Teriflunomide Sodium

Teriflunomide sodium, a novel derivative of leflunomide, was developed to treat systemic lupus erythematosus.

The objectives of this trial were to study the safety, pharmacokinetics, and pharmacogenetics of teriflunomide sodium in healthy Chinese subjects in order to support its accelerated development.

A clinical study was designed as a single-dose, randomized, parallel, open-label study. Healthy volunteers were randomly assigned to take teriflunomide sodium 10 mg or leflunomide 10 mg. Eligible healthy volunteers were monitored over a 98-day observation period. Blood and urine samples were collected and analyzed for teriflunomide and its metabolite concentrations, and ABCG2 and CYP2C9 genotypes were detected. The safety profile was also collected.

All adverse events were mild in intensity, and all subjects completed this trial without any other treatment. After a single administration of teriflunomide sodium and leflunomide, teriflunomide maximal concentrations were 1.32 ± 0.341 mg/L and 0.718 ± 0.169 mg/L, and area under the concentration-time curve from time zero to infinity (AUC_∞) was 423 ± 229 mg·h/L and 303 ± 159 mg·h/L, respectively. Overall, teriflunomide AUC_∞ in ABCG2 34A/A mutants was 70.4% lower than in wild-type ABCG2 34G/G after administration of teriflunomide sodium. In addition, after administration of leflunomide, teriflunomide AUC_∞ in ABCG2 34A/A mutants was 30.0% lower than in subjects carrying ABCG2 34G/G.

Teriflunomide sodium was generally safe and well tolerated in healthy Chinese subjects. The relative bioavailability of teriflunomide between teriflunomide sodium and leflunomide after a single dose administration was approximately 150%. Additionally, ABCG2 34G>A was found to significantly affect teriflunomide pharmacokinetics, which suggested ABCG2 34G>A may be a significant influencing factor.

This study was registered at the China National Medical Products Administration ( http://www.nmpa.gov.cn ; registration number 2014L01935), and also at the China platform for registry and publicity of drug clinical trials ( http://www.chinadrugtrials.org.cn ; registration number CTR20150314).

A simple high‐performance liquid chromatography coupled with tandem mass spectrometry method was developed and fully validated to simultaneously determine teriflunomide (TER) and its metabolite 4‐trifluoro‐methylaniline oxanilic acid (4‐TMOA) in human plasma and urine. Merely 50 μL plasma and 20 μL urine were employed in sample preparation using protein precipitation and direct dilution method, respectively. An Agilent Zorbax eclipse plus C18 column was selected to achieve rapid separation for TER and 4‐TMOA within 3 min. Electrospray ionization under multiple reaction monitoring was used to monitor the ion transitions for TER (m/z 269.0 → 159.9), 4‐TMOA (m/z 231.9 → 160.0), internal standard teriflunomide‐d4 (m/z 273.0 → 164.0) and 2‐amino‐4‐trifluoromethyl benzoic acid (m/z 203.8 → 120.1), operating in the negative ion mode. This method proved to have better accuracy and precision over concentration range of 10–5000 ng/mL in plasma as well as 10–10,000 ng/mL in urine. After a full validation, this method was successfully applied in a pharmacokinetic study of teriflunomide sodium and leflunomide in Chinese healthy volunteers.