Coadministration of phenytoin and felbamate: Evidence of additional phenytoin dose-reduction requirements based on pharmacokinetics and tolerability with increasing doses of felbamate

Purpose: This open-label study investigated the pharmacokinetic interaction of phenytoin (PHT) and felbamate (FBM). Methods: Ten subjects with epilepsy receiving PHT monotherapy were administ ered increasing doses of FBM (1,200, 1,800, 2,400-3,600 mg/day) at 2-week i ntervals. PHT doses were reduced by 20% on an individual basis when evidenc e of clinically significant intolerance was present. With intolerance, the PHT dose was reduced before the next incremental FBM dose: Blood samples we re analyzed for FBM, PHT, and PHT metabolite 5-(4-hydroxyphenyl)-5-phenylhy dantoin (HPPH). Results: Total PHT plasma concentrations increased with coadministered FBM. PHT C-max increased from 15.9 mu g/ml at baseline to 20.9 mu g/ml after 1, 200 mg/day FBM and to 26.8 mu g/ml after 1,800 mg/day FBM. Four subjects re quired a 20% PHT dose reduction after 1,800 mg/day FBM and six after the ad ministration of 2,400 mg/day FBM. All subjects required further 20% PHT red uctions before 3,600 mg/day FBM, FBM C-max and AUC(tau) were reduced, and a pparent clearance increased compared with data from FBM monotherapy. Conclusions: With the initiation of FBM therapy in subjects receiving PHT, the PHT dosage should be reduced by 20%. Further PHT dose reductions are li kely to be necessary if the FBM dose is increased. The requirements for red uctions in dose might be predicted by clinical signs of PHT intolerance.