Combination of two Na⁺ channel-inhibiting anticonvulsants lacosamide and phenytoin: An additive, synergistic, or antagonistic effect?

The classic Na⁺ channel-inhibiting anticonvulsants, such as phenytoin (DPH), and the new-generation lacosamide (LCM) selectively bind to the fast and slow inactivated states of the channel, respectively. The effect of a combination of the two anticonvulsants acting on the same protein with differently modulated receptors by neuronal activities, a possible clinical scenario, is investigated in native mouse neurons and heterologously-expressed human Na⁺ channels. A combination of DPH and LCM does not necessarily show stronger inhibition on different neuronal epileptiform burst discharges than that of a single drug. There is more likely a doubly occupied channel and thus a supra-additive effect of the two drugs at prolonged weak and strong depolarization which moves most channels to the fast and slow inactivated states, respectively. However, single occupancy or mutual exclusion and thus an infra-additive effect may prevail with prolonged modest or short strong depolarization which presumably moves the channel chiefly to the intermediate inactivated states. Although there could be gaps between in vitro and clinical settings, the results implicate that a combination of DPH and LCM for seizure therapy is in general warranted, especially if the seizure discharges are characterized by prolonged strong membrane depolarization or its equivalents (a condition also endowing LCM the best effect). However, cases of no increment, or even a decrement, in efficacy shall be carefully monitored. On the other hand, the rare cardiac adverse events reported for LCM use are not expected to increase with the combination because of the little additive effect on intermediate inactivated states. Abbreviations: AUC, area-under-the-curve; ANOVA, analysis of variance; CA1, cornu ammonis area 1 of the hippocampus; CHO–K1, Chinese hamster ovary K1; CI, combination index; DPH, phenytoin; EEG, electroencephalography; FBS, fetal bovine serum; GFP, green fluorescent protein; I_f, fast inactivated states; I_i, intermediate inactivated states; I_s, slow inactivated states; LCM, lacosamide; Nav1.7, voltage-gated sodium channel subtype 1.7; SEM, standard error of the mean.