Abstracts

Rationale: The objective of this abstract is to report a probable drug-drug interaction between oral cannabidiol and warfarin. Methods: Use of cannabis products for the treatment of epilepsy and other chronic diseases is increasing rapidly. Investigations into interactions between cannabis products and other pharmaceuticals are scarce. This case report observes a clinically significant interaction between pharmaceutical grade cannabidiol (Epidiolex) and warfarin. A 44 year-old Caucasian gentleman with a past medical history of Marfan syndrome, mechanical mitral valve replacement, warfarin therapy, and post-stroke epilepsy was enrolled in the University of Alabama at Birmingham open-label program for compassionate use of cannabidiol. At the time of study enrolment, he was taking warfarin 7.5 mg daily with a goal International Normalized Ratio (INR) of 2-3. Prior to study entry, his INR had been stable for at least 6 months with levels ranging from 2.0 to 2.6 (Figure 1). At the initial study visit, his baseline INR was obtained and he was placed on the starting dose of CBD at 5mg/kg/day divided twice daily (BID). With up-titration of CBD oil by 5mg/kg/day increments, a non-linear increase in the INR was noted (Table 1, Figure 2). Warfarin dosage adjustments were made by his primary care physician as reflected in Table 1 in effort to maintain an INR within his therapeutic range. Overall there was a 14% reduction in warfarin dose from baseline with uptitration of CBD. Results: Warfarin activity is affected by polymorphisms in CYP2C91. The drug is a mixture of enantiomers that are metabolized by distinct CYPP450 cytochromes. R-warfarin is metabolized primarily by CYP1A2 and CYP3A4. S-warfarin is metabolized primarily by CYP2C92. Drugs that compete as substrates for these cytochromes or inhibit their activity may increase warfarin plasma concentrations and INR, potentially increasing the risk of bleeding. Conversely, drugs that induce these metabolic pathways may decrease warfarin plasma concentrations and INR, potentially leading to reduced efficacy. It is possible that both warfarin and CBD are affected by genetic variations in CYP enzyme pathways. CBD is a substrate of CYP3A4 and CYP2C193. Any utilization of the same enzymatic pathway could subsequently delay the degradation of warfarin and therefore prolong its action. According to current recommended guidance, careful titration of purified CBD in patients taking concomitant medications metabolized by CYP3A4 or CYP2C19 is advised, with plasma monitoring of such medications or their metabolites to be undertaken at the Investigator's discretion. Conclusions: This finding suggests an interaction between warfarin and cannabidiol and underscores the importance of monitoring appropriate laboratory work in patients receiving concomitant cannabis products, in this case cannabidiol, and other pharmaceuticals. Funding: The UAB CBD program received general funds from the state of Alabama.