Lacosamide Has No Effect on the Enzymatic Activity of CYP3A4 (P01.076)

Abstract

Objective: To evaluate the effect of lacosamide, an antiepileptic drug (AED) used to treat adults with partial-onset seizures, on cytochrome P450 isoenzyme 3A4 (CYP3A4) activity using midazolam as a substrate. Background As epilepsy is commonly treated with multiple AEDs, it is important to ascertain potential interactions between therapies. Design/Methods: In this single-centre, open-label trial, healthy male volunteers (19–50 years, BMI 19–30kg/m 2 ) received a single oral dose of midazolam 7.5mg on Day 1 of treatment period 1 to obtain baseline pharmacokinetic (PK) parameters. During treatment period 2, volunteers received multiple doses of oral lacosamide 200mg b.i.d. (400mg/day) on Days 1–13, a single 200mg dose 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 AUC (0-∞) , AUC (0-tz) , C max , t max and t ½ for midazolam and its main metabolite 1-hydroxy midazolam, and C trough for lacosamide. Statistical comparisons between baseline midazolam PK parameters and those measured during coadministration were made using ANOVA and least squares mean ratios. Results: No change from baseline in the plasma concentration-versus-time profile was observed for midazolam or 1-hydroxy midazolam during coadministration with lacosamide (N=33), except for a slight increase in midazolam C max . For all three period 2 treatment timepoints, AUC (0-∞) and AUC (0-tz) were similar to baseline. AUC (0-tz) 90% confidence intervals for all treatment-to-baseline ratios were within the bioequivalence range of 0.80–1.25. Additionally, there was no change with treatment time for any secondary PK parameter of midazolam or 1-hydroxy midazolam. The portion of midazolam metabolized to 1-hydroxy midazolam did not change during the study. Conclusions: CYP3A4 enzymatic activity was not affected by a single lacosamide 200mg dose or repeated 400mg daily doses. There was no clinically relevant evidence for CYP3A4 induction or inhibition by lacosamide. Supported by: UCB Pharma. Disclosure: Dr. Cawello has received personal compensation with UCB Pharma as an employee. Dr. Surmann has received personal compensation for activities with UCB Pharma. Dr. Waitzinger has received personal compensation for activities with Bial, Eisai Inc., Sunovion Pharmaceuticals, Inc., and UCB Pharma as a consultant.