When CBZ is reduced or discontinued, TPM doses may need to be lowered to maintain equivalent plasma concentrations. Adjusting the CBZ dose for pharmacokinetic reasons when TPM is administered as adjunctive treatment does not appear to be necessary.

Felbamate (FBM) monotherapy was evaluated in 44 patients with uncontrolled partial onset seizures in a unique, single-center, randomized, double-blind, parallel-group trial. During the 56-day baseline period, patients were required to have at least 8 seizures and to be receiving only one standard antiepileptic drug (AED) at a therapeutic level; a second AED was allowed if at a subtherapeutic level. Patients were randomized to valproate (VPA), 15 mg/kg, or to FBM, 3,600 mg/day. In the treatment phase, previous AEDs were discontinued by study day 28 (by one-third decrements on study days 1, 14, and 28). Study end points were completion of 112 study days or the fulfilling of escape criteria. Criteria for escape relative to baseline were: two-fold increase in monthly seizure frequency, two-fold increase in highest 2-day seizure frequency, single generalized tonic-clonic seizure (GTC) if none occurred during baseline, or significant prolongation of GTCs. The predetermined primary efficacy variable was the number of patients escaping in each treatment group. Nineteen patients on VPA and 3 on FBM met escape criteria (p less than 0.001, chi-square test). When overall seizure frequency among study completers was compared with baseline, the FBM group had a 50 to 65% reduction in seizure frequency. FBM adverse experiences were all mild or moderate in severity, and the incidence of adverse experiences was lower in monotherapy. FBM monotherapy was effective in the treatment of partial onset seizures with or without generalization and demonstrated a favorable safety profile.

Summary:Purpose: To evaluate the potential pharmacokinetic interactions between topiramate (TPM) and phenytoin (PHT) in patients with epilepsy by studying their pharmacokinetics (PK) after monotherapy and concomitant TPM/PHT treatment.Methods: Twelve patients with epilepsy stabilized on PHT monotherapy were enrolled in this study, with 10 and seven patients completing the phases with 400 and 800 mg TPM daily doses, respectively. TPM was added at escalating doses, and after stabilization at the highest tolerated TPM dose, PHT doses were tapered. Serial blood and urine samples were collected for PK analysis during the monotherapy phase or the lowest PHT dose after taper and the concomitant TPM/PHT phase. Potential metabolic interaction between PHT and TPM also was studied in vitro in human liver microsomal preparations.Results: In nine of the 12 patients, PHT plasma concentrations remained stable, with a mean (±SD) area under the curve (AUC) ratio (combination therapy/monotherapy) of 1.13 ± 0.17 (range, 0.89-1.23). Three patients had AUC ratios of 1.25, 1.39, and 1.55, respectively, and with the addition of TPM (800, 400, and 400 mg daily, respectively), their peak PHT plasma concentrations increased from 15 to 21 mg/L, 28 to 36 mg/L, and 27 to 41 mg/L, respectively. Human liver microsomal studies with S-mephenytoin showed that TPM partially inhibited CYP2C19 at very high concentrations of 300 M (11% inhibition) and 900 M (29% inhibition). Such high plasma concentrations would correspond to doses in humans that are 5 to 15 times higher than the recommended dose (200-400 mg). TPM clearance was approximately twofold higher during concomitant TPM/PHT therapy Conclusions: This study provides evidence that the addition of TPM to PHT generally does not cause clinically significant PK interaction. PHT induces the metabolism of TPM, causing increased TPM clearance, which may require TPM dose adjustments when PHT therapy is added or is discontinued. TPM may affect PHT concentrations in a few patients because of inhibition by TPM of the CYP2C19-mediated minor metabolic pathway of PHT. Key Words: Topiramate-PhenytoinAntiepileptics-Pharmacokinetics-Drug interactionsEpilepsy.Topiramate [TPM; Topamax; 2,3:4,5-bis-O-(1-methylethylidene)-␤-D-fructopyranose sulfamate] (Fig. 1) is a structurally novel, sulfamate-substituted monosaccharide, the antiepileptic activity of which is mediated by multiple mechanisms of action (1,2). The mechanism of action of TPM include interference with voltage-gated Na + channels, blockade of kainate/AMPA-type glutamate receptors, enhancement of ␥-aminobutyric acid (GABA)-receptor action by interaction with a nonbenzodiazepine (non-BZD) receptor site, inhibitory effect on Ca 2+ activated L-channel currents, and inhibition of carbonic anhydrase isoenzymes (2,3). TPM is currently approved in more than 80 countries and is available as tablets and as a sprinkle formulation for adult and pediatric (age 2-16 years) use (4).The pharmacokinetics of TPM are characterized by rapid absorption, a long half-life (...

Summary: Purpose: This open-label study investigated the pharmacokinetic interaction of phenytoin (PHT) and felbamate (FBM).Methods: Ten subjects with epilepsy receiving PHT monotherapy were administered increasing doses of FBM ( I ,200, 1,800, 2,400-3,600 mg/day) at 2-week intervals. PHT doses were reduced by 20% on an individual basis when evidence of clinically significant intolerance was present. With intolerance, the PHT dose was reduced before the next incremental FBM dose. Blood samples were analyzed for FBM, PHT, and PHT metabolite 5-(4-hydroxyphenyl)-5-phenylhydantoin (HPPH).Results: Total PHT plasma concentrations increased with coadministered FBM. PHT C, , , increased from 15.9 pg/ml at baseline to 20.9 yg/ml after 1,200 mg/day FBM and to 26.8 pg/ml after 1,800 mg/day FBM. Four subjects required a 20% PHT dose reduction after 1,800 mg/day FBM and six after the administration of 2,400 mg/day FBM. All subjects required further 20% PHT reductions before 3,600 mg/day FBM. FBM C,,,, and AUC, were reduced, and apparent 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 likely to be necessary if the FBM dose is increased. The requirements for reductions in dose might be predicted by clinical signs of PHT intolerance.