CMSC 2012: Procedure Developed to Quickly Eliminate Teriflunomide from the Plasma

SAN DIEGO — Cholestyramine and activated charcoal can be used to virtually eliminate the long half-life oral investigational multiple sclerosis (MS) drug, teriflunomide, from the plasma in 11 days, according to research presented at the Fourth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers (CMSC) and America’s Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).

Teriflunomide, a disease-modifying therapy in development for the treatment of the relapsing form of MS, is the active metabolite of leflunomide, which has been used in the treatment of rheumatoid arthritis since 1998. By inhibiting dihydro-orotate dehydrogenase (DHODH), an enzyme that is key in the de novo synthesis of pyrimidine, teriflunomide has demonstrated both antiproliferative and anti-inflammatory effects.

However, teriflunomide has a long elimination half-life of approximately 19 days and can persist in the bloodstream for 6 months or longer after stopping treatment. As this prolonged half-life could be problematic in cases of emerging toxicity or in cases of planned or unplanned pregnancy, finding a rapid, safe way to eliminate teriflunomide from the bloodstream is important.

Aaron Miller, MD, of the Mount Sinai School of Medicine in New York, and colleagues administered the bile acid sequestrant, cholestyramine (8 g or 4 g three times per day), or activated charcoal (50 g twice per day) to 123 healthy adult volunteers participating in 4 clinical trials after they had received a loading dose of teriflunomide 70 mg/day for 3-4 days to quickly achieve steady state followed by repeated doses of teriflunomide 14 mg/day for 8-11 days.

Cholestyramine, 8 g per day, was the most effective, followed by cholestyramine, 4 g/day, but activated charcoal was also successful in reducing teriflunomide concentrations by more than 98% in only 11 days. During administration of cholestyramine or activated charcoal, gastrointestinal events and transient liver transaminase increase were noted.

“The elimination of teriflunomide can be accelerated by cholestyramine or activated charcoal, which both prevent re-absorption and thus enterohepatic recirculation. This may be useful in specific situations in which accelerated elimination is desirable, such as emerging toxicity, or planned or unplanned pregnancy,” the authors concluded.

This research was supported by Genzyme, a sanofi company.