Effect of Felbamate on the Plasma Protein Binding of Valproate

Abstract

Coadministration of felbamate is known to raise plasma valproate concentrations. In an attempt to explain this interaction, the effect of felbamate (FBM) on the plasma protein binding of valproate (VPA) was investigated in vitro and in healthy subjects. In fresh drug-free human plasma spiked with 20.0, 60.0 and 100.0 mg NaVPA/L without and with 75.5 mg FBM/L, the overall mean (± SD) unbound VPA fraction was 10.3 ± 1.6% without and 11.7 ± 2.1% with FBM. Regression analysis, used to distinguish FBM effects on plasma protein binding from effects due to altered total VPA concentration (VPA shows concentrationdependent protein binding), indicated that the mean percentage unbound VPA rose by 1.44% (95% CI = 0.59 to 2.30%). In 12 subjects the mean (± SD) trough concentrations of total VPA in plasma rose from 21.0 ± 6.1 mg/L to 45.1 ± 9.5 mg/L (p < 0.01) when VPA was taken, and the overall mean (± SD) unbound VPA fraction increased from 10.5 ± 0.77% to 11.7 ± 1.17%. Regression analysis indicated that there was a mean increase of 0.68% (95% CI = 0.13 to 1.23%) in plasma-unbound VPA because of a direct effect of FBM on plasma protein binding, the remaining 0.5% increase being due to the altered VPA concentration. While FBM appears to displace VPA from plasma proteins, this interaction is small and unlikely to make any important contribution to the overall effect of adding FBM to VPA, although the total interaction between the two may be large enough to necessitate a lowering of VPA dose.