Susan E. Marino

Neuropsychological and behavioral effects of antiepilepsy drugs.

Antiepilepsy drugs work by decreasing neuronal irritability, which may also result in the non-desired side effect of decreased neuropsychological function. In addition to cognitive side effects, antiepilepsy drugs (AEDs) may be associated with behavioral effects which may range from irritability and hyperactivity to positive psychotropic effects on mood. There have been many new medications released since the 1990s, and although they tend to have more favorable side effect profiles compared to their older counterparts, there continues to be a risk of decreased cognitive function with the majority of these agents. The effects of in utero antiepilepsy drug exposure are increasingly being investigated, and differential drug risk is beginning to be described for both anatomic and cognitive outcomes. Patients with epilepsy undergoing neuropsychological evaluations are commonly on AEDs, and it is important for the clinician to recognize the potential contribution of AED therapy to neuropsychological profiles. The present article serves to provide an overview of our current understanding regarding the risks of antiepilepsy drug use for both cognitive and behavioral side effects.

Association of carbamazepine major metabolism and transport pathway gene polymorphisms and pharmacokinetics in patients with epilepsy

AIM The aim of this study was to evaluate the association of genetic variants in the major genes involved in carbamazepine (CBZ) metabolism and transport with its pharmacokinetics in epilepsy patients. MATERIALS & METHODS Twenty-five SNPs within seven CBZ pathway genes, namely CYP3A4, CYP3A5, EPHX1, NR1I2, UGT2B7, ABCB1 and ABCC2, were analyzed for association with CBZ pharmacokinetics in 90 epilepsy patients. RESULTS The CYP3A4*1B SNP was significantly associated with CBZ clearance. Significant association of EPHX1 SNPs was observed with greater carbamazepine-10,11-trans dihydrodiol:carbamazepine 10-11 epoxide ratios. Among drug transporters, ABCB1 and ABCC2 SNPs were significantly associated with altered CBZ clearance. CONCLUSION SNPs within CBZ pathway genes contribute to interpatient variation in CBZ pharmacokinetics and might contribute to pharmacoresistant epilepsy. Although our results need further clinical validation in a larger patient cohort, they indicate that genetic variation in CBZ pathway genes could influence its pharmacokinetics, and hence would have clinical significance.

Varying rates of Clostridium difficile-associated diarrhea at prevention epicenter hospitals

BACKGROUND Clostridium difficile-associated diarrhea (CDAD) causes substantial healthcare-associated morbidity. Unlike other common healthcare-associated pathogens, little comparative information is available about CDAD rates in hospitalized patients. OBJECTIVES To determine CDAD rates per 10,000 patient-days and per 1,000 hospital admissions at 7 geographically diverse tertiary-care centers from 2000 to 2003, and to survey participating centers on methods of CDAD surveillance and case definition. METHODS Each center provided specific information for the study period, including case numbers, patient-days, and hospital characteristics. Case definitions and laboratory diagnoses of healthcare-associated CDAD were determined by each institution. Within institutions, case definitions remained consistent during the study period. RESULTS Overall, mean annual case rates of CDAD were 12.1 per 10,000 patient-days (range, 3.1 to 25.1) and 7.4 per 1,000 hospital admissions (range, 3.1 to 13.1). No significant increases were observed in CDAD case rates during the 4-year interval, either at individual centers or in the Prevention Epicenter hospitals as a whole. Prevention Epicenter hospitals differed in their CDAD case definitions. Different case definitions used by the hospitals applied to a fixed data set resulted in a 30% difference in rates. No associations were identified between diagnostic test or case definition used and the relative rate of CDAD at a specific medical center. CONCLUSIONS Rates of CDAD vary widely at tertiary-care centers across the United States. No significant increases in case rates were identified. The varying clinical and laboratory approaches to diagnosis complicated comparisons between hospitals. To facilitate benchmarking and comparisons between institutions, we recommend development of a more standardized case definition.

Simplified surveillance for nosocomial bloodstream infections

OBJECTIVE To compare a surveillance definition of noso comial bloodstream infections requiring only microbiology data to the Centers for Disease Control and Preventions (CDC) current definition. SETTING Six teaching hospitals. METHODS We classified a representative sample of 73 positive blood cultures from six hospitals growing common skin contaminant isolates using a definition for bacteremia requiring only microbiology data and the CDC definition for primary bloodstream infection (National Nosocomial Infections Surveillance [NNIS] System review method). The classifications assigned during routine prospective surveillance also were noted, and the time required to classify isolates by the two methods was compared. RESULTS Among 65 blood cultures growing common skin contaminant isolates obtained from adults, the agreement rate between the microbiology data method and the NNIS review method was 91%. Agreement was significantly poorer for the eight blood cultures growing common skin contaminant isolates obtained from pediatric patients. The microbiology data method requires approximately 20 minutes less time per isolate than does routine surveillance. CONCLUSIONS A definition based on microbiology data alone yields the same result as the CDCs definition in the large majority of instances. It is more resource-efficient than the CDCs current definition.

Zonisamide discontinuation due to psychiatric and cognitive adverse events A case-control study

Objectives: Zonisamide (ZNS) is an antiepileptic drug (AED) that has been associated with psychiatric adverse events (PAE) and cognitive adverse events (CAE); controlled studies evaluating these adverse events are limited. Our objectives were to 1) determine the incidence of PAE and CAE leading to the discontinuation of ZNS and 2) identify risk factors for PAE and CAE associated with the discontinuation of ZNS. Methods: All patients exposed to ZNS at MINCEP Epilepsy Care between March 2000 and September 2008 were identified. Reasons for discontinuing ZNS were documented. Separate case-control studies were performed to identify risk factors associated with the discontinuation of ZNS due to PAE or CAE via multivariate binary logistic regression. Results: A total of 544 patients were exposed to ZNS during the study period. PAE and CAE were the most frequently identified reasons for terminating ZNS therapy. The incidence of PAE severe enough to be associated with the discontinuation of ZNS was 6.9%; the incidence of CAE was 5.8%. Factors associated with termination of ZNS therapy due to PAE were past psychiatric history (p = 0.005), symptomatic generalized epilepsy (p = 0.027), and lower maximum ZNS serum concentration (mean = 17.9 mg/L vs 34.7 mg/L, p < 0.001). Independent variables associated with discontinuing ZNS due to CAE were greater number of concomitant AEDs (p = 0.011) and lower maximum ZNS serum concentration (mean = 16.6 mg/L vs 30.6 mg/L, p = 0.002). Conclusions: We have identified clinically relevant risk factors associated with the discontinuation of ZNS. Our findings support the concept that selected patients are relatively more vulnerable to CNS adverse events when exposed to ZNS.

Steady-State Carbamazepine Pharmacokinetics Following Oral and Stable-Labeled Intravenous Administration in Epilepsy Patients: Effects of Race and Sex

Carbamazepine is a widely prescribed antiepileptic drug. Owing to the lack of an intravenous formulation, its absolute bioavailability, absolute clearance, and half‐life in patients at steady state have not been determined. We developed an intravenous, stable‐labeled (SL) formulation in order to characterize carbamazepine pharmacokinetics in patients. Ninety‐two patients received a 100‐mg infusion of SL‐carbamazepine as part of their morning dose. Blood samples were collected up to 96 hours after drug administration. Plasma drug concentrations were measured with liquid chromatography–mass spectrometry, and concentration–time data were analyzed using a noncompartmental approach. Absolute clearance (l/hr/kg) was significantly lower in men (0.039 ± 0.017) than in women (0.049 ± 0.018; P = 0.007) and in African Americans (0.039 ± 0.017) when compared with Caucasians (0.048 ± 0.018; P = 0.019). Half‐life was significantly longer in men than in women as well as in African Americans as compared with Caucasians. The absolute bioavailability was 0.78. Sex and racial differences in clearance may contribute to variable dosing requirements and clinical response.

Intravenous topiramate: comparison of pharmacokinetics and safety with the oral formulation in healthy volunteers.

Although oral topiramate (TPM) products are widely prescribed for migraines and epilepsy, injectable TPM is not available for human use. We have developed a solubilized TPM formulation using a cyclodextrin matrix, Captisol with the long‐term goal of evaluating its safety and efficacy in neonatal seizures. This study in healthy adult volunteers was performed as required by the U.S. Food and Drug Administration (FDA) to demonstrate the pharmacokinetics and safety prior to initiation of studies involving children. This study allowed investigation of absolute bioavailability, absolute clearance, and distribution volume of TPM, information that could not be obtained without using an intravenous TPM formulation.

Genetic and environmental correlates of topiramate-induced cognitive impairment

Topiramate is an antiepileptic drug that has marked treatment‐limiting side effects on specific aspects of cognitive performance in both patients and healthy volunteers. Because these severe side effects occur only in certain individuals, identifying genetic or environmental variables that influence cognitive response would be of great utility in determining whether to administer this drug to a patient. We gave an acute 100 mg oral dose of topiramate to 158 healthy volunteers and measured how the drug changed their performance on a diverse battery of cognitive tests. We found a wide range of responses to topiramate, and we demonstrated that not all tests in the battery were equally affected. There was no correlation between the effect of topiramate and either education level or baseline cognitive performance. Of interest, there was an up to 55‐fold variation in the topiramate plasma levels of the participants. Our genome‐wide association study (GWAS) of cognitive response did not reveal any genome‐wide significant associations; the study was powered to find variants explaining at least 25% of the variation in cognitive response. Combining the results of this GWAS with a retrospective study of cognitive complaints in 290 epilepsy patients who received topiramate as part of their treatment also did not result in a significant association. Our results support the need for additional genetic studies of topiramate that use larger sample sizes.

Characterization of the Time Course of Carbamazepine Deinduction by an Enzyme Turnover Model

AbstractBackground and objective: Carbamazepine is a potent inducer of drug metabolizing enzymes, which results in a number of clinically significant drug-drug interactions. Deinduction occurs when long-term carbamazepine therapy is discontinued. The goal of this study was to develop a population pharmacokinetic model to describe the time course of carbamazepine deinduction. Patients and methods: Stable-labelled carbamazepine was administered intravenously on three occasions during the deinduction period to 15 patients with epilepsy for whom carbamazepine therapy was being discontinued. Data were analysed using a nonlinear mixed-effects model (NONMEM®). An enzyme turnover model consisting of a one-compartment model linked with a hypothetical enzyme compartment was applied to characterize the time course of carbamazepine deinduction. Model evaluation was performed using the bootstrap approach and a visual predictive check. Results: In the final model, the deinduction process was accomplished by decreasing the rate of enzyme synthesis, resulting in a decrease in the relative amount of enzymes. The estimated rate constant for enzyme degradation was 0.00805 h−1, corresponding to a half-life of the combined enzymes of 86.1 hours (3.6 days). Conclusion: An enzyme turnover model adequately characterized the experimental data. Based on the predicted enzyme half-life from the final model, the deinduction process should be completed within 2 weeks after carbamazepine therapy is terminated.

Factors affecting Antiepileptic Drug Pharmacokinetics in Community-Dwelling Elderly

Because aging is associated with changes in physiological processes, it is widely believed that antiepileptic drug pharmacodynamics and pharmacokinetics in elderly patients differ from those in younger adults. In order to better characterize these differences, this chapter reports on preliminary results from an investigation of the effect of age on steady-state phenytoin (PHT) and carbamazepine (CBZ) pharmacokinetics. Parenteral formulations of stable-labeled PHT, fosphenytoin (FOS), and CBZ were administered to elderly (> or =65 years of age) and adult (18-64 years of age) patients on maintenance regimens of PHT or CBZ; a labeled 100-mg dose was infused over 10 min, then the remainder of the patients AED dose was administered as unlabeled drug. Blood samples were collected just before administration of the labeled drug and for up to 192 h afterward. Samples were then assayed for the concentrations of labeled and unlabeled drug. Preliminary results from 60 patients on PHT therapy (41 elderly, mean age 76 years; 19 younger adults, mean age 41 years) indicate that PHT bioavailability did not differ between the two age groups; however, absorption and elimination half-lives were more variable in the elderly patients. The elimination half-life for the entire patient population was approximately twofold longer than the value reported in the product labeling (40-50 h vs 22 h). Preliminary results from 67 patients on CBZ therapy (14 elderly, mean age 70 years; 53 younger adults, mean age 41 years) showed no apparent difference between elderly and adult patients in any parameter; however, the mean CBZ elimination half-life for the combined groups (21 h) was longer than previous estimates. These results indicate that the effect of age on CBZ and PHT absorption may result in greater variability in plasma concentrations in elderly patients, whereas the effect on half-life is modest.