Carbamazepine plus stiripentol: is polytherapy by design possible?

Abstract

To test the idea that the combination of carbamazepine (CBZ) plus stiripentol (STP) is synergistic, an alumina-gel monkey model (N = 4) was used to compare polytherapy electroencephalographic (EEG) effects to those of CBZ monotherapy. The research design included five consecutive phases (2-3 weeks each): baseline, CBZ, CBZ + STP, CBZ, and postdrug baseline. Both drugs were administered in suspension through a chronic gastric catheter every 4 h (to minimize plasma level oscillations). Doses of CBZ were adjusted to maintain CBZ concentration at the same level in the drug periods (except during the initial polytherapy phase, where levels were allowed to increase prior to adjustment). Phased-reversed interictal spikes were manually counted (expressed as a rate per minute). Relative to baseline, CBZ (Cmin = 0.59; Cmax = 2.36 micrograms/ml) increased interictal EEG spikes by an average of 42%. Relative to CBZ monotherapy, the addition of STP (Cmin = 12.02; Cmax = 13.21 micrograms/ml) was associated with an average decrease in spike rate of 39%. This effect was reversible since removal of STP was associated with an increase in spike rate of 66%. The CBZ-epoxide/CBZ ratio decreased from 0.29 to 0.06 when STP was added and increased to 0.30 when STP was removed. The data fit a pharmacodynamic interpretation and suggest that in the case of CBZ + STP the benefits may outweigh the usual disadvantages of polytherapy.