Anticonvulsant Activity of Felbamate in Amygdala Kindling Model of Temporal Lobe Epilepsy in Rats

Summary: Purpose : Previous studies have demonstrated that felbamate (FBM, 2-phenyl-1,3-propanediol dicarbamate) at nontoxic doses exerts potent anticonvulsant activity in a variety of animal epilepsy or seizure models. We further characterized the anticonvulsant activity of FBM by using the kindling model of temporal lobe epilepsy (TLE).
Methods : The experiments were performed in fully kindled rats. The anticonvulsant effect of FBM was assessed by determining seizure severity, after discharge (AD) duration and seizure duration either at the focal seizure threshold, or after supra threshold stimulation. In addition, the neurological performance of kindled rats after FBM administration was evaluated in the open field and by the rotorod test.
Results : FBM at doses of 12.5–50 mg/kg, given intraperitoneally (i.p.) 60 min before testing, dose-dependently increased the AD threshold (ADT). The maximal effect was achieved after the highest dose tested and reached almost 600% of the control ADT. This dose of FBM significantly diminished other seizure parameters, e.g., seizure severity, seizure duration, and AD duration. When the rats were stimulated with suprathreshold current (500 μA) seizure severity was moderately but significantly reduced. No behavioral abnormalities were noted in kindled rats after administration of either of the doses.
Conclusions : FBM potently increases the threshold for focal seizures and reduces seizure severity, seizure duration, and AD duration at doses that produce no adverse behavioral effects in amygdala-kindled rats. These data are thus compatible with clinical experience with FBM in TLE and substantiate that kindling is a good predictor of anticonvulsant activity against TLE.     

Plasma Levels and Pharmacokinetics of Antiepileptic Drugs in Children

Abstract: The Michaelis-Menten pharmacokinetics and bioavailability of phenytoin were evaluated in children. The Vmax was inversely related to age, but there was no such relationship for Km. The fraction excreted in urine as 5-(p-hydroxyphenyl)-5-phenylhydantoin, the main metabolite of phenytoin after oral administration, was not significantly different among the patients aged two months to 16 years; suggesting that no functional difference existed between children and adults that would alter the drug absorption from the gastrointestinal tract.
Children on sodium valproate mono-therapy were divided into three different age groups. The daily dose per kilogram of body weight correlated poorly with the plasma concentration in each age group. However, the plasma level to dose ratio increased with the advancement of the group age. Also in children treated only with carbamazepine at daily doses of 10–15 mg/kg body weight, the younger age group achieved the lower steady-state plasma concentrations of carbamazepine. In contrast, the concentration of carbamaze-pine-10, ll-epoxide, the main metabolite of carbamazepine, expressed as a percentage of the parent drug, was higher in the younger age group.     

Plasma levels and pharmacokinetics of antipileptic drugs in children

The Michaelis-Menten pharmacokinetics and bioavailability of phenytoin were evaluated in children. The Vmax was inversely related to age, but there was no such relationship for Km. The fraction excreted in urine as 5-(p-hydroxyphenyl)-5-phenylhydantoin, the main metabolite of phenytoin after oral administration, was not significantly different among the patients aged two months to 16 years; suggesting that no functional difference existed between children and adults would alter the drug absorption from the gastrointestinal tract. Children on sodium valproate mono-therapy were divided into three different age groups. The daily dose per kilogram of the body weight correlated poorly with the plasma concentration in each age group. However, the plasma level to dose ratio increased with the advancement of the group age. Also in children treated only with carbamazepine at daily doses of 10-15 mg/kg body weight, the younger age group achieved the lower steady-state plasma concentrations of carbamazepine. In contrast, the concentration of carbamazepine-10, 11-epoxide, the main metabolite of carbamazepine, expressed as a percentage of the parent drug, was higher in the younger age group.     

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 administered increasing doses of FBM (1,200, 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 Cmax increased from 15.9 microg/ml at baseline to 20.9 microg/ml after 1,200 mg/day FBM and to 26.8 microg/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 Cmax and AUCT 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.     

Pharmacokinetics of cannabidiol in children with refractory epileptic encephalopathy

Growing interest in the clinical use of cannabidiol (CBD) as adjuvant therapy for pediatric refractory epileptic encephalopathy emphasizes the need for drug treatment optimization. The aim of this study was to characterize the pharmacokinetics of CBD in pediatric patients with refractory epileptic encephalopathy receiving an oil‐based oral solution. To evaluate CBD concentrations, six serial blood samples per patient were collected after the morning dose of CBD, at least 21 days after the beginning of treatment. Twelve patients who received a median (range) dose of 12.2 (5.3‐19.4) mg/kg/d (twice daily) were included in the analysis. Median (range) CBD time to maximum plasma concentration, maximum plasma concentration, and area under the concentration versus time curve up to 6 hours after dosing were 3.2 hours (1.9‐6.2), 49.6 ng/mL (14.4‐302.0), and 226.3 ng ? h/mL (70.5‐861.3), respectively. CBD systemic exposure parameters were in the lower range of previous reports in pediatric patients receiving doses in a similar range. Most of our patients (83%) showed little CBD plasma level fluctuation during a dosing interval, comparable to that encountered after oral administration of an extended release drug delivery system. CDB administration was generally safe and well tolerated, and a novel levothyroxine‐CBD interaction was recorded. Similar to other studies, large interindividual variability in CBD exposure was observed, encouraging the use of CBD therapeutic drug monitoring.     

Relative bioavailability of topiramate administered rectally

OBJECTIVE: To determine the relative bioavailability and tolerability of a topiramate (TPM) suspension after rectal administration. DESIGN/METHOD: Seven healthy men and five healthy non-pregnant women were enrolled. A 100 or 200 mg tablet of TPM was given orally and a 200 mg dose was given rectally in a randomized, open-label, crossover study with at least a 2-week washout period between doses. Plasma samples were collected prior to dosing and the following times after each dose: 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, and 96 h. Relative bioavailability was determined by calculating the ratio of the dose-normalized area under the curve (AUC/D) for the rectal and oral doses. RESULTS: Ten subjects completed the study. Two of the first seven subjects who received a 200 mg initial oral dose, withdrew because of side effects. The remaining subjects received a 100 mg oral dose. Three subjects received a 200 mg dose orally and rectally, and seven subjects received 100 mg orally and 200mg rectally. The average AUC/D was 0.72+/-0.18 h/l for the rectal dose and 0.76+/-0.20 h/l for the oral dose. The relative bioavailability (n=10) for TPM administered rectally was 0.95+/-0.17 with a range of 0.68-1.2. There were no statistically significant differences between the oral or rectal pharmacokinetic parameters. CONCLUSIONS: In healthy adults, rectally administered TPM is absorbed to a similar extent as the oral dosage form. Rectal administration is an acceptable route of administration for TPM, when the oral route is temporarily unavailable.     

Tolerability and Pharmacokinetics of Monotherapy Felbamate Doses of 1,200–6,000 mg/day in Subjects with Epilepsy

: Purpose: Felbamate (FBM) pharmacokinetic parameters, safety and tolerability in the dose range of 1,200–6,000 mg/day were assessed in two open-label studies with similar designs. Methods: In study A, newly diagnosed subjects with epilepsy receiving FBM monotherapy at a starting dose of 1,200 mg/day (400 mg/three times daily, t.i.d.) and increased 1,200 mg/day, if tolerated, at 14-day intervals to 3,600 mg/day were investigated. In study B, epilepsy subjects with prior FBM monotherapy exposure received ascending FBM doses in five consecutive 14-day periods with a starting dose of 3,600 mg/day (1,200 mg t.i.d.) FBM. In each successive period, if FBM was well tolerated, the dose was increased by 600 mg/day to a maximum of 6,000 mg/day (2,000 mg t.i.d.). Results: The pharmacokinetic parameter estimates maximum observed concentration (C_max), area under the concentration–time curve (AUCτ) C_trough, and C_av showed a linear dependence to dose above the 1,200–6,000 mg/day FBM dose range (F-tests; p <0.0001) with apparent clearance (Cl/kg) and T_max (time to C_max) independent of dose. When AUCτ, C_maxand C_troughwere adjusted for dose, there were no significant differences between the dosing periods. Conclusions: The data establish that plasma concentrations of FBM are linear with respect to dose to 6,000 mg/day. In addition, FBM was safely administered at these doses for periods as long as 14 days to epileptic subjects with prior exposure to FBM. FBM-naive subjects appeared to report more adverse experiences (generally of mild to moderate severity) than did subjects with prior FBM exposure.     

Clinical Efficacy of New Antiepileptic Drugs in Refractory Partial Epilepsy: Experience in the United States With Three Novel Drugs

Summary: A number of new antiepileptic drugs (AEDs), including topiramate (TPM), felbamate (FBM), and gabapentin (GBP), are approved or believed to be close to approval for marketing in the United States. Key efficacy findings for these AEDs in refractory partial epilepsy were reviewed. Large and significant drug-placebo differences were observed with TPM in two large dose-finding trials conducted in the United States. The minimal effective dose of TPM in the population studied was determined to be approximately 200 mg/day, and doses above 600 mg/day produced good efficacy but little incremental benefit versus the lower dosages for the overall study population. FBM is active in partial epilepsy, although seizure reduction is less marked and drug interactions complicate the findings. GBP is also active in this population, but only the 1,800 mg/day dosage was significantly better than placebo with respect to percent re-sponders. It may be useful to explore higher dosage ranges for both FBM and GBP if they can be well tolerated.     

The effect of chronic felbamate administration on anticonvulsant activity and hepatic drug-metabolizing enzymes in mice and rats

The possibility of tolerance development from chronic administration of felbamate (FBM) was investigated in mice and rats. Chronic administration (15 days) of FBM (150 mg/kg i.p.) in mice had no significant effect on either intravenous pentylenetetrazol (PTZ) seizure threshold or hexobarbital sleep time; however, hexobarbital sleep time was significantly increased after a single dose. Chronic administration (5-7 days) of FBM (48 or 95 mg/kg orally) in rats also had no significant effect on either maximal electroshock seizure activity or hexobarbital sleep time. Chronic administration of FBM at 238 mg/kg slightly decreased anti-subcutaneous PTZ activity in chronically treated rats (one of eight protected) as compared with those receiving only a single dose (three of eight protected), but there was no significant change in hexobarbital sleep time. Chronic treatment of rats for 7 days with 48 mg/kg had no significant effect on any hepatic parameters. However, 95 or 238 mg/kg of FBM significantly increased p-nitroanisole O-demethylase activity. It is concluded that the increased hexobarbital sleep time induced by an acute dose of FBM reflects the CNS-depressant effect of the substance. The increased p-nitroanisole O-demethylase activity observed after chronic administration may be indicative of some liver microsomal induction. Overall, FBM in doses ranging from 48 to 238 mg/kg appears to have minimal potential for tolerance development.     

Disposition of progabide and valproic acid following intraperitoneal administration in rhesus monkey

The pharmacokinetic characteristics of progabide, a new gamma-aminobutyric acid-mimetic drug, were evaluated following single- and multiple-dose administration of a progabide suspension through a chronic intraperitoneal catheter. Several issues pertaining to the bioavailability of progabide were addressed: first-pass effect, incomplete dissolution, and dose and time dependency. Four male monkeys received five treatments: three intraperitoneal doses (50, 100, and 150 mg), one oral dose (50 mg), and one intravenous bolus dose (150 mg). Bioavailability following intraperitoneal administration was incomplete, consistent with a first-pass effect predicted from intravenous data. There were no significant differences between the absolute bioavailabilities of the three intraperitoneal doses, which ranged between 40 and 49%. The apparent half-life (t 1/2) observed after intraperitoneal administration was significantly longer than the elimination half-life by the intravenous route and tended to increase with dose. This behavior is consistent with dissolution rate-limited absorption. The bioavailability of the suspension administered orally was compared with that of the intraperitoneal route, and no difference was found. However, the apparent t 1/2 by the oral route was significantly longer than that of the intraperitoneal route. In multiple-dosing studies, four different dosing regimens (all intraperitoneal) were examined, including 50 mg every 2 or every 6 h, 20 mg every 2 h, and 40 mg every 4 h. In all these regimens, plasma levels exhibited an accumulation compared with single-dose predictions. Large oscillations in plasma levels were observed when the dosing interval was 6 h and side effects were observed when the dosing interval was 2 h.(ABSTRACT TRUNCATED AT 250 WORDS)     

Functional and pharmacokinetic studies of tetrahydroaminoacridine in patients with amyotrophic lateral sclerosis

Assuming the presence of clinically significant cholinergic hypofunction in amyotrophic lateral scleroses (ALS), seven patients with ALS were treated with 100-200 mg tetrahydroaminoacridine (THA) together with 11 g lecithin daily for up to 7 weeks. In a separate experiment pharmacokinetics and effects on muscle strength and neurophysiological parameters were studied following the injection of 30 mg THA intravenously. Following the injection of THA an increase in muscle strength was observed in two patients. There were no consistent pharmacokinetic differences that could explain the effect on intravenous THA on muscle strength in these two patients. The plasma clearance of THA was high and the oral bioavailability low with large interindividual differences (6-36%). No beneficial effect was seen during oral medication and side-effects were common. There were no conclusive changes observed regarding neurophysiological parameters after drug administration. THA has probably no place in the treatment of ALS.     

Blood-Brain Barrier Penetration of Felbamate

The brain uptake index (BUI) method of Oldendorf was used to examine blood-brain barrier (BBB) drug transport in mice, rats, and rabbits; felbamate (FBM) extraction (E) in a single transcapillary passage was 5-20%, and drug uptake in rat brain was not concentration-dependent. Like diazepam, FBM was retained in mouse brain. To ensure that radioactivity measurements reflected the disposition of parent drug and not some metabolite, extracts of mouse brain were prepared for further analysis. No FBM metabolites were detected in brain 5 min after administration: In silica gel thin-layer chromatography (TLC), a single [14C]FBM peak was detected--Rf = 0.504 (70:30 acetone:hexane). Confirmatory high-performance liquid chromatography (HPLC) separations [30% methanol, 1.3 ml/min, C18 column, ultraviolet (UV) detection 254 nm] indicated a single peak containing greater than 93% of the radioactivity in the FBM fraction (12-min retention time). In a single transit through the liver (a nonbarrier tissue with fenestrated capillaries), FBM E was 82%. The octanol:buffered saline partition coefficient of FBM was (log PFBM =) 0.54 +/- 0.01. Thus, lipid-mediated BBB penetration of FBM is similar to that of phenytoin (PHT) and phenobarbital (PB). Plasma proteins do not affect FBM entry to the brain: neither human serum, nor bovine or human serum albumin (BSA, HSA), nor human alpha 1 acid glycoprotein (orosomucoid) significantly modified BBB FBM extraction. Erythrocyte-borne FBM may also dissociate and gain access to the brain in a single transcapillary passage. Differences between newborn and adult rabbit BBB FBM extraction and between different anesthetic agents are attributable to cerebral blood flow (CBF) rates. The permeability-surface area products (PS = [CBF].[E]) for FBM in rats, rabbits, and mice were 0.09, 0.16 and 0.30 ml/min/g, respectively. Preliminary autoradiographic analyses of frozen brain sections suggest that [14C]FBM distributes relatively uniformly throughout the brain and that minor variations apparently are a function of differing CBF rates.     

Long-term use of felbamate: Clinical outcomes and effect of age and concomitant antiepileptic drug use on its clearance

Purpose:   To determine the effects of long-term use of felbamate (FBM) on weight, complete blood count, liver function tests, and seizure control, and also to determine the effect of age on FBM clearance.
Methods:   A computerized prospective database was used to identify all subjects who had FBM listed as one of their antiepileptic drugs (AEDs) during their most recent clinic visit. Medical records from each patient were then reviewed for inclusion criteria [treatment >2 years, FBM initiated at the study clinic, data for pre-FBM (Time-1; T1), one-year exposure to FBM (Time-2; T2), and the latest visit (Time-3; T3)]. Clinical information was abstracted from clinic charts.
Results:   Seventy-seven patients (F = 41, M = 36; ages 10–69 years) met entry criteria. Mean treatment time was 7.4 years, with the longest 20.3 years. Significant weight loss (mean 5.1 kg; p < 0.001) occurred from T1 to T2, but weight was regained by T3. No clinically significant changes in laboratory parameters occurred. Older age was associated with a significant decrease in FBM clearance (p = 0.01). Significant reduction in generalized tonic–clonic seizures was seen at both T2 (p < 0.001) and T3 (p < 0.001) compared with seizure frequency at T1.
Discussion:   Our results suggest that long-term FBM use is associated with persistent decrease of seizures and no clinically significant changes in major laboratory parameters. Older age correlated with reduced apparent clearance of FBM. The patient population described in this study were long-term users of FBM who were continuing to use the drug, and thus this study does not constitute an "intent to treat" study.     

Pharmacokinetics of the new antiepileptic and CNS drug RWJ-333369 following single and multiple dosing to humans

PURPOSE: To characterize the pharmacokinetics of the new antiepileptic and CNS drug RWJ-333369 following single and multiple oral doses to healthy subjects, including the effect of food on bioavailability. METHOD: Two studies were conducted. The first study had a randomized, double-blind, placebo-controlled, sequential, ascending-dose crossover design. Subjects were divided into four dose groups (100, 250, 500, and 750 mg) of 10 to 11 subjects each. RWJ-333369 or placebo was administered for two 7-day periods, separated by a 14-day washout. In the second study RWJ-333369 (750 mg) was administered to 12 healthy subjects under fasted and fed conditions. Plasma and urine samples were analyzed for RWJ-333369 by liquid chromatography-mass spectroscopy. Safety was assessed throughout the studies. RESULTS: Mean (range) pharmacokinetic parameters in the above studies were: oral clearance (CL/F) 3.4-4.2 L/h, half-life (t(1/2)) 10.6-12.8 h, and renal clearance (CLr) 0.042-0.094 L/h, indicating that RWJ-333369 is eliminated primarily by metabolism. These parameters were not significantly different (p > 0.05) for the four dose groups and for single and multiple dosing. C(max) and AUC increased proportionally with dose and decreased with food by 11% and 5%, respectively. CONCLUSIONS: Following single and repetitive (q12h) doses of 100-750 mg, RWJ-333369 had linear pharmacokinetics; food did not alter pharmacokinetics to a clinically relevant extent. RWJ-333369 is extensively metabolized and has a low CL/F that equals < 5% of the liver blood flow. Thus, orally administered RWJ-333369 has no hepatic first-pass effect. The 12-h half-life will enable bid dosing with an immediate-release oral formulation.     

Pharmacokinetic properties and metabolism of idebenone

Four phase 1 studies were conducted to assess the pharmacokinetics and metabolism of idebenone (including parent drug and inactive metabolites QS10, QS6, and QS4) and to evaluate the safety of a wide range of idebenone doses and regimens in healthy adult men. After a single oral dose of idebenone 150 mg, 750 mg, or 1050 mg in fasted or fed subjects, blood samples were taken for up to 72 hours. In one study, after a single oral dose and a 7-day washout period, subjects received repeated doses of idebenone 150 mg or 750 mg every 8 hours for 14 days. In the repeated-dose study, urine samples also were taken. Plasma and urine samples were analysed with the use of liquid chromatography with tandem mass spectrometry. Non-compartmental standard pharmacokinetic methods were used. In these studies, a total of 69 subjects ranging in age from 19 to 41 years (body weight, 57–94.6 kg) were included. Plasma concentrations of parent idebenone were low but increased in proportion to dose and increased approximately five-fold in the presence of food. Total QS4 was the main metabolite in plasma and urine. The most common adverse events were loose stool, fatigue, headache, and disturbances in attention. Idebenone was well tolerated in single oral doses up to 1050 mg and in repeated daily doses up to 2250 mg. Idebenone showed linear pharmacokinetics after single and repeated oral dosing. Administration after a meal resulted in the highest exposure to parent idebenone.     

Felbamate-Induced Headache

We prospectively investigated drug-induced headaches (HA) among 60 epileptic patients receiving felbamate (FBM). Twenty patients (33%) experienced HA. HA was pounding in 11 (55%), steady in 9 (45%), moderate or severe in 19 (95%), occurred at least once a week in all patients, and was relieved by nonnarcotic analgesics in 14 (70%). Mean duration on FBM before HA onset was 19 days. HA occurred with higher FBM doses and was relieved in 8 of 13 patients (62%) with FBM dose reduction. FBM was discontinued in most cases because of risks of anemia or hepatitis; not because of HA. Other side effects included insomnia (25%), gastrointestinal symptoms (27%), and agitation or restlessness (23%). HA is a common dose-related complication of FBM, occurs early after initiation of FBM treatment, and is relieved by dose reduction.     

Oral anticoagulation therapy in children

Treatment of thromboembolic complications in children has been the subject of considerable research in the last decade. Recommendations for oral anticoagulant therapy in children have been extrapolated from adult clinical trials. Coumarin derivatives are the preeminent oral antithrombotic agents used in children. Warfarin, acenocoumarol and phenprocoumon are the vitamin K antagonists used in children with thrombotic complications in different countries according to their experience and familiarity within a country or region. Prospective studies from Canada and Argentina propose guidelines for administering and monitoring warfarin and acenocoumarol therapy in children. These studies highlight the difficulty of their use in pediatric patients. Infants younger than 12 months of age require increased doses to achieve and maintain the therapeutic target INR, adjustments of loading dose to achieve the target INR faster with no overshooting, more frequent INR testing and dose adjustments, and fewer INR in the target range. The current indications for oral anticoagulants in children with thrombotic complications, the side effects of these agents and the reversal of the anticoagulant effect are discussed.     

Rectal absorption of lamotrigine compressed tablets

PURPOSE: Interruption of oral drug administration poses a significant clinical problem for antiepileptic drugs that have no parenteral formulation. If a drug is absorbed rectally, rectal administration can be a useful alternative when the oral route of administration is not possible. The purpose of this study was to compare the single-dose pharmacokinetics of lamotrigine (LTG) compressed tablets after rectal and oral administration in healthy volunteers. METHODS: A single LTG compressed tablet (100 mg) was administered orally and rectally to 12 volunteers in this single-dose, two-period, crossover study with a 2-week washout between doses. For rectal administration, tablets were crushed and suspended in 10 mL of water. Plasma samples were collected from 0 to 120 hr after each dose and analyzed for LTG by an HPLC method developed for this investigation. RESULTS: LTG plasma concentrations were lower after rectal administration versus oral administration. The average area under the curve was 28.90 +/- 9.5 microg/mL/hr after rectal administration and 51.71 +/- 19.2 microg/mL/hr after oral administration. The average maximum LTG concentration was 0.53 +/- 0.14 microg/mL after rectal administration and 1.45 +/- 0.35 microg/mL after oral administration. The relative bioavailability for LTG compressed tablets was 0.63 +/- 0.33 for rectal administration. There were no drug-related rashes or serious side effects. CONCLUSIONS: LTG suspension prepared from LTG compressed tablets is absorbed rectally, although not to the same extent or rate as when given orally.     

Felbamate Increases Phenytoin but Decreases Carbamazepine Concentrations

Felbamate (FBM), a novel antiepileptic drug, was observed to have opposite effects on the serum concentrations of phenytoin (PHT) and carbamazepine (CBZ). Data from two male subjects who stabilized while they received both PHT and CBZ, with serum concentration fluctuations of less than 20 and 25%, respectively, form the basis of this report. Both patients required a greater than or equal to 20% reduction in PHT dose while receiving 38-40 mg/kg/day of FBM. When FBM was tapered to less than 20 mg/kg/day, a sudden drop in PHT concentrations occurred in both patients. As PHT concentrations rose, CBZ concentrations fell in both patients. The CBZ epoxide to parent ratio increased to 0.46 and 0.39, respectively during FBM treatment. The ratios were 0.18 in both patients when not receiving FBM. CBZ concentrations returned to baseline values after FBM was discontinued. This unusual and unexpected effect of FBM on two standard antiepileptic drugs underscores the need for evaluating pharmacokinetic interactions before major drug trials.