ABSTRACT
Felbamate (FBM) is a novel antiepileptic drug (AED) undergoing clinical trials in the United States. During a double-blind, cross-over clinical trial, patients received concomitant phenytoin (PHT) and carbamazepine (CBZ). Dosages of PHT and CBZ were adjusted to maintain serum concentrations +/- 20 and +/- 25% of baseline values. All patients required a PHT dosage decrease of 10-30% during active FBM treatment to maintain stable concentrations. CBZ serum concentrations decreased significantly in patients receiving active FBM. The mean decrease was 1.3 micrograms/ml and occurred in 30 of 32 patients. Therefore, FBM apparently causes a bidirectional effect on the serum concentrations of PHT and CBZ when all three drugs are taken concomitantly.
Subject(s)
Anticonvulsants/pharmacology , Carbamazepine/blood , Epilepsy/drug therapy , Phenytoin/blood , Propylene Glycols/pharmacology , Adolescent , Adult , Anticonvulsants/administration & dosage , Carbamazepine/administration & dosage , Clinical Trials as Topic , Double-Blind Method , Drug Interactions , Drug Therapy, Combination , Epilepsy/blood , Felbamate , Female , Humans , Male , Middle Aged , Phenylcarbamates , Phenytoin/administration & dosage , Propylene Glycols/administration & dosage , United StatesABSTRACT
Felbamate is a novel antiepileptic drug currently undergoing clinical trials in the United States. Serum felbamate concentration data from a phase II safety and efficacy trial were analyzed using NONMEM. A one-compartment, open model with first-order absorption and elimination was used. Body weight, sex, concurrent folic acid therapy, and phenytoin dose and dose:concentration ratio did not affect the estimates for felbamate clearance (Cl). Carbamazepine dose and dose:concentration ratio (CDCR) led to significant improvements in the objective function. The final models for felbamate clearance and volume of distribution (Vd) were as follows: Cl(L/hr) = 2.43 + 0.429*CDCR/240, Vd (L) = 51. The coefficient of variation of clearance was only about 12%, which may be indicative of the highly selective patient population. The clearance estimates are similar to those obtained in healthy volunteers and in patients receiving lower dosages of felbamate. The volume of distribution estimate, however, is slightly smaller than that reported previously. Valuable pharmacokinetic information can be obtained from the routine monitoring of serum concentrations during safety and efficacy trials.
Subject(s)
Anticonvulsants/pharmacokinetics , Propylene Glycols/pharmacokinetics , Adolescent , Adult , Body Weight/drug effects , Clinical Trials as Topic , Double-Blind Method , Felbamate , Female , Humans , Male , Metabolic Clearance Rate , Middle Aged , Models, Biological , Phenylcarbamates , Propylene Glycols/blood , Random Allocation , Risk Factors , Sex FactorsABSTRACT
Carbamazepine (CBZ) and carbamazepine 10,11 epoxide (CBZ-E) concentrations were measured during a safety and efficacy trial of progabide. The average CBZ and CBZ-E serum concentrations were calculated from serial measurements during placebo and active treatment periods. Significant decreases in CBZ and significant increases in CBZ-E were observed after the first dose of progabide, and these changes persisted during 3 months of active treatment. Ninety-five percent of the patients had increases in the epoxide/CBZ ratio at the end of 3 months of treatment. These changes are consistent with displacement of CBZ from protein binding sites and inhibition of CBZ-E metabolism induced by progabide and are analagous to the interaction between valproate and CBZ.
Subject(s)
Carbamazepine/metabolism , Epilepsy/metabolism , gamma-Aminobutyric Acid/analogs & derivatives , Adolescent , Adult , Carbamazepine/blood , Carbamazepine/therapeutic use , Double-Blind Method , Drug Interactions , Epilepsy/blood , Epilepsy/drug therapy , Female , Humans , Male , Placebos , gamma-Aminobutyric Acid/blood , gamma-Aminobutyric Acid/metabolism , gamma-Aminobutyric Acid/therapeutic useABSTRACT
Parenteral phenytoin solution (Dilantin) was given rectally three times a day for three days to two beagle dogs. This was well tolerated, with no evidence of mucosal irritation noted either on endoscopic nor on rectal mucosal biopsy. When given in this manner, phenytoin is absorbed to a limited degree in canines. Parenteral phenytoin solution can be safely administered rectally, despite a pH of 12. Further study in normal volunteers is needed to assess the usefulness of this route of administration in situations in which the oral and/or parenteral route of administration is unavailable.
Subject(s)
Intestinal Absorption , Phenytoin/pharmacokinetics , Administration, Rectal , Animals , Dogs , Phenytoin/administration & dosage , Phenytoin/toxicityABSTRACT
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.
