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

Seyed Hamidreza Mahmoudpour; Luca Valerio; Jonathan Douxfils; Charles E. Mahan; Marius Jankowski; Kurt Quitzau; Stavros V. Konstantinides; Stefano Barco

doi:10.1055/a-1120-4064

Hämostaseologie, Table of Contents

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

¹Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Mainz, Germany

²Department of Biometry and Bioinformatics, Institute for Medical Biostatistics, Epidemiology, and Informatics (IMBEI), University Medical Center Mainz, Mainz, Germany

,

Luca Valerio

¹Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Mainz, Germany

,

Jonathan Douxfils

³Department of Pharmacy, Namur Thrombosis and Hemostasis Center (NTHC), Namur Research Institute for Life Sciences (NARILIS), University of Namur, Namur, Belgium

,

Charles E. Mahan

⁴Presbyterian Healthcare Services, University of New Mexico, Albuquerque, United States

,

Marius Jankowski

¹Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Mainz, Germany

,

Kurt Quitzau

¹Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Mainz, Germany

,

Stavros V. Konstantinides

¹Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Mainz, Germany

⁵Department of Cardiology, Democritus University of Thrace, Alexandroupolis, Greece

,

Stefano Barco

¹Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Mainz, Germany

⁶Clinic of Angiology, University Hospital and University of Zurich, Zurich, Switzerland

› Author Affiliations

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 (T_reg) 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

Full Text

References

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
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
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
4 Rosenberg SA. IL-2: the first effective immunotherapy for human cancer. J Immunol 2014; 192 (12) 5451-5458
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
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
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
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
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
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
11 Wang TF, Li A, Garcia D. Managing thrombosis in cancer patients. Res Pract Thromb Haemost 2018; 2 (03) 429-438
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
38 Novartis Pharmaceuticals Canada Inc. Product Monograph Proleukin (Aldesleukin) Interleukin-2 Lyophilized Powder 22 Million IU/Vial. Date of approval 25 July 2018
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
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
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
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
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
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
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

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Supplementary Material