The Interactions of Nintedanib and Oral Anticoagulants-Molecular Mechanisms and Clinical Implications

Abstract

Nintedanib is a synthetic orally active tyrosine kinase inhibitor, whose main action is to inhibit the receptors of the platelet-derived growth factor, fibroblast growth factor and vascular endothelial growth factor families. The drug also affects other kinases, including Src, Flt-3, LCK, LYN. Nintedanib is used in the treatment of idiopathic pulmonary fibrosis, chronic fibrosing interstitial lung diseases and lung cancer. The mechanism of action suggests that nintedanib should be considered one of the potential agents for inhibiting and revising the fibrosis process related to COVID-19 infections. Due to the known induction of coagulation pathways during COVID-19 infections, possible interaction between nintedanib and anticoagulant seems to be an extremely important issue. In theory, nintedanib could increase the bleeding risk, thrombosis and lead to thrombocytopenia. The data from clinical trials on the concomitant use of nintedanib and antithrombotic agents is very limited as this patient group was within the standard exclusion criteria. Nintedanib is an important therapeutic option, despite its interaction with anticoagulants. If anticoagulant therapy is necessary, the more effective and safer option is the concomitant administration of DOACs and nintedanib, especially when drug-monitored therapy will be used in patients at high risk of bleeding complications.

Keywords: direct oral anticoagulants; idiopathic pulmonary fibrosis; nintedanib.

Scheme 1

Phosphorylation reaction of phosphate moieties transfer from ATP to tyrosine residues of specific proteins [17].

Figure 1

Transmembrane receptor RTK, different types of reversible inhibition and graphical representation of nintedanib RTK pharmacophore features. (a) X-ray structure of nintedanib bond in the active site of the VEGFR-2 crystal with the enlarged area showing the structural elements around the ligand-binding site (PDB ID: 3C7Q, 2.10 Å) [21]. The molecular mechanism of action of nintedanib consists of the competitive binding to the adenosine triphosphate (ATP) pocket. The result is inhibition of intracellular signaling vital for the proliferation, migration, and transformation of fibroblasts, which are fundamental to IPF [22]. (b) The literature-derived classification of reversible inhibitor types: where type I is binding to the active kinase hinge area (DFG-in) while type II is binding to the respective inactive area (DGF-out). Both inhibitor types compete directly with ATP by stabilizing enzymatically relevant kinase conformations. Inhibitors of type III and IV allosterically interact outside the hinge area (i.e., in its close vicinity or back) or activate remote residues in the kinase domain [14,23]. (c) Pharmacophore points defined according to the literature for nintedanib structure [1,14].

Figure 2

Compression of the selected backbone representation of the crystal structures of the RTK: VEGFR-2 crystal (PDB ID: 3C7Q, 2.10 Å) [21], FGF1 (PDB ID: 1FGK, 2.00 Å) [40], PDGFRα (PDB ID: 6JOL, 1.90 Å) [41].

Figure 3

Coagulation cascade (blue rectangles and circles) and the action points of various anticoagulants and antiplatelet agents (yellow rectangles) (UFH, unfractionated heparin; LMWH, low-molecular weight heparin; TF, tissue factor; ASA, acetylsalicylic acid; P2Y₁₂, receptor for endogenous nucleotides type 12, TxA₂, thromboxane A₂, GP IIb/IIIa, glycoprotein IIb/IIIa). Route of administration: red font—parenteral forms, green font—oral agents.