Research Institute for Life Sciences (NARILIS), University of Namur, Namur, Belgium
,
Charles E. Mahan
4   Presbyterian Healthcare Services, University of New Mexico, Albuquerque, United States
,
Marius Jankowski
1   Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Mainz, Germany
,
Kurt Quitzau
1   Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Mainz, Germany
,
Stavros V. Konstantinides
1   Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Mainz, Germany
5   Department of Cardiology, Democritus University of Thrace, Alexandroupolis, Greece
,
Stefano Barco
1   Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Mainz, Germany
6   Clinic of Angiology, University Hospital and University of Zurich, Zurich, Switzerland
› Institutsangaben
› Weitere Informationen
Auch verfügbar auf
    Lizenzen und Reprints

Abstract

Recombinant interleukin-2 (rIL-2) is indicated for metastatic renal cell carcinoma and melanoma. Over recent years low-dose rIL-2 has been studied for the treatment of autoimmune diseases and acute coronary syndrome because of its ability to expand and activate T regulatory (Treg) cells. However, several medical conditions potentially benefiting from rIL-2 administrations are characterized by an intrinsic prothrombotic risk, thus requiring concurrent anticoagulation. In our systematic review of the literature, we investigated the potential for drug interactions between oral anticoagulants and rIL-2 by assessing the influence of rIL-2 administration on transporters and cytochromes determining the pharmacokinetics of (direct) oral anticoagulants. We extracted data from 12 studies, consisting of 11 animal studies and one study in humans. Eight studies investigated the pharmacokinetics of P-glycoprotein (P-gp) substrates and reported that the intraperitoneal rIL-2 administration may inhibit intestinal P-gp. Four studies on hepatic cytochrome P450 yielded conflicting results. The only human study included in this systematic review concluded that rIL-2 suppresses the hepatic cytochrome P450, but only if given at higher doses. Based on the results from animal studies, the co-administration of rIL-2 and dabigatran etexilate, a substrate of intestinal P-gp, may lead to higher dabigatran plasma concentrations and bioavailability. Human studies should confirm whether this potential interaction is clinically relevant.

Keywords

interleukin-2 - drug interaction - oral anticoagulants - systematic review

Authors' Contributions

S.H.M. and S.B. designed the study. S.H.M., M.J., L.V., and S.B. extracted and analyzed the data. S.H.M. and S.B. drafted the manuscript. S.V.K., K.Q., J.D., and C.E.M. critically apprised and revised the manuscript. All authors reviewed the manuscript.


Supplementary Material



Publikationsverlauf

Eingereicht: 24. Juli 2019

Angenommen: 23. Januar 2020

Artikel online veröffentlicht:
23. April 2020

© 2020. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Rosenzwajg M, Lorenzon R, Cacoub P. et al. Immunological and clinical effects of low-dose interleukin-2 across 11 autoimmune diseases in a single, open clinical trial. Ann Rheum Dis 2019; 78 (02) 209-217
    CrossrefPubMedSuche in Google Scholar
  • 2 Klatzmann D, Abbas AK. The promise of low-dose interleukin-2 therapy for autoimmune and inflammatory diseases. Nat Rev Immunol 2015; 15 (05) 283-294
    CrossrefPubMedSuche in Google Scholar
  • 3 Todd JA, Evangelou M, Cutler AJ. et al. Regulatory T cell responses in participants with type 1 diabetes after a single dose of interleukin-2: a non-randomised, open label, adaptive dose-finding trial. PLoS Med 2016; 13 (10) e1002139
    CrossrefPubMedSuche in Google Scholar
  • 4 Rosenberg SA. IL-2: the first effective immunotherapy for human cancer. J Immunol 2014; 192 (12) 5451-5458
    CrossrefPubMedSuche in Google Scholar
  • 5 Luther N, Shahneh F, Brähler M. et al. Innate effector-memory T-cell activation regulates post-thrombotic vein wall inflammation and thrombus resolution. Circ Res 2016; 119 (12) 1286-1295
    CrossrefPubMedSuche in Google Scholar
  • 6 Prochaska JH, Luther N, Brahler M. et al. Acute deep vein thrombosis suppresses peripheral T cell effector function. Br J Haematol 2019; 184 (05) 847-850
    CrossrefPubMedSuche in Google Scholar
  • 7 Mahmoudpour SH, Jankowski M, Valerio L. et al. Safety of low-dose subcutaneous recombinant interleukin-2: systematic review and meta-analysis of randomized controlled trials. Sci Rep 2019; 9 (01) 7145
    CrossrefPubMedSuche in Google Scholar
  • 8 Zhao TX, Kostapanos M, Griffiths C. et al. Low-dose interleukin-2 in patients with stable ischaemic heart disease and acute coronary syndromes (LILACS): protocol and study rationale for a randomised, double-blind, placebo-controlled, phase I/II clinical trial. BMJ Open 2018; 8 (09) e022452
    CrossrefPubMedSuche in Google Scholar
  • 9 Kearon C, Ageno W, Cannegieter SC, Cosmi B, Geersing GJ, Kyrle PA. Subcommittees on Control of Anticoagulation, and Predictive and Diagnostic Variables in Thrombotic Disease. Categorization of patients as having provoked or unprovoked venous thromboembolism: guidance from the SSC of ISTH. J Thromb Haemost 2016; 14 (07) 1480-1483
    CrossrefPubMedSuche in Google Scholar
  • 10 Carrier M, Blais N, Crowther M. et al. Treatment algorithm in cancer-associated thrombosis: Canadian expert consensus. Curr Oncol 2018; 25 (05) 329-337
    CrossrefPubMedSuche in Google Scholar
  • 11 Wang TF, Li A, Garcia D. Managing thrombosis in cancer patients. Res Pract Thromb Haemost 2018; 2 (03) 429-438
    CrossrefPubMedSuche in Google Scholar
  • 12 Kjerpeseth LJ, Ellekjær H, Selmer R, Ariansen I, Furu K, Skovlund E. Trends in use of warfarin and direct oral anticoagulants in atrial fibrillation in Norway, 2010 to 2015. Eur J Clin Pharmacol 2017; 73 (11) 1417-1425
    CrossrefPubMedSuche in Google Scholar
  • 13 Lippi G, Mattiuzzi C, Cervellin G, Favaloro EJ. Direct oral anticoagulants: analysis of worldwide use and popularity using Google Trends. Ann Transl Med 2017; 5 (16) 322
    CrossrefPubMedSuche in Google Scholar
  • 14 Yu AYX, Malo S, Svenson LW, Wilton SB, Hill MD. Temporal trends in the use and comparative effectiveness of direct oral anticoagulant agents versus warfarin for nonvalvular atrial fibrillation: a Canadian population-based study. J Am Heart Assoc 2017; 6 (11) e007129
    CrossrefPubMedSuche in Google Scholar
  • 15 Testa S, Legnani C, Antonucci E. et al; Coordinator of START2-Register. Drug levels and bleeding complications in atrial fibrillation patients treated with direct oral anticoagulants. J Thromb Haemost 2019; 17 (07) 1064-1072
    CrossrefPubMedSuche in Google Scholar
  • 16 Testa S, Paoletti O, Legnani C. et al. Low drug levels and thrombotic complications in high-risk atrial fibrillation patients treated with direct oral anticoagulants. J Thromb Haemost 2018; 16 (05) 842-848
    CrossrefPubMedSuche in Google Scholar
  • 17 Lamb DA, Bungard TJ, Lowerison J. et al. Jurisdictional guidance on DOAC use-will it affect practice? A comparison of European, American, and Canadian product monographs. Ann Pharmacother 2020; 54 (03) 277-282
    CrossrefPubMedSuche in Google Scholar
  • 18 Chang SH, Chou IJ, Yeh YH. et al. Association between use of non-vitamin K oral anticoagulants with and without concurrent medications and risk of major bleeding in nonvalvular atrial fibrillation. JAMA 2017; 318 (13) 1250-1259
    CrossrefPubMedSuche in Google Scholar
  • 19 Vranckx P, Valgimigli M, Heidbuchel H. The significance of drug-drug and drug-food interactions of oral anticoagulation. Arrhythm Electrophysiol Rev 2018; 7 (01) 55-61
    CrossrefPubMedSuche in Google Scholar
  • 20 Mueck W, Schwers S, Stampfuss J. Rivaroxaban and other novel oral anticoagulants: pharmacokinetics in healthy subjects, specific patient populations and relevance of coagulation monitoring. Thromb J 2013; 11 (01) 10
    CrossrefPubMedSuche in Google Scholar
  • 21 Gelosa P, Castiglioni L, Tenconi M. et al. Pharmacokinetic drug interactions of the non-vitamin K antagonist oral anticoagulants (NOACs). Pharmacol Res 2018; 135: 60-79
    CrossrefPubMedSuche in Google Scholar
  • 22 Mueck W, Kubitza D, Becka M. Co-administration of rivaroxaban with drugs that share its elimination pathways: pharmacokinetic effects in healthy subjects. Br J Clin Pharmacol 2013; 76 (03) 455-466
    CrossrefPubMedSuche in Google Scholar
  • 23 Di Minno A, Frigerio B, Spadarella G. et al. Old and new oral anticoagulants: food, herbal medicines and drug interactions. Blood Rev 2017; 31 (04) 193-203
    CrossrefPubMedSuche in Google Scholar
  • 24 Mendell J, Zahir H, Matsushima N. et al. Drug-drug interaction studies of cardiovascular drugs involving P-glycoprotein, an efflux transporter, on the pharmacokinetics of edoxaban, an oral factor Xa inhibitor. Am J Cardiovasc Drugs 2013; 13 (05) 331-342
    CrossrefPubMedSuche in Google Scholar
  • 25 Parasrampuria DA, Truitt KE. Pharmacokinetics and pharmacodynamics of edoxaban, a non-vitamin K antagonist oral anticoagulant that inhibits clotting factor Xa. Clin Pharmacokinet 2016; 55 (06) 641-655
    CrossrefPubMedSuche in Google Scholar
  • 26 Abbara C, Rouchon C, Hosten B, Farinotti R, Bonhomme-Faivre L. Enhanced oral bioavailability of paclitaxel by recombinant interleukin-2 in mice with murine Lewis lung carcinoma. Drug Metabol Drug Interact 2004; 20 (04) 219-231
    CrossrefPubMedSuche in Google Scholar
  • 27 Bonhomme-Faivre L, Pelloquin A, Tardivel S. et al. Recombinant interleukin-2 treatment decreases P-glycoprotein activity and paclitaxel metabolism in mice. Anticancer Drugs 2002; 13 (01) 51-57
    CrossrefPubMedSuche in Google Scholar
  • 28 Cantoni L, Carelli M, Ghezzi P, Delgado R, Faggioni R, Rizzardini M. Mechanisms of interleukin-2-induced depression of hepatic cytochrome P-450 in mice. Eur J Pharmacol 1995; 292 (3-4): 257-263
    PubMedSuche in Google Scholar
  • 29 Castagne V, Bonhomme-Faivre L, Urien S. et al. Effect of recombinant interleukin-2 pretreatment on oral and intravenous digoxin pharmacokinetics and P-glycoprotein activity in mice. Drug Metab Dispos 2004; 32 (02) 168-171
    CrossrefPubMedSuche in Google Scholar
  • 30 Elkahwaji J, Robin MA, Berson A. et al. Decrease in hepatic cytochrome P450 after interleukin-2 immunotherapy. Biochem Pharmacol 1999; 57 (08) 951-954
    CrossrefPubMedSuche in Google Scholar
  • 31 Hosten B, Abbara C, Cibert M. et al. Interleukin-2 treatment effect on imatinib pharmacokinetic, P-gp and BCRP expression in mice. Anticancer Drugs 2010; 21 (02) 193-201
    CrossrefPubMedSuche in Google Scholar
  • 32 Hosten B, Abbara C, Petit B. et al. Effect of interleukin-2 pretreatment on paclitaxel absorption and tissue disposition after oral and intravenous administration in mice. Drug Metab Dispos 2008; 36 (08) 1729-1735
    CrossrefPubMedSuche in Google Scholar
  • 33 Hosten B, Challuau D, Gil S. et al. Recombinant interleukin-2 pre-treatment increases anti-tumor response to paclitaxel by affecting lung P-glycoprotein expression on the Lewis lung carcinoma. Anticancer Drugs 2006; 17 (02) 195-199
    CrossrefPubMedSuche in Google Scholar
  • 34 Jamois C, Comets E, Mentré F, Marion S, Farinotti R, Bonhomme-Faivre L. Pharmacokinetics and neutrophil toxicity of paclitaxel orally administered in mice with recombinant interleukin-2. Cancer Chemother Pharmacol 2005; 55 (01) 61-71
    CrossrefPubMedSuche in Google Scholar
  • 35 Kurokohchi K, Matsuo Y, Yoneyama H, Nishioka M, Ichikawa Y. Interleukin 2 induction of cytochrome P450-linked monooxygenase systems of rat liver microsomes. Biochem Pharmacol 1993; 45 (03) 585-592
    CrossrefPubMedSuche in Google Scholar
  • 36 Thal C, el Kahwaji J, Loeper J. et al. Administration of high doses of human recombinant interleukin-2 decreases the expression of several cytochromes P-450 in the rat. J Pharmacol Exp Ther 1994; 268 (01) 515-521
    PubMedSuche in Google Scholar
  • 37 Veau C, Faivre L, Tardivel S. et al. Effect of interleukin-2 on intestinal P-glycoprotein expression and functionality in mice. J Pharmacol Exp Ther 2002; 302 (02) 742-750
    CrossrefPubMedSuche in Google Scholar
  • 38 Novartis Pharmaceuticals Canada Inc. Product Monograph Proleukin (Aldesleukin) Interleukin-2 Lyophilized Powder 22 Million IU/Vial. Date of approval 25 July 2018
    PubMed
  • 39 Delavenne X, Ollier E, Basset T. et al. A semi-mechanistic absorption model to evaluate drug-drug interaction with dabigatran: application with clarithromycin. Br J Clin Pharmacol 2013; 76 (01) 107-113
    CrossrefPubMedSuche in Google Scholar
  • 40 Kishimoto W, Ishiguro N, Ludwig-Schwellinger E, Ebner T, Schaefer O. In vitro predictability of drug-drug interaction likelihood of P-glycoprotein-mediated efflux of dabigatran etexilate based on [I]2/IC50 threshold. Drug Metab Dispos 2014; 42 (02) 257-263
    CrossrefPubMedSuche in Google Scholar
  • 41 Härtter S, Sennewald R, Nehmiz G, Reilly P. Oral bioavailability of dabigatran etexilate (Pradaxa(®) ) after co-medication with verapamil in healthy subjects. Br J Clin Pharmacol 2013; 75 (04) 1053-1062
    CrossrefPubMedSuche in Google Scholar
  • 42 Barco S, Coppens M, van den Dool EJ, van de Kerkhof D, Stroobants AK, Middeldorp S. Successful co-administration of dabigatran etexilate and protease inhibitors ritonavir/lopinavir in a patient with atrial fibrillation. Thromb Haemost 2014; 112 (04) 836-838
    Thieme ConnectPubMedSuche in Google Scholar
  • 43 Kumar P, Gordon LA, Brooks KM. et al. Differential influence of the antiretroviral pharmacokinetic enhancers ritonavir and cobicistat on intestinal P-glycoprotein transport and the pharmacokinetic/pharmacodynamic disposition of dabigatran. Antimicrob Agents Chemother 2017; 61 (11) e01201-17
    CrossrefPubMedSuche in Google Scholar
  • 44 Gnoth MJ, Buetehorn U, Muenster U, Schwarz T, Sandmann S. In vitro and in vivo P-glycoprotein transport characteristics of rivaroxaban. J Pharmacol Exp Ther 2011; 338 (01) 372-380
    CrossrefPubMedSuche in Google Scholar
  • 45 Chu X, Bleasby K, Evers R. Species differences in drug transporters and implications for translating preclinical findings to humans. Expert Opin Drug Metab Toxicol 2013; 9 (03) 237-252
    CrossrefPubMedSuche in Google Scholar