SUMMARYPurpose: To test for bioequivalence of 200 mg lacosamide oral tablet and syrup formulations. Additional objectives were to compare the pharmacokinetic profile of lacosamide in saliva and plasma, and to evaluate its tolerability.Methods: This open-label, randomized, two-way crossover trial was conducted in 16 healthy Caucasian male participants in Germany. The bioequivalence of 200 mg lacosamide tablet and syrup was evaluated using plasma to determine maximum measured concentration (C max ) and area under the curve from zero to the last time point (AUC) (0-tz) . Plasma and saliva samples for evaluation of pharmacokinetic parameters of lacosamide and the major metabolite O-desmethyl lacosamide (SPM 12809) were taken over 15 time points (0.5-72 h) and used to statistically compare bioavailability of the two. Urine samples were collected predose and over five time points (0-48 h) to evaluate the cumulative amount of unchanged drug and metabolite. Key Findings: Lacosamide median time to reach C max (t max ) was 1 h for tablet and 0.5 h for syrup in plasma and saliva. Mean terminal half life (t ½ ) for tablet and syrup was 12.5 and 12.4 h in plasma, and 13.1 and 13.3 h in saliva, respectively. Tablet and syrup mean plasma AUC (0-tz) was 84.5 and 83.3 lg/mL*h, respectively. Mean AUC (0-tz) in saliva was 93.2 lg/mL*h for tablet and syrup. Mean C max for tablet was 5.26 lg/mL in plasma and 5.63 lg/mL in saliva. Syrup mean C max was 5.14 and 8.32 lg/mL in plasma and saliva, respectively. Within 2 h of syrup administration, elevated lacosamide concentration in saliva compared to plasma was observed. The ratio of lacosamide syrup to tablet was 0.98 for C max and 0.99 for AUC (0-tz) in plasma, and 1.00 for AUC (0-tz) in saliva; the 90% confidence intervals (CIs) for these parameters were within the range of 0.80-1.25, which meets accepted bioequivalence criteria. The syrup-to-tablet ratio for C max in saliva was 1.48, and the 90% CIs exceeded the accepted upper boundary for bioequivalence (1.32-1.66). Both formulations were well tolerated. Metabolite concentration versus time profiles for saliva were similar to plasma following tablet and syrup administration. Significance: The tablet and syrup formulations of lacosamide 200 mg were bioequivalent and well tolerated. Saliva samples were demonstrated to be a suitable surrogate to evaluate lacosamide tablet pharmacokinetics in the central compartment. Due to residual syrup in the buccal cavity, limitations exist when using saliva to evaluate the pharmacokinetics of lacosamide syrup <2 h after administration.

Lacosamide is a new antiepileptic drug for adjunctive treatment of adult partial-onset seizures. Two open-label, multiple-dose clinical trials were conducted to evaluate the potential for pharmacokinetic interaction between lacosamide and carbamazepine. The influence of carbamazepine on lacosamide pharmacokinetics (trial A) and lacosamide on carbamazepine pharmacokinetics (trial B) was investigated in 19 (trial A) and 18 (trial B) healthy male participants. Trial A participants received lacosamide 200 mg bid alone and with carbamazepine 200 mg bid. Trial B participants received carbamazepine 200 mg bid alone and with lacosamide 200 mg bid. Pharmacokinetic parameters, area under the concentration-time curve during a dosage interval at steady state (AUC(tau,ss)), and maximum steady-state plasma drug concentration during a dosage interval (C(max,ss)) of lacosamide, carbamazepine, and carbamazepine-10,11-epoxide were measured and compared for each drug alone and together. The AUC(tau,ss) and C(max,ss) point estimates (combined vs sole treatment) showed relative bioavailability of approximately 100% for both drugs. All 90% confidence intervals of AUC(tau,ss) and C(max,ss) were within the generally accepted bioequivalence ranges of 80% to 125%. No changes in rate or extent of absorption or terminal half-life were observed. These results suggest that lacosamide and carbamazepine have a low potential for pharmacokinetic drug-drug interaction in clinical use.

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