Rapid Elimination Procedure of Teriflunomide with Colestipol Hydrochloride (TERCOL)

Background: Teriflunomide is an oral disease modifying therapy approved for the treatment of relapsing multiple sclerosis. It works by selectively and reversibly inhibiting dihydroorotate dehydrogenase, which impairs proliferation of stimulated T and B lymphocytes. Teriflunomide is rapidly absorbed, highly protein bound and involved in enterohepatic recycling, which contributes to its long half-life. This results in slow elimination from plasma, which on average takes 6-8 months, though it can take up to 2 years for plasma concentrations to reach a minimum level (<0.02µg/ml). This slow elimination can become problematic in certain clinical situations, such as in females who become pregnant due to the potential teratogenic effects. In these settings an accelerated elimination procedure (AEP) is recommended. Currently, oral administration of cholestyramine or activated charcoal is available, but these agents are restricted by adverse effects (AEs), limited administration routes and dosing frequencies. This study aimed to investigate colestipol HCL as an alternative to cholestyramine for the elimination of teriflunomide.

Objectives: To determine if colestipol HCL can accelerate the elimination of teriflunomide, monitor AEs of colestipol HCL and teriflunomide, and determine the duration of therapy for adequate elimination.

Methods: This was a single-center, two-period, two-treatment, single-sequence, PK interaction study. Participants were treated with teriflunomide for 14 days, followed by an AEP with colestipol HCL for 15 days. Teriflunomide concentrations and AEs were monitored throughout the study. If plasma teriflunomide concentration was >0.02µg/ml at the end of AEP, subjects received cholestyramine until teriflunomide concentration was ≤ 0.02µg/ml. 

Results: A total of 14 subjects participated before futility analysis confirmed the need for discontinuation. Of these 14, 10 subjects completed the study into the washout phase. Mean plasma teriflumomide concentrations were 17.95 µg/ml at Day 22, 9.36 µg/ml at Day 28 µg/ml, 2.01 µg/ml at Day 40, and 1.31 µg/ml at Day 50. Teriflunomide and colestipol HCL related AEs are shown in Table 3.

Conclusions: Administration of colestipol HCL for 15 days was sufficient to reduce plasma teriflunomide concentrations by an average of ≥ 96%. Despite the protocol amendment to include extended follow-up time of teriflunomide PK levels, colestipol HCL was not able to completely eliminate teriflunomide in the majority of subjects. AEs experienced by subjects were consistent with known AEs related to both teriflunomide and colestipol HCL, with the vast majority reported as mild in nature. Although colestipol HCL did not completely eliminate teriflunomide with the same effectiveness as cholestyramine, for some patients it may offer an alternative method for accelerated elimination of teriflunomide with potentially improved tolerability, a more favorable administration and dosing option.