Variability of total phenytoin serum concentrations within elderly nursing home residents.

BACKGROUND: Approximately 6% of all elderly nursing home residents receive phenytoin. Phenytoin concentrations are often measured to guide therapy. OBJECTIVE: To evaluate the intraresident variability among multiple measurements of total phenytoin serum concentrations in nursing home residents. METHODS: This was an observational study of 56 elderly (>or=65 years) nursing home residents from 32 nursing homes who had at least 3 phenytoin concentrations measured while on the same dose of phenytoin for at least 4 weeks and who were not taking any interfering concomitant medications. These were a subset of 387 elderly nursing home residents from 112 nursing homes across the United States who had total phenytoin concentration measurements between June 1998 and December 2000. RESULTS: The mean age was 80.1 years (range, 65 to 100 years) and 58.9% were women. The mean daily dose of phenytoin per resident was 4.9 +/- 1.5 mg/kg. Total phenytoin concentrations within an elderly nursing home resident varied as much as two- to threefold, even though there was no change in dose. The person with the smallest variability had a minimum concentration of 10.0 micro g/mL and a maximum of 10.4 micro g/mL. The person with the largest variability had a minimum concentration of 9.7 micro g/mL and a maximum of 28.8 micro g/mL. CONCLUSIONS: There is considerable variability in the total phenytoin concentrations in the elderly nursing home resident and measurement of a single total phenytoin concentration should not be used to guide treatment.

Management of seizures in brain tumor patients at the end of life.

Few data exist on the management of seizures in brain tumor patients near the end of life. This article provides information on the epidemiology and phenomenology of seizures, as well as on differential diagnostic considerations. Based largely on empirical data from the pediatric epilepsy literature, guidelines for management of seizures near the end of life are given, with emphasis on the use of rectal antiepileptic drugs.

Population pharmacokinetics of carbamazepine in adults with epilepsy.

STUDY OBJECTIVE: To conduct a population pharmacokinetic analysis of carbamazepine (CBZ). DESIGN: Retrospective chart review. SETTING: Ambulatory neurology clinics at three medical centers. PATIENTS: Patients diagnosed with epilepsy from 1991-1995. The index set included 829 adults receiving CBZ. A separate validation set consisted of 50 patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Final regression equations were apparent oral clearance (Cl/F) (L/hr) = (0.0134 x TBW + 3.58), x 1.42 if receiving phenytoin only; x 1.17 if receiving phenobarbital or felbamate; x 1.62 if receiving phenytoin and phenobarbital or felbamate; x 0.749 if age > or = 70 years; apparent volume of distribution (Vd/F) (L) = 1.97 x total body weight; absorption rate constant [hr(-1)] = 0.441. Interindividual variability in Cl/F and Vd/F was 26% and 82%, respectively. Residual variability was 1.8 mg/L. Predictive performance analysis of the validation set provided a mean prediction error of 0.6 mg/L and median absolute error of 2.4 mg/L. CONCLUSIONS: These routinely collected data provided quantitative estimates of changes in CBZ Cl/F due to comedication and an age-related decrease in Cl/F The derived regression equations reasonably predicted concentrations in a separate validation set.

A randomized double-blind study of carbamazepine in the treatment of cocaine abuse.

A 12-week, randomized, double-blind, placebo-controlled, fixed-dose outpatient study of carbamazepine (400 mg and 800 mg) in the treatment of cocaine dependence was performed. Data were analyzed with respect to both treatment condition and carbamazepine serum levels. Outcome variables included subject retention, cocaine urinalysis, self-reported cocaine use, cocaine craving, patient and clinical global impressions, the Drug Impairment Rating Scale for Cocaine, and side effects. Compared with placebo, the 400 mg treatment condition exhibited a greater decrease in the rate of positive cocaine urinalyses and a reduction in intensity and duration of craving over the course of the study. Higher serum carbamazepine levels were associated with a lower rate of positive cocaine urinalysis, fewer days of self-reported cocaine use, briefer craving episodes, and greater subject interval retention. The clinical and methodologic implications of these findings and of the study design are discussed.

Current developments in neurology, Part II: Advances in the pharmacotherapy of Alzheimer disease, Parkinson's disease, and stroke.

Disorders of the central nervous system provide innumerable challenges to the clinician. Often the underlying pathophysiology is not completely understood, thus preventing the design of treatment strategies aimed at correcting the underlying process. In this decade of the brain, basic science research combined with difficult but necessary clinical trials may answer some of these seemingly over-whelming questions for these devastating illnesses.

Current developments in neurology, Part I: Advances in the pharmacotherapy of headache, epilepsy, and multiple sclerosis.

When caring for patients with disorders of the central nervous system such as migraine headaches, epilepsy, or MS, clinicians are faced with increasingly complex pharmacotherapeutic options. Pharmacotherapeutic strategies directed toward prevention, reversal, or cure of these diseases are hampered by an incomplete understanding of the underlying pathophysiology. In this decade of the brain, basic science research combined with difficult but necessary clinical trials may answer some seemingly overwhelming questions for these devastating illnesses.

Pharmacokinetics of tiagabine as add-on therapy in patients taking enzyme-inducing antiepilepsy drugs.

The effect of hepatic enzyme-inducing antiepilepsy drugs (AEDs) on the clinical pharmacokinetics of tiagabine, a new AED, was studied in the steady-state condition. Patients with epilepsy entered this two-day study on a previously stable regimen of one to three enzyme-inducing drugs (phenytoin, phenobarbital, carbamazepine, and/or primidone) and tiagabine.HCl (24, 40, 56, or 80 mg daily). Patients were confined on both days, and serial blood samples were collected. Plasma tiagabine concentrations were determined by high-performance liquid chromatography; pharmacokinetic parameters were calculated using noncompartmental methods. Tiagabine pharmacokinetics were linear at all doses, as substantiated by the lack of significant differences among groups for dose-adjusted Cmax, Cmin, and AUC0-6. Some diurnal variation occurred, as evidenced by a statistically significant time effect for dose-adjusted AUC0-6. The effect was small, however, and possibly not clinically relevant. The harmonic mean half-lives of 3.8 to 4.9 h were remarkably constant across dosages and shorter than those of historical control subjects not taking enzyme-inducing AEDs suggesting that epilepsy patients not taking enzyme-inducing AEDs may require lower tiagabine.HCl doses to achieve the plasma levels observed in patients taking these drugs.

Predicting unbound phenytoin concentrations in patients receiving valproic acid: a comparison of two prediction methods.

OBJECTIVE: To compare the predictive performance of 2 equations that estimate unbound (free) phenytoin plasma concentrations when valproic acid (VPA) and phenytoin are administered concurrently. DESIGN: Eighty-eight adults receiving VPA and phenytoin concurrently were included in the study. Steady-state plasma concentration measurements of total phenytoin, total VPA, and unbound phenytoin were collected prospectively in the inpatient group (group 1) and retrospectively in the outpatient group (group 2). Using the equations developed by Haidukewych and May, unbound phenytoin concentrations were calculated. The mean predicted unbound phenytoin concentrations then were compared with mean actual unbound phenytoin concentrations measured in the laboratory. Identical assays were performed to measure unbound phenytoin, total phenytoin, and VPA from each patient group. SETTING/PARTICIPANTS: Antiepileptic drug concentration measurements were collected from 43 inpatients (mean age 34.8 y) from the epilepsy unit at Abbott Northwestern Hospital and 45 outpatients (mean age 37.3 y) at the MINCEP Epilepsy Care clinic, Minneapolis, MN. MAIN OUTCOME MEASURES: Mean prediction error (MPE) and mean squared error (MSE) were calculated to determine which equation was the least biased and most precise in predicting unbound phenytoin when total VPA and phenytoin concentrations are known. Linear regression of predicted unbound phenytoin on measured unbound phenytoin values determined the correlation coefficients (r). A paired Student's t-test also was performed comparing mean predicted unbound phenytoin concentration with mean actual unbound phenytoin concentrations in both groups. RESULTS: The MPE from May's equation was -0.49 and -0.45 for groups 1 and 2, respectively; using the Haidukewych equation, MPE was -0.02 and 0.08 for groups 1 and 2, respectively. The MSE using May's equation was 0.34 for both groups. Using the Haidukewych equation, group 1 MSE was 0.07, and for group 2, 0.12. Correlation coefficients were more than 0.91 (p < 0.001) from each equation in both patient groups. In group 1, mean actual unbound phenytoin concentration was 2.02 micrograms/mL; May's equation predicted 1.52 micrograms/mL (p < 0.001) and the Haidukewych equation predicted 2.00 micrograms/mL (p = 0.64). In group 2, mean actual unbound phenytoin concentration was 2.10 micrograms/mL; May's equation predicted 1.65 micrograms/mL (p < 0.001) and the Haidukewych equation predicted 2.18 micrograms/mL (p = 0.11). CONCLUSIONS: Haidukewych's equation predicts unbound phenytoin concentrations with the least bias and most precision with statistical significance. May's equation consistently underpredicted unbound phenytoin concentrations. Because unbound phenytoin fraction is not constant (and usually more than the expected 10%) in patients comedicated with VPA, unbound phenytoin concentrations cannot be predicted even though total VPA and phenytoin concentrations are known. If unbound phenytoin concentrations cannot be readily measured, Haidukewych's equation is a reliable predictor of unbound phenytoin concentrations.

Involuntary movement disorders associated with felbamate.

Two children developed involuntary movements while taking felbamate as an adjunct to their antiepileptic regimen. One exhibited choreoathetosis and the other an acute dystonic reaction. In both children the symptoms resolved with no recurrence after felbamate discontinuance.

Neuropharmacology and drug interactions in clinical practice.

Absorption, distribution, and clearance are key pharmacokinetic principles. These parameters can be highly variable among patients and among compounds, and are factors that must be considered in the wide variability in response to medications. Current antiepileptic drugs (AEDs) present many challenges in their administration. However, understanding and utilizing pharmacokinetic principles can assist the clinician in the appropriate optimization of AEDs.

The effect of felbamate on valproic acid disposition.

INTRODUCTION: Felbamate is a new antiepileptic drug approved for partial and secondarily generalized seizures. DESIGN: Subjects with epilepsy (three men and seven women; age range, 20 to 39 years; weight range, 53 to 88 kg) who were previously stabilized with valproic acid, 9.5 to 31.7 mg/kg/day, received both 600 and 1200 mg felbamate twice a day in an open-label, randomized, crossover study. RESULTS: Coadministration of 1200 or 2400 mg felbamate increased the mean valproic acid area under the curve (from 802.2 to 1025.4 and 1235.9 mg/hr/ml, respectively), peak concentrations (from 86.1 to 115.1 and 133.4 mg/ml, respectively), and average steady-state concentrations (from 66.9 to 85.5 and 103.0 mg/ml, respectively). No changes were observed in valproic acid time to peak concentration or protein binding. Average steady-state felbamate concentrations were 34.7 mg/ml for 600 mg administered twice daily and 61.2 mg/ml for 1200 mg administered twice daily. CONCLUSION: When felbamate is added to a regimen of valproic acid, valproic acid doses may require reduction because coadministration of felbamate decreased steady-state valproic acid clearance (28% and 54%, respectively; p < 0.01).

Pharmacokinetics and interactions of antiepileptic drugs.

The pharmacokinetics and drug interactions of the agents of choice for treating epilepsy are examined. For effective treatment of epilepsy, target serum antiepileptic drug (AED) concentrations must be reached quickly and maintained. AEDs for acute treatment are formulated for quick absorption, while maintenance therapy is usually administered orally. AEDs have narrow therapeutic ranges. Individual differences in response necessitate that optimization of each regimen be based on the individual patient's clinical condition. Agents of choice for acute treatment are diazepam, lorazepam, midazolam, valproic acid, and phenytoin. Phenytoin, carbamazepine, valproic acid, phenobarbital, and benzodiazepines are typically used in maintenance therapy. The absorption, distribution, and metabolism or excretion characteristics of AEDs must be taken into account in optimizing the therapeutic regimen. Different AED formulations can have different absorption profiles. Drug interactions can affect all aspects of the pharmacokinetics of AEDs and should be considered when agents are removed from a regimen, as well as when they are added. Various factors can threaten seizure control and cause unexpected toxicity. Such problems can be avoided or controlled if the pharmacist is aware of the pharmacokinetics and potential interactions of the AEDs involved.

Felbamate.

OBJECTIVE: To provide an up-to-date review of the current literature on felbamate (FBM) and its use as an antiepileptic medication (AEM). DATA SOURCES: All published literature (manuscripts and abstracts) on FBM was reviewed. The initial bibliography (up to September 1992) was provided by the manufacturer (Carter-Wallace Laboratories); subsequent literature was obtained from American Epilepsy Society presentations in December 1992 and manuscripts published up to January 1993. STUDY SELECTION/DATA EXTRACTION: All pertinent literature was reviewed. Information from the publications was abstracted and organized by the author. DATA SYNTHESIS: FBM is effective in complex partial seizures either as monotherapy or as an adjunct in patients receiving other AEMs. In addition, it has shown efficacy in some seizures associated with the Lennox-Gastaut syndrome. Adverse effects appear to be mild. When FBM is given as monotherapy, the primary adverse effects are insomnia and weight loss. Patients receiving multiple AEMs may have increased adverse effects. CONCLUSIONS: FBM appears to be an effective new AEM. Additional studies as to its role in newly diagnosed and pregnant patients are needed. Pharmacokinetic studies in children, patients with renal failure, and patients on nonepilepsy drugs also are needed.

Advances in pharmacotherapy: recent developments in the treatment of epilepsy.

Epilepsy is a disorder of the central nervous system in which the clinical symptoms are recurrent seizures. An increased understanding of the underlying mechanism of seizures and more definitive diagnostic procedures have improved the care of the patient with epilepsy. An improved classification of various seizure types, including specific epilepsy syndromes has helped optimize use of the standard antiepileptic drugs. Research on the mechanism of seizures has led to new antiepileptic drugs. More definitive diagnostic procedures have led to more accurate identification of patients likely to benefit from epilepsy surgery. This review focuses on these areas.

Effect of felbamate on carbamazepine and its major metabolites.

Felbamate is a novel antiepileptic drug that is now available in the United States. During a previous double-blind, crossover, placebo-controlled safety and efficacy study, concomitant phenytoin concentrations increased, whereas carbamazepine concentrations decreased. We evaluated the effect of felbamate on the concentrations of carbamazepine and of its major metabolites, carbamazepine-10,11-epoxide (epoxide) and carbamazepine-trans-10,11-diol (diol) in 26 patients. After the addition of felbamate, mean epoxide concentrations increased from 1.8 micrograms/ml during placebo or baseline periods to 2.4 micrograms/ml during felbamate treatment (p < 0.05); there was no significant change in diol concentrations. Mean carbamazepine concentrations decreased from 7.5 micrograms/ml during placebo treatment to 6.1 micrograms/ml during felbamate treatment (p < 0.05). Mechanisms that could account for the increase in steady-state epoxide concentrations are induction of carbamazepine metabolism to epoxide, inhibition of the conversion of epoxide to diol, or both.

Felbamate for partial seizures: results of a controlled clinical trial.

Felbamate (2-phenyl-1,3-propanediol dicarbamate) has a favorable preclinical profile in animal models of epilepsy. We present the results of a double-blind, randomized, placebo-controlled clinical trial in patients with partial seizures. Criteria for entry included a requirement for four or more partial seizures per month despite concomitant therapeutic blood levels of phenytoin and carbamazepine. Fifty-six patients (mean age, 31.4 years; 32 men, 24 women) completed the trial. The mean seizure frequencies for the 8-week periods analyzed were felbamate = 34.9, placebo = 40.2. Felbamate was statistically superior to placebo in seizure reduction, percent seizure reduction, and truncated percent seizure reduction. The mean felbamate dosage was 2,300 mg/d. Plasma felbamate concentrations ranged from 18.4 to 51.9 mg/l, mean = 32.5 mg/l. Adverse experiences during felbamate therapy were minor and consisted primarily of nausea and CNS effects. This trial indicates that felbamate is safe and effective in the treatment of comedicated patients with severely refractory epilepsy.

Antiepileptic medications in development.

Recently, there has been an increase in the research devoted to the study of investigational antiepileptic medications. This has led to extensive clinical trials of several new compounds. This review focuses on four of these antiepileptic medications in development: felbamate, gabapentin, lamotrigine, and vigabatrin. Each has a unique mechanism of action and great potential for the treatment of epilepsy.