Abstracts

Rationale: Lacosamide is an antiepileptic drug (AED) used for the treatment of adults with partial-onset seizures. Since polytherapy is common in this population, it is important to ascertain potential interactions between AEDs. In this study, the effect of lacosamide on cytochrome P450 isoenzyme 3A4 (CYP3A4) activity was evaluated using midazolam as a substrate.Methods: Healthy male volunteers aged 19 50 years, with a body mass index of 19 30kg/m² took part in this single-center, open-label trial. During treatment period 1, they received a single oral dose of midazolam 7.5mg on Day 1 to obtain baseline pharmacokinetic (PK) parameters. Subsequently, during treatment period 2, they received multiple doses of oral lacosamide 200mg twice daily (400mg/day) on Days 1 13; a single dose of 200mg on the morning of Day 14, and three single doses of concomitant midazolam 7.5mg on Days 1, 4 and 14. Serial blood sampling was performed to determine the AUC_{(0 ?)}, AUC_{(0 tz)}, C_max, t_max and t for midazolam and its main metabolite 1-hydroxy midazolam, and C_trough for lacosamide. Safety was also monitored. Statistical comparisons between baseline midazolam PK parameters and those measured during coadministration with lacosamide were made using ANOVA and least squares mean ratios. This was done for midazolam and the 1-hydroxy midazolam metabolite.Results: Data from 33 volunteers were included in the PK analysis and 36 in the safety analysis. With the exception of a slight increase in the C_max of midazolam, no further change from baseline in the plasma concentration vs time profile was observed with the coadministration of lacosamide, neither for midazolam nor for its metabolite, 1-hydroxy midazolam. For all three treatment timepoints of period 2, AUC_{(0 ?)} and AUC_{(0 tz)} were similar to baseline values. The 90% confidence interval of AUC_{(0 tz)} for all the treatment-to-baseline ratios were within the bioequivalence range of 0.80 1.25. In addition, there was no change in any of the secondary PK parameters with treatment time for midazolam or 1-hydroxy midazolam. Most notably, the portion of midazolam metabolized to 1-hydroxy midazolam did not change during the study. No new safety signals were noted. Conclusions: The enzymatic activity of CYP3A4 was not affected by a single 200mg dose or repeated daily doses of 400mg of lacosamide. Results of this study showed no clinically relevant evidence for induction or inhibition of CYP3A4 by lacosamide. Funded by UCB