(752): Low potential for drug-drug-interaction of lacosamide

Abstract

Lacosamide is a new drug being developed for the treatment of epilepsy and neuropathic pain. Preclinical and clinical pharmacological data have been established in a series of trials and phase 3 development is currently ongoing for both indications. Information about the pharmacokinetic drug-drug-interaction (DDI) potential of lacosamide is an important part of its safety profile. Regarding the DDI potential the results of several preclinical studies as well as of 9 Phase 1 trials (n=184 subjects) and a Phase 2 trial (n=91 patients) are presented. In vitro lacosamide is not substantially metabolized. In vitro results also show no or low potential to inhibit or to induce CYP isoforms. Since lacosamide has low binding to plasma proteins (<15%), drug displacement interactions are unlikely. In a Phase 1 trial lacosamide was administered to extensive and poor metabolizers of CYP2C19 and the results showed that the activity of CYP2C19 has no clinically relevant effect on the metabolic fate of lacosamide. Further phase 1 DDI trials have been performed with the antiepileptic drugs carbamazepine (inducer of CYP450 system) and valproic acid (inhibitor of CYP450 system) under steady-state conditions. In these trials, lacosamide had no influence on rate or extent of absorption of carbamazepine or valproic acid and vice versa. DDI trials with digoxin and metformin showed no relevant influence of these drugs on lacosamide and vice versa. Lacosamide did not influence the pharmacokinetics and pharmacodynamics of the oral contraceptive Microgynon® (containing 0.03mg ethinyl estradiol and 0.15mg levonorgestrel). Coadministration of food did not alter the rate or extent of gastrointestinal absorption of lacosamide. A clinical trial in subjects with epilepsy showed no influence of lacosamide on plasma levels of common antiepileptic drugs including phenytoin. No DDI have been observed in these studies. Therefore the data suggest that lacosamide has low potential for DDI in clinical use.