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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
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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



Publication History

Received: 24 July 2019

Accepted: 23 January 2020

Article published online:
23 April 2020

© 2020. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

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