Abstracts

Rationale: Lacosamide (LCM) is approved in several countries as an adjunctive therapy for the treatment of partial onset seizures in adults. The titration regimen recommends initiating LCM at 100 mg/day (50 mg bid) which should be increased to an initial therapeutic dose of 200 mg/day (100 mg bid) after one week. This schedule results in steady state levels at the lowest recommended therapeutic dose (200 mg/day) within 10 days. In clinical situations where rapid therapeutic effect is warranted, it might be desirable to establish steady state LCM concentrations associated with therapeutic dose steady-state levels at treatment initiation. The objective of this work was to evaluate the equivalence between the titration dosing regimen and a treatment regimen initiated with an intravenous (iv) or oral loading dose (LD) followed by twice daily oral dosing. Methods: Based on the pharmacokinetics (PK) of LCM and the predictions of the mathematical PK model, a loading dose of 200mg LCM is expected to result in a LCM exposure equivalent to the exposure of LCM 100mg twice-daily at steady state. To test this hypothesis, a simulation was performed using a 1-compartment model with first order absorption (oral) or zero-order input (iv infusion) and first order elimination. The simulations were based on the following dosing schedules: oral or iv LD of 200mg LCM followed by administration of a maintenance dose of oral or iv LCM 100mg twice daily (200 mg/day). The results were compared to data of Phase 1 studies as well as a Phase 3b, multicenter, open-label study designed to assess the safety and tolerability of rapid initiation of adjunctive LCM with a single iv loading dose. Results: The simulation of LCM plasma concentration time profiles showed that a single loading dose of 200mg (oral or iv) would enable faster achievement (at end of i.v. LD infusion and within approximately 1h after oral loading) of plasma concentrations associated with a therapeutic dose, in comparison with the titration regimen (after 10 days; 50mg LCM twice daily for one week followed by 100mg LCM twice daily). Simulated plasma concentrations at steady state conditions were comparable with LCM concentrations measured in adult patients with focal seizures on LCM 100 mg twice daily (200 mg/day) (Cawello et al, Epilepsia 2010; 51(Sup. 4): 68) confirming the predictability of the loading dose principle. Conclusions: Based on the present evaluation, single LCM loading dose regimen resulted in similar plasma concentrations compared to those achieved with the titration dose regimen after 10 days. Furthermore the comparison between simulated and clinical data showed similar concentration-time curves and confirmed the predictions of equivalence. These data supports the hypothesis, that the initiation of a LCM single loading dose leads to faster achievement of plasma concentrations associated with therapeutic dose steady state plasma levels and provides an important treatment option for adult patients with POS. Funded by UCB.