Investigation of the Effectiveness and Tolerability of Colesevelam HCl for Accelerated Elimination of Teriflunomide in Healthy Subjects

Background: Teriflunomide is a once-daily oral immunomodulator approved for the treatment of relapsing-remitting MS. Teriflunomide has a half-life of 19 days, and it takes an average of 8 months for plasma concentrations to reach 0.02 μg/mL, the lower limit of detection. In cases of emerging toxicity, overdose, or pregnancy, elimination of teriflunomide can be accelerated by oral administration of cholestyramine. Colesevelam HCl may offer an alternative method of elimination if well tolerated by patients.

Objectives: To investigate the efficacy of oral colesevelam HCl for the accelerated elimination of teriflunomide and capture information on tolerability and safety of colesevelam HCl.

Methods: This was an open-label single-center study. Healthy men and women aged 18–45 years received teriflunomide 70 mg once daily for 5 days, immediately followed by an 11-day accelerated elimination procedure (AEP) of colesevelam HCl (4.375-g total daily dose, [4 + 3] 625-mg tablets). Blood was sampled throughout the study for determination of plasma teriflunomide concentration via validated liquid chromatography with tandem mass spectrometry methodology. If plasma teriflunomide concentration was >0.02 μg/mL at Day 17 (end of AEP), subjects received precautionary cholestyramine 4 g 3 times daily (12-g total daily dose) until teriflunomide concentration was ≤0.02 μg/mL. Safety and tolerability were evaluated.

Results: A total of 18 subjects were treated. Mean (standard deviation) plasma teriflunomide concentration was 36.3 (6.42) μg/mL at Day 6 (start of AEP) and 1.33 (0.833) μg/mL at Day 17 (end of 11-day AEP), a mean 96.1% decrease (coefficient of variation 3.51%). After the AEP, all subjects received cholestyramine for 11 days to attain teriflunomide ≤0.02 μg/mL. There were no serious adverse events (AEs). Moderate treatment-emergent AEs considered related to treatment occurred in 2 subjects: 1 subject experienced headache on teriflunomide and on colesevelam HCl; 1 subject experienced flatulence, nausea, and abdominal pain on cholestyramine. All subjects recovered from AEs.

Conclusions: Administration of colesevelam HCl for 11 days was sufficient to reduce plasma teriflunomide concentrations by >96%. Where an AEP to eliminate teriflunomide is indicated, in some patients colesevelam HCl may offer an alternative method of elimination of teriflunomide with improved gastrointestinal tolerability.