Factors in Variability of Serial Gabapentin Concentrations in Elderly Patients with Epilepsy.

OBJECTIVES: To characterize and quantify the variability of serial gabapentin concentrations in elderly patients with epilepsy. METHODS: This study included 83 patients (age ≥ 60 yrs) from an 18-center randomized double-blind double-dummy parallel study from the Veterans Affairs Cooperative 428 Study. All patients were taking 1500 mg/day gabapentin. Within-person coefficient of variation (CV) in gabapentin concentrations, measured weekly to bimonthly for up to 52 weeks, then quarterly, was computed. Impact of patient characteristics on gabapentin concentrations (linear mixed model) and CV (linear regression) were estimated. RESULTS: A total of 482 gabapentin concentration measurements were available for analysis. Gabapentin concentrations and intrapatient CVs ranged from 0.5 to 22.6 µg/ml (mean 7.9 µg/ml, standard deviation [SD] 4.1 µg/ml) and 2% to 79% (mean 27.9%, SD 15.3%), respectively, across all visits. Intrapatient CV was higher by 7.3% for those with a body mass index of ≥ 30 kg/m2 (coefficient = 7.3, p=0.04). CVs were on average 0.5% higher for each 1-unit higher CV in creatinine clearance (coefficient = 0.5, p=0.03) and 1.2% higher for each 1-hour longer mean time after dose (coefficient = 1.2, p=0.04). CONCLUSIONS: Substantial intrapatient variability in serial gabapentin concentration was noted in elderly patients with epilepsy. Creatinine clearance, time of sampling relative to dose, and obesity were found to be positively associated with variability.

Population pharmacokinetics of carbamazepine in elderly patients.

BACKGROUND: Carbamazepine is a commonly used antiepileptic drug in elderly patients. This study analyzed prospective data collected as part of a randomized, double-blinded trial of newly diagnosed epilepsy patients. The aims of this study were to determine the pharmacokinetic parameters and their variability of carbamazepine in elderly patients and to quantify the effect of covariates on these parameters. METHODS: Prospectively collected carbamazepine concentrations from 121 patients aged 60 years or older were used to develop a population pharmacokinetic model. Data were analyzed by a nonlinear mixed effects model (NONMEM). A 1-compartment model with first-order absorption and elimination was used to characterize the time course of carbamazepine concentration. Model evaluation and the predictive performance of the final model were assessed using the nonparametric bootstrap approach. RESULTS: The apparent clearance (CL/F) of carbamazepine in this community-dwelling elderly population was estimated to be 3.59 L/h with an interindividual variability of 18.1%. The CL/F increases 23% in patients comedicated with phenytoin. The volume of distribution (V/F) was estimated to be 102 L with an interindividual variability of 74.7%. CONCLUSIONS: Carbamazepine clearance was not associated with body weight or any parameterization of body size nor was age or race or any marker of hepatic or renal function in community dwelling elderly patients. Elderly patients on concurrent phenytoin therapy may require a smaller 23% higher dose on average, about half that reported for younger patients.

Population pharmacokinetics of lamotrigine in elderly patients.

Lamotrigine is being used more frequently in elderly patients. Dosing of lamotrigine in elderly patients is based largely on studies from younger adults and not evidence-based data from elderly patients. The goal of this study is to determine the pharmacokinetic parameters, such as clearance, and the factors that have a significant effect on these parameters to provide evidence-based information that can be used to dose elderly patients taking lamotrigine. Lamotrigine plasma concentrations from 148 elderly patients (aged 59-92 years) were used to develop a population pharmacokinetic model. Data were analyzed using NONMEM. Model evaluation was performed using the bootstrap approach and predictive check. The results showed that the blood urea nitrogen/serum creatinine ratio, weight, and phenytoin use significantly affect apparent clearance of lamotrigine. These results show that clinicians may need to take into account these covariates when dosing lamotrigine in this population.

Diagnosing epilepsy in the elderly.

Elderly individuals represent the fastest-growing segment of the US population. Seizures are common among elderly persons, and the etiology, clinical presentation, and prognosis of seizure disorders can often differ between elderly patients and younger individuals. However, published information regarding the diagnosis and management of epilepsy in elderly patients is scarce. Because a number of conditions that are common in elderly patients may resemble epilepsy, diagnosis can be challenging. Cardiovascular conditions, migraines, drug effects, infections, metabolic disturbances, sleep disorders, and psychiatric disorders are all associated with signs and symptoms that may often mimic epilepsy. New paradigms must be put into practice to establish an accurate diagnosis in the elderly patient; besides an initial evaluation, the patient history and an electroencephalogram should be obtained. Proper diagnosis is essential for proper treatment in the elderly patient.

Recruitment and retention in clinical trials of the elderly.

The recruitment and retention of elderly patients in clinical trials provide many challenges. Factors affecting recruitment, retention, and cost of recruitment are discussed in this chapter. Various methods are described that were used in recruiting and retaining elderly patients in a Veterans Affairs (VA) Administration clinical trial that compared two newer antiepileptic drugs (AEDs), gabapentin and lamotrigine, to the established standard AED, carbamazepine. Various strategies were utilized in the VA study to improve recruitment, and each strategy's overall effectiveness was monitored. Modification of the patient inclusion criteria, by lowering the age of eligibility from 65 to 60 years, added approximately 100 patients to the study. Replacing five trial sites that had poor recruiting records, extending the patient recruitment period by 3 months, and conducting site visits also improved patient recruitment rates, such that 82.4% of target enrollment (720 patients) was achieved. The main reasons that screened patients were excluded from the study included: lack of seizures during the prior 3 months, unstable medical condition, adequate treatment with an AED, satisfaction with current treatment, and the inability to give informed consent. Retaining patients for 1 year was the primary outcome measure of this trial, with 46.8% of patients completing the year. The most common reasons for early termination were study drug-related adverse events (43.0%) and lack of seizure control (10.8%). Comorbidities and polypharmacy occurred more frequently in the elderly, and both had a negative influence on recruitment and retention.