Tocilizumab and mesenteric arterial thrombosis: drug-drug interaction with anticoagulants metabolized by CYP 450 and/or by P-glycoprotein

B. Clarivet (1) , P. Robin (2, 1) , Y. Pers (2, 1) , R. Ferreira (1) , J. Lebrun (1) , C. Jorgensen (2, 1) , D. Hillaire-Buys (1) , V. Brés (1) , Jean-Luc Faillie (1)

1 CHU Montpellier
2 Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB)

AIM: Based on a case report, we analyze the potential drug-drug interactions for tocilizumab and anticoagulant treatments. METHOD: We report a case of mesenteric arterial thrombosis (MAT) associated with tocilizumab. We searched for other case reports in the WHO global individual case safety report (ICSR) database, VigiBase (high-level terms = Gastrointestinal vascular occlusion and infarction, according to MedDRA). RESULTS: A 52 year-old woman with RA, obesity, hypertension, hyperlipidemia and atrial fibrillation (AF) presented with abdominal pain. She was included 10 months before the event in a clinical trial evaluating subcutaneous tocilizumab 162 mg weekly. A mesenteric ischemia with superior MAT was diagnosed and an urgent surgical treatment was done. The patient died the following day from a refractory cardiogenic shock. We identified two other reports of MAT with tocilizumab in the VigiBase, both associated with an anticoagulant treatment (warfarine or rivaroxaban). Ten other cases were identified, for which anticoagulant treatment was not specified. CONCLUSION: Among 13 cases of gastrointestinal vascular events with tocilizumab, three were associated with a previous anticoagulant treatment. Considering the rarity of MAT, the question arises of a possible interaction tocilizumab-anticoagulant. IL-6 inhibits expression of CYP450 and treatment with tocilizumab can restore CYP450 metabolism. Our case, occurring with dabigatran, suggests a possible interaction with P-gp. Therefore a specific attention is necessary when TCZ is introduced in patients under anticoagulant treatments not only for those metabolized by CYP450 but also for those whose absorption/excretion involves P-gp.

Mots clés: Rheumatoid Arthritis; Enoxaparin; Dabigatran; Rivaroxaban; Nicardipine

Domaines: Pharmacologie; Immunothérapie; Rhumatologie et système ostéo-articulaire; Cardiologie et système cardiovasculaire

B. Clarivet, P. Robin, Y. Pers, R. Ferreira, J. Lebrun, et al.. Tocilizumab and mesenteric arterial thrombosis: drug-drug interaction with anticoagulants metabolized by CYP 450 and/or by P-glycoprotein. European Journal of Clinical Pharmacology, 2016, 72 (11), pp.1413 - 1414. ⟨10.1007/s00228-016-2107-0⟩. ⟨hal-01834388⟩