Delayed elimination of high dose methotrexate due to co-administration of omeprazole: a case report.

I AOUINTI, E GAIES, S TRABELSI, I SALOUAGE, R CHARFI, N JEBABLI, M LAKHAL, A KLOUZ. centre national de pharmacovigilance de Tunis, service de pharmacovigilance, Tunisia

Introduction

Methotrexate (MTX) is a folic acid analog. It can be used at high or low doses. MTX High Doses (HD-MTX) is indicated for the treatment of cancer diseases and its use requires strict precautions to prevent toxic side effects. It has numerous drug interactions, the most known are interaction with trimethoprim - sulfamethoxazole (TMP-SMX) and non steroidal antiinflammatory drugs (NSAIDs), which can exacerbate toxicity of MTX.

We report herein a case of delayed elimination of HD-MTX due to co-administraion of omeprazole assessed in Service of Clinical Pharmacology of Tunis.

Case report

B.A, a 17-year-old female having acute lymphoblastic leukemia (ALL). She is treated since september 2011 by HD-MTX (5g/m2/24h) without omeprazole every month for 6 months. The elimination of MTX was usually averaged at H72 throughout previous cycles. The seventh cycle of HD-MTX started in 16/03/12. Because of epigastralgia, it was associated this time to omeprazole 20 mg per day during the entire cycle. The monitoring of MTX plasma levels showed a high MTX concentration at H24 (23µmol/l) and a delayed elimination. In fact, MTX remained above 0,2 µmol/l until H164. The patient’s serum creatinin was normal but the liver function was altered marked by transaminases increase observed at H48 (AST= 2N, ALT= 5N).

Discussion and conclusion

It is controversial as to whether or not co-administration of Proton Pump Inhibitors (PPIs) affects elimination of plasma MTX in HD-MTX therapy. In fact, delayed elimination of MTX was not observed in every patient receiving PPIs and the reason remains unclear. Mechanisms of the delayed elimination may include the renal hydrogen / potassium adenosine triphosphate pump (H+/K+ ATPase) and genetic factors. Because of the severity of this type of drug interaction and the frequent ambulatory use of PPIs, it is important to mention such drug-drug interaction and to find an alternative for omeprazole during HD-MTX cycles.