Inability to achieve a therapeutic INR value while on concurrent warfarin and rifampin.

Abstract

W is an effective anticoagulant medication that has been used in the treatment and prevention of venous thromboembolism for more than 50 years. To this day, it remains the foundation of anticoagulation therapy due to its efficacy and lack of acceptable alternative options. Although it is a highly effective agent, there are many drawbacks to its use. Response to the drug is highly variable and is influenced by numerous patient-specific factors, including age, comorbidities, liver function, albumin level, and genetic polymorphisms in the enzymes that metabolize the drug. It is also subject to a wide variety of drug-drug, drug-herbal, and drug-food interactions. Consequently, warfarin regimens must be tailored for each individual patient. There is a clinically significant drug-drug interaction between warfarin and rifampin. Rifampin is an anti-infective agent that is considered a first-line agent in the treatment of Mycobacterium tuberculosis. It also has activity against other bacteria, including Staphylococcus aureus and Haemophilus influenzae. Rifampin is a potent inducer of both the cytochrome P-450 enzyme system and P-glycoprotein system. Warfarin is metabolized in the liver by cytochrome P-450 isoenzymes, predominately CYP 2C9. It induces both the metabolism of the more potent S-warfarin enantiomer as well as the less potent R-warfarin enantiomer. When used concurrently with warfarin, rifampin induces the hepatic metabolism of warfarin and thereby reduces its anticoagulant properties. In 1975, the first case report recognizing this drug-drug interaction was published. Since this initial report, there have been only a few related articles or reports published regarding this highly significant interaction. Although this interaction has been long recognized, there exists a paucity of data regarding how to manage such patients. Various drug information references list this drugdrug interaction as highly significant. Clinical pharmacology suggests that a 2to 3-fold increase in warfarin dose may be necessary during concurrent therapy to account for this drug-drug interaction. However, it does not provide guidance as to how rapidly the dose should be increased upon initiation of rifampin. Likewise, it does not offer any guidance regarding how quickly the dose must be reduced following cessation of rifampin therapy. The following is a report of a patient who failed to achieve therapeutic international normalized ratio (INR) value despite a 5-fold increased warfarin dose while on concurrent rifampin therapy. Following the report are some recommendations for management of such patients.