Effect of eslicarbazepine acetate on the steady-state pharmacokinetics and pharmacodynamics of warfarin in healthy subjects during a three-stage, open-label, multiple-dose, single-period study

摘要: Abstract Background: The anticoagulant warfarin, which is administered as a racemic mixture of R - and S -enantiomers, has been reported to interact with other drugs, including some antiepileptics. Eslicarbazepine acetate (ESL) once-daily voltage-gated sodium channel blocker that developed for the treatment partial epilepsy indications. Objective: aim this work was investigate whether multiple-dose administration ESL had any effect on steady-state pharmacokinetics pharmacodynamics warfarin in healthy volunteers stabilized at subtherapeutic level. Methods: Subjects received 1200 mg once daily 8 days concomitantly dose individually optimized stable prothrombin international normalized ratio (INR) 1.3 1.8 during previous run-in phase (up 21 days). Coadministration followed by 7-day recovery period when again alone. effects -warfarin INR were assessed. For assay, blood sampling occur stage 1 (run-in period), 3 before starting dosing; 2 (combined predose 0.5, 1, 2, 4, 6, 8, 12, 16, 24 hours postdose, 7 predose; (after combined period) 3, 5, predose, day after final dose. determination INR, 7, assay -enantiomers (eslicarbazepine -licarbazepine), predose. C max AUC 0-t defined primary pharmacokinetic parameters. Tolerability evaluated monitoring adverse events, clinical laboratory safety tests, vital signs, 12-lead ECG. Results: Of 15 subjects enrolled, 13 (7 men 6 women) completed study. mean (SD) age 28.1 (7.3) years (range, 20–42 years), weight 67.3 (10.7) kg 54.0–84.4 kg), 14 (93.3%) white. Reductions (test:reference geometric means [GMR] = 0.81 [90% CI, 0.76 0.86] S-warfarin ss GMR=0.77 0.72 0.82]) observed, without clinically relevant changes INR. 1.45 (0.10) used alone (control) 1.51 (0.25) added 2. In relation slight increase 4.04% 1.03% 9.12%] following discontinuation administration, change −5.42% found −8.85% −1.98%]. not associated No deaths, serious or discontinuations due events noted, no findings variables. During course study, 9 (60%) total 32 events. Catheter-site ecchymosis, venipuncturesite hematoma, dizziness, vasovagal reaction, adhesive-tape allergy most common reported. coadministration 17 (epigastric discomfort, asthenia, lipothymia, irritability, macular rash) considered possibly related treatment; only lipothymia reached moderate intensity, all symptoms subsided sequelae discontinued. Conclusions: short-term study subjects, small, but statistically significant, reduction systemic exposure S-warfarin. There significant R-warfarin coagulation measured Protocol identifier: UFH/BIA-2093-108.