Effect of Repeated Doses of Teriflunomide on a Single Oral Dose of Bupropion in Healthy Male Subjects (P04.143)

Objective: To assess the effect of repeated doses of teriflunomide on the pharmacokinetics (PK) of bupropion, a probe substrate for cytochrome P450 (CYP) 2B6. Background Teriflunomide is a novel oral disease-modifying therapy in development for the treatment of relapsing forms of multiple sclerosis (RMS). In vitro studies indicated that teriflunomide may inhibit, but not induce, the activity of CYP2B6. Therefore, a clinical study was undertaken to assess its interaction with a CYP2B6 substrate in an effort to supplement the understanding of teriflunomide9s safety and interaction profile. Design/Methods: This open-label, non-randomized, two-period, two-treatment, single-sequence PK interaction study was conducted in 17 healthy adult male subjects. Subjects received a single oral dose of bupropion (150 mg) on Day 1 of Period 1 and Day 12 of Period 2. Oral teriflunomide was administered during Period 2 as a loading dose (70 mg/day) for 4 days followed by a maintenance dose (14 mg/day) for 10 days. Due to the long teriflunomide half-life, this dosing regimen was used to mimic steady state therapeutic concentrations. The effect of teriflunomide on bupropion and hydroxybupropion (an active metabolite) on non-compartmental PK parameters was evaluated by calculating their geometric mean ratios (GMRs; for teriflunomide+bupropion vs bupropion alone) with 90% confidence intervals (CIs). Adverse events (AEs) were also recorded. Results: Teriflunomide administration had no effect on the Cmax and AUC of bupropion as the 90% CI was included within the predefined [0.80 - 1.25] interval. GMRs (90% CIs) of bupropion peak plasma concentration (Cmax), area under the curve until the last measurable concentration (AUClast) and extrapolated to infinity (AUC), were 1.03 (0.94, 1.12), 0.93 (0.87, 0.99) and 0.93 (0.87, 0.99), respectively. No serious AEs were observed and no treatment discontinuations occurred due to treatment-emergent AEs. Conclusions: Teriflunomide is not considered as an inhibitor or an inducer of CYP2B6 at the anticipated therapeutic dose. Supported by: sanofi-aventis. Disclosure: Dr. Turpault has received personal compensation for activities with Sanofi-Aventis Pharmaceuticals, Inc. as an employee. Dr. King has received personal compensation for activities with Sanofi-Aventis as an employee. Dr. Lewanczyk has received personal compensation for activities with Sanofi-Aventis as a contractor. Mr. Rockich has received personal compensation for activities with Sanofi-Aventis as an employee. Dr. Menguy-Vacheron has received personal compensation for activities with Sanofi-Aventis Pharmaceuticals, Inc., as an employee.