Overview of acute seizure management in US nursing homes.

INTRODUCTION: Residents in NH are more likely to be diagnosed with epilepsy or seizures, which are associated with higher mortality and complicate care. This setting provides unique challenges in the treatment of seizures however, little is known about current management practices in NH. Most studies in the literature concentrate on the use of antiseizure medications (ASMs) but little is known about the management of the acute seizure and clinical guidance is needed to ensure the safety of this vulnerable population. The objective of this study was to survey current practices, identifying knowledge deficits and inform future educational endeavors, including acute seizure action plans (ASAPs). METHODS: A survey was developed pertaining to a broad spectrum of clinical aspects in the management of acute seizures in NH, distinguishing first time seizures from those in the setting of a known seizure disorder. It was sent to NH medical directors throughout the US and data was gathered from those who had at least one new case of new onset/epilepsy in the last 3 years. RESULTS: Ninety-one NH directors responded with 52 % having a seizure protocol. Nurses are responsible in the majority of cases for protocol activation. Regardless of the patient's seizure history, rescue medications are given in the majority of cases, oral benzodiazepines, followed by intravenous and then rectal benzodiazepines. Newer intranasal and intramuscular formulations of benzodiazepines were less frequently prescribed. The most commonly prescribed ASM is levetiracetam, followed by lamotrigine, valproic acid and phenytoin. Staff training and in-service education occur infrequently. Respondents thought no-cost seizure education would be highly beneficial. CONCLUSIONS AND IMPLICATIONS: Only approximately half of NH have protocols for the acute management of seizures. Rescue medications are given regardless of seizure history and often older ASMs are used for long-term management. Our study highlights areas of knowledge deficits and treatment areas for improvement, identifying the need and potential for ASAPs in NHs.

Medical Cannabis Received by Patients According to Qualifying Condition in a US State Cannabis Program: Product Choice, Dosing, and Age-Related Trends.

Background: Little is known about the distribution of cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) to patients participating in state medical cannabis programs. The Minnesota cannabis program requires third-party testing of products with limited formulations of cannabis for distribution to patients. Objective: To characterize the distribution of cannabis products, their CBD/THC content, and dosing among patients with qualifying conditions. Methods: This is a retrospective analysis of ∼50% of registered users receiving medical cannabis in Minnesota (June 16, 2016, to November 15, 2019). Data included formulation, CBD/THC prescribed doses, and qualifying conditions. The primary end points were calculated using daily dose and duration of use. Comparisons were made for CBD and THC total daily dose dispensed, patient age, and approved product. Nonparametric statistical tests were used (significance was set at p < 0.05). Results: A total of 11,520 patients were listed with 1 qualifying condition. The most common condition was intractable pain (60.0%). Median dispensation duration varied from 53 days (cancer) to 322 days (muscle spasms). Most (≥62.8%) patients across all qualifying conditions received both CBD and THC. Median THC dose was lower in older (≥65 years) compared with younger adults with intractable pain (p < 0.0001) and cancer patients (p = 0.0152), and the same pattern was found CBD dose with seizure (p = 0.0498) patients. For commercial products with Food and Drug Administration indications, the median CBD total daily dose was 86.9% lower than the recommended doses for patients with seizures (Epidiolex: Jazz Pharmaceuticals, Palo Alto CA) and median THC total daily dose was 65.3% (Syndros: Benuvia Manufacturing, Round Rock, TX) or 79.3% lower (Marinol: Banner Pharmacaps, Inc., High Point, NC) for cancer patients. Conclusions: A majority of patients received products containing both CBD and THC. Dosages varied by age group and were lower than recommended for conditions with Food and Drug Administration-approved products. Complex pharmacokinetics of THC and CBD, possible age-related changes in physiology, unknown efficacy, and potential for drug interactions all increase the need for monitoring of patients receiving cannabis products. (Curr Ther Res Clin Exp. 2023; 84:XXX-XXX).

New Onset (Incidence) of Epilepsy and Seizures in Nursing Home Residents.

OBJECTIVE: The point prevalence of epilepsy is high in nursing homes (NH), but the incidence of epilepsy after admission is unknown. This study was done to determine the incidence of epilepsy/seizure (epi/sz) comorbid with other conditions in older adult NH residents. DESIGN: Retrospective evaluation of Minimum Data Set records to identify new onset epi/sz in NH residents. SETTING AND PARTICIPANTS: Five cross-sectional cohorts of all residents in any Medicare/Medicaid certified NH in the United States on July 15 of each year 2003-2007. MEASURES: Epi/sz was identified by International Classification of Diseases, Ninth Revision codes (345.xx or 780.39) or check box on the Minimum Data Set. Those with no such code on admission and with 1 to 3 plus years of follow-up (n = 3,609,422) were followed through 2007 or end of stay. RESULTS: Overall incidence of epi/sz was 16.42/1000 patient years (PY). Incidence was highest in the first year after admission and declined thereafter. There were more women (n = 2,523,951) than men (n = 1,089,631), but men had a higher incidence (21.17/1000PY) compared with women (14.81/1000PY). Although the 65‒74 years of age cohort included fewer residents (n = 594,722) compared with the age 85 years + cohort (n = 1,520,167), the younger residents had the highest incidence (28.53/1000 PY) compared with the oldest, 10.22/1000 PY for the age 85+ years cohort. The highest incidences were among those with brain tumor (122.55/1000PY), followed by head injury (45.66/1000PY). Overall, 714,340 had a diagnosis of stroke, and incidence was 27.52/1000PY. Those with none of selected risk factors had an overall incidence of 12.45/1000PY. CONCLUSIONS AND IMPLICATIONS: The incidence of epi/sz in older individuals after admission to a NH is high. There is a need to develop practice approaches to best manage this large cohort. There does not appear to be a uniform approach to managing new onset epilepsy in NHs at this time. Studies to develop evidence for practice guidelines are needed.

Intravenous and Intramuscular Allopregnanolone for Early Treatment of Status Epilepticus: Pharmacokinetics, Pharmacodynamics, and Safety in Dogs.

Allopregnanolone (ALLO) is a neurosteroid that modulates synaptic and extrasynaptic GABAA receptors. We hypothesize that ALLO may be useful as first-line treatment of status epilepticus (SE). Our objectives were to (1) characterize ALLO pharmacokinetics-pharmacodynamics PK-PD after intravenous (IV) and intramuscular (IM) administration and (2) compare IV and IM ALLO safety and tolerability. Three healthy dogs and two with a history of epilepsy were used. Single ALLO IV doses ranging from 1-6 mg/kg were infused over 5 minutes or injected IM. Blood samples, vital signs, and sedation assessment were collected up to 8 hours postdose. Intracranial EEG (iEEG) was continuously recorded in one dog. IV ALLO exhibited dose-proportional increases in exposure, which were associated with an increase in absolute power spectral density in all iEEG frequency bands. This relationship was best described by an indirect link PK-PD model where concentration-response was described by a sigmoidal maximum response (Emax) equation. Adverse events included site injection pain with higher IM volumes and ataxia and sedation associated with higher doses. IM administration exhibited incomplete absorption and volume-dependent bioavailability. Robust iEEG changes after IM administration were not observed. Based on PK-PD simulations, a 2 mg/kg dose infused over 5 minutes is predicted to achieve plasma concentrations above the EC50, but below those associated with heavy sedation. This study demonstrates that ALLO is safe and well tolerated when administered at 1-4 mg/kg IV and up to 2 mg/kg IM. The rapid onset of effect after IV infusion suggests that ALLO may be useful in the early treatment of SE. SIGNIFICANCE STATEMENT: The characterization of the pharmacokinetics and pharmacodynamics of allopregnanolone is essential in order to design clinical studies evaluating its effectiveness as an early treatment for status epilepticus in dogs and people. This study has proposed a target dose/therapeutic range for a clinical trial in canine status epilepticus.

An association between resting state EEG parameters and the severity of topiramate-related cognitive impairment.

INTRODUCTION: Many commonly prescribed drugs cause cognitive deficits. We investigated whether parameters of the resting-state electroencephalogram (rsEEG) are related to the severity of cognitive impairments associated with administration of the antiseizure drug topiramate (TPM) and the benzodiazepine lorazepam (LZP). METHODS: We conducted a double-blind, randomized, placebo-controlled crossover study. After a baseline visit, subjects completed three sessions at which they received either a single dose of TPM, LZP, or placebo. Four-hours after drug administration and at baseline, subjects completed a working memory (WM) task after their rsEEG was recorded. After quantifying drug-related behavioral (WM accuracy (ACC)/reaction time (RT)) and electrophysiological (alpha, theta, beta (1,2), gamma power) change for each subject, we constructed drug-specific mixed effects models of change for each WM and EEG measure. Regression models were constructed to characterize the relationship between baseline rsEEG measures and drug-related performance changes. RESULTS: Linear mixed effects models showed theta power increases in response to TPM administration. The results of the regression models revealed a number of robust relationships between baseline rsEEG parameters and TPM-related, but not LZP-related, WM impairment. CONCLUSIONS: We showed for the first time that parameters of the rsEEG are associated with the severity of TPM-related WM deficits; this suggests that rsEEG measures may have novel clinical applications in the future.

Severity of Topiramate-Related Working Memory Impairment Is Modulated by Plasma Concentration and Working Memory Capacity.

Drug side effects that impair cognition can lead to diminished quality of life and discontinuation of therapy. Topiramate is an antiepileptic drug that elicits cognitive deficits more frequently than other antiepileptic drugs, impairing multiple cognitive domains including language, attention, and memory. Although up to 40% of individuals taking topiramate may experience cognitive deficits, we are currently unable to predict which individuals will be most severely affected before administration. The objective of this study was to show the contributions of plasma concentration and working memory capacity in determining the severity of an individual's topiramate-related cognitive impairment. Subjects were enrolled in a double-blind, placebo-controlled crossover study during which they received a single dose of either 100, 150, or 200 mg topiramate. Working memory function was assessed using a modified Sternberg working memory task with 3 memory loads administered 4 hours after dosing. After adjustment for differences in working memory capacity, each 1 µg/mL of topiramate plasma concentration was associated with a 3.6% decrease in accuracy for all memory loads. Placebo effects occurred as a function of working memory capacity, with individuals with high working memory capacity experiencing less severe placebo-related impairment compared with those with low working memory capacity. Our results demonstrate that severity of topiramate-related cognitive deficits occurs as a function of both drug exposure and baseline cognitive function. By identifying patient- and exposure-related characteristics that modulate the severity of cognitive side effects, topiramate dosing strategies may be individually tailored in the future to prevent unwanted cognitive impairment.

Food effect on pharmacokinetics of cannabidiol oral capsules in adult patients with refractory epilepsy.

OBJECTIVE: To evaluate the pharmacokinetics of a purified oral cannabidiol (CBD) capsule administered with and without food in adults with refractory epilepsy. METHODS: Adult patients who were prescribed CBD for seizures, had localization-related intractable epilepsy with ≥4 seizures per month, and qualified for Minnesota cannabis were enrolled. A single dose of 99% pure CBD capsules was taken under both fasting (no breakfast) and fed (high fat 840-860 calorie) conditions. Blood sampling for CBD plasma concentrations was performed under each condition between 0 and 72 hours post-dose and measured by a validated liquid chormatography-mass spectometry assay. CBD pharmacokinetic profiles including maximum concentration (Cmax ), area-under-the-curve from zero to infinity (AUC0-∞ ), and time-to-maximum concentration (Tmax ) were calculated. The confidence intervals (CIs) for log-transformed Cmax and AUC0-∞ ratios between fed and fasting states were calculated. Seizure and adverse events information was collected. RESULTS: Eight patients completed the study. On average Cmax was 14 times and AUC0-∞ 4 times higher in the fed state. The 90% CI for the ratio of fed versus fast conditions for Cmax and AUC0-∞ were 7.47-31.86 and 3.42-7.82, respectively. No sequence or period effect for Cmax and AUC0-∞ was observed. No adverse events were reported. SIGNIFICANCE: Administering CBD as a capsule rather than a liquid allows for more precise determination of pharmacokinetics parameters and is more representative of CBD swallowed products. The fat content of a meal can lead to significant increases in Cmax and AUC0-∞ and can account for variability in bioavailability and overall drug exposure within patients with oral products.

Simultaneous Quantification of 13 Cannabinoids and Metabolites in Human Plasma by Liquid Chromatography Tandem Mass Spectrometry in Adult Epilepsy Patients.

BACKGROUND: A sensitive, robust method was developed and validated to quantitate 13 major natural cannabinoid parent and metabolite compounds in human plasma at or below 0.5 ng/mL. METHODS: A liquid chromatography tandem mass spectrometry method was developed and validated to measure 13 cannabinoid compounds: cannabidiol (CBD), cannabidiolic acid, cannabidivarin, cannabinol, cannabigerol, cannabigerolic acid, cannabichromene, Δ-tetrahydocannabinol (THC), Δ-tetrahydrocannabinolic acid A (THCA), Δ-tetrahydrocannabivarin (THCV), 11-hydroxy-Δ-tetrahydrocannbinol (11-OH-THC), 11-nor-9-carboxy-Δ-tetrahydrocannbinol (THC-COOH), and 11-nor-9-carboxy-Δ-tetrahydrocannabinol glucuronide (THC-COOH-glu). Samples (200 µL) were extracted through protein precipitation and separated with a Kinetex EVO C18 column and a 65%-95% gradient of methanol and 0.2% ammonium hydroxide/H2O at a flow rate of 0.4 mL/min. Samples were obtained from patients with epilepsy receiving cannabis for the treatment of seizures. RESULTS: The extracted lower limit of quantification was 0.05 ng/mL for CBD, cannabidivarin, cannabinol, and 11-OH-THC; 0.10 ng/mL for cannabidiolic acid, cannabigerol, cannabichromene, cannabigerolic acid, THC, THCA, and THCV; and 0.50 ng/mL for THC-COOH and THC-COOH-glu. Mean quality control intraday accuracy and precision for all analytes ranged 96.5%-104% and 2.7%-4.9%, respectively, whereas interday accuracy and precision ranged 98%-103.3% and 0.2%-3.6%, respectively. An absolute matrix effect was observed for some analytes, however, with minimal relative matrix effect. Lack of nonspecific drug binding to extraction glass and plasticware was verified. Patient CBD levels ranged from 0.135 to 11.13 ng/mL. CONCLUSIONS: The validated method met FDA guidelines for bioanalytical assays precision and accuracy criteria. The assay reliably confirmed the use of particular medical cannabis formulations in patient samples as well as reliably measured low CBD concentrations from single-dose CBD exposure.

Iron supplements in nursing home patients associated with reduced carbamazepine absorption.

Persons in nursing homes receive a number of medications that may interfere with the pharmacokinetics of carbamazepine (CBZ). The aim of our study was to determine factors that may affect the pharmacokinetics of CBZ in elderly nursing home patients. METHODS: CBZ concentration data collected from 60 nursing homes across the US were evaluated. Inclusion criteria included residency in a nursing home for at least 2 months, age 65 years or older, a stable dosing regimen of CBZ for at least 4 weeks (considered steady state), available CBZ concentration, and complete information regarding all co-medications. Using a nonlinear mixed-effects model, the data were adequately described by a one-compartment model with first-order absorption and elimination. Goodness-of-fit plots, plausibility of parameter estimates, visual predictive check and nonparametric bootstrap were used to evaluate the models. MAIN FINDINGS: The final data set consisted of 345 CBZ concentrations from 99 subjects (38 males, 61 females). The population estimate of apparent clearance (CL/F) for a 70-kg person was 3.69 L/hr (RSE 6.9%). Residents were receiving either immediate (93.9%) or extended release (6.1%) formulation of CBZ and the Ka of each formulation was fixed to literature values. Age, sex, and co-medications had no effect on CL/F and apparent volume of distribution. Iron supplementation, which was taken by 16% of the residents, resulted in a 33% decrease in bioavailability (p < 0.001). No other medications were found to have an effect. CONCLUSIONS: Results from this pharmacokinetic study indicate that use of iron supplementation is associated with a reduction in absorption of CBZ and may need to be considered when dosing CBZ in patients taking iron supplementation.

Individual Differences in Working Memory Capacity Predict Topiramate-Related Cognitive Deficits.

PURPOSE/BACKGROUND: Topiramate (TPM) and lorazepam (LZP) are two examples of frequently prescribed medications that are associated with a high incidence of cognitive impairment; however, the factors that underlie interindividual differences in side effect profiles have not been fully characterized. Our objective was to determine whether working memory capacity (WMC), the amount of information that can be stored and manipulated in memory over short time intervals, is one such factor. METHODS/PROCEDURES: Twenty-nine healthy volunteers completed a double-blind, randomized, placebo-controlled crossover study during which they received placebo (PBO), TPM, and LZP in random order. Four hours after drug administration, a blood draw was taken to establish drug concentrations, and subjects performed a verbal working memory task while the accuracy and reaction time of their responses were recorded. Working memory capacity was calculated based on accuracy rates during the PBO session, and the role of WMC in moderating the severity of drug-related cognitive impairment was assessed by examining drug-related performance changes from PBO as a function of WMC. FINDINGS/RESULTS: Both TPM and LZP had a negative impact on task performance, although only TPM-related deficits were modulated by WMC; high WMC was associated with more severe impairments and heightened sensitivity to increasing TPM concentrations. IMPLICATIONS/CONCLUSIONS: We have identified a potential clinical risk factor, high WMC, which is associated with drug-related adverse cognitive events. These data provide objective evidence in support of clinical observations that high-functioning patients are more likely to experience severe cognitive impairments.

Lamotrigine pharmacokinetics following oral and stable-labeled intravenous administration in young and elderly adult epilepsy patients: Effect of age.

OBJECTIVE: The objectives of this study were to investigate the effect of age on pharmacokinetic parameters of lamotrigine (LTG) and estimate parameter variability. METHODS: Patients (>18 years old) who were already on a steady-state dose of LTG therapy with no interacting comedications were enrolled. Patients with significant cardiac disease, severe kidney dysfunction, or moderate-to-severe liver dysfunction were excluded. Fifty milligrams of a stable-labeled intravenous LTG formulation (SL-LTG) replaced 50 mg of a patient's normal daily oral LTG dose. Thirteen blood samples were collected in each person over 96 hours. SL-LTG and unlabeled LTG concentrations were measured simultaneously by gas chromatography-mass spectrometry. Concentration-time data were analyzed by nonlinear mixed-effects modeling (NONMEM version 7.3). RESULTS: Twenty-eight patients representing 16 young (18-48 years old) and 12 elderly (63-87 years old) patients were included, yielding 382 unlabeled and 351 SL-LTG concentrations. A two-compartment model with first-order absorption and elimination adequately described the plasma concentration-time data. Bioavailability of oral LTG was approximately 74% and did not differ by age. LTG clearance was 27.2% lower in elderly than in young patients (1.80 L/h for a 70-kg patient). SIGNIFICANCE: Although LTG bioavailability was not affected by age, LTG clearance was 27.2% lower in elderly versus young patients of comparable body weight, possibly indicating lower dosages being needed in this population.

Status epilepticus in the elderly.

Children and the elderly (≥60 years of age) have the highest incidence of status epilepticus (SE). Because of their general health, elderly individuals are much more likely than younger (<60 years of age) persons to have more severe consequences from seizures. The incidence of SE is 15.5/100 000 in the 60-69 age group, 21.5/100 000 in the 70-79 age group and 25.9/100 000 in persons 80 and older. The most common cause in the elderly is acute symptomatic, with stroke and hypoxia the most frequent. The overall mortality of SE is quite high and occurs early, often within the first few days, and is related to the cause, with mortality of more than 80% in persons with anoxia. Although the cause of SE is an important factor in mortality, the aging body and brain may contribute to an unfavorable outcome. Treatment in the elderly is essentially the same as in younger adults with benzodiazepines (lorazepam, diazepam, clonazepam) and longer acting antiseizure drugs (phenytoin, fosphenytoin, valproate, levetiracetam, and lacosamide. At this time there are no evidence-based studies regarding Axis 2 (etiology) and Axis 4 (age). All current interventions for SE involve antiseizure drugs that were developed for treatment of chronic epilepsy. Treatments should be developed that are more specific for the various etiologies and involve drugs that work on the underlying cause of the SE.

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.

Antiseizure, antidepressant, and antipsychotic medication prescribing in elderly nursing home residents.

OBJECTIVE: The incidence of epilepsy is highest in the elderly and the prevalence of epilepsy is higher in nursing home residents than in other cohorts. Co-medications that act in the central nervous system (CNS) are frequently prescribed in this population. The objective was to identify the most commonly prescribed antiseizure drugs (ASDs) and determine the frequency of use of antipsychotic and antidepressant medications in elderly nursing home residents receiving ASDs. METHODS: Data were obtained from a pharmacy database serving 18,752 patients in Minnesota and Wisconsin nursing homes. Prescribing information was available on ASD, antidepressant, and antipsychotic drugs on one day in October 2013. The frequency distribution by age, formulation, trademarked/generic drugs, route of administration, and multiple drug combinations were determined. RESULTS: Overall, 66.8% of 18,752 residents received at least one CNS-active drug as classified by the Generic Product Identifier classification system. For those 65years and older, ASDs were prescribed for 14.3% residents. Gabapentin comprised 7.3%; valproate 3.0%; levetiracetam 1.8%; and phenytoin 0.9%. An antidepressant was used in 64.2% of persons prescribed an ASD. Antidepressant use varied for specific ASDs and ranged from 50 to 75%. An antipsychotic medication was used in 30% of persons prescribed an ASD and ranged from 16.8 to 54.2% for specific ASDs. Both antidepressant and antipsychotic use occurred in 22.2% of persons prescribed an ASD, respectively. SIGNIFICANCE: The pattern of CNS-active drug use has changed from previous years in this geographic region. Use of phenytoin has declined markedly, but antidepressant use has increased substantially. The CNS side effect profile of these medications and the possible long-term consequences in this population can greatly complicate their therapy.

Prevalence of epilepsy/seizures as a comorbidity of neurologic disorders in nursing homes.

OBJECTIVE: To determine the prevalence of epilepsy/seizure (epi/sz) comorbid with other neurologic disorders in elderly nursing home residents and to examine demographic and regional variability and associations with clinical characteristics. METHODS: We studied 5 cross-sectional cohorts of all residents in any Medicare/Medicaid-certified nursing home in the United States on July 15 of each year from 2003 to 2007. Epi/sz was identified by ICD-9 codes (345.xx or 780.39) or check box (Minimum Data Set). Epi/sz prevalence was stable across all years, so only 2007 data were examined further. Logistic regression with generalized estimating equations was used to model cross-sectional prevalence of epi/sz as a function of demographics and neurologic comorbidities of interest, with adjustment for clinical characteristics, including cognitive status, comorbidity burden, medication burden, and activities of daily living. RESULTS: Point prevalence of epi/sz in 2007 was 7.7% (n = 91,372 of N = 1,186,579) differing by geographical region, race/ethnicity, age group, and sex. Neurologic conditions having the highest association with epi/sz were brain tumor (epi/sz prevalence 23.4%-35.2%), head injury (17.9%), hemiplegia (17.7%), and stroke (13.7%). Epi/sz comorbid with stroke or dementia had a strong decreasing association with age (65-74 years had ≈3.8-times higher odds of epi/sz than 85+ years). Activities of daily living, comorbidity burden, and cognition scores were worse in persons with than without epi/sz. CONCLUSIONS: The prevalence of epi/sz in the elderly nursing home population is >7-fold higher compared to community-dwelling elderly and is 7 to 30 times higher among those with certain comorbid neurologic conditions. Demographics and clinical characteristics had weaker associations with epi/sz prevalence.

Pharmacokinetics and Saturable Absorption of Gabapentin in Nursing Home Elderly Patients.

Pharmacokinetic data of gabapentin (GBP) in community-dwelling elderly patients show a significant effect of advanced age on GBP pharmacokinetics due to altered renal function. However, there are no data in elderly nursing home (NH) patients to evaluate gabapentin absorption and elimination. Our objective was to characterize the pharmacokinetics of GBP in elderly nursing home patients maintained on GBP therapy. This was a prospective pharmacokinetic study in elderly nursing home patients (≥60 years) receiving GBP for the management of chronic pain or epilepsy from seven nursing homes. Pharmacokinetic parameters were estimated by nonlinear mixed-effects modeling. A one-compartment model described the data and clearance (CL) was associated with estimated glomerular filtration rate (eGFR) (p < 0.0001). The GBP CL in elderly nursing home patients was 2.93 L/h. After adjusting for the effect of GFR, GBP CL was not affected by age, sex, body weight, or comorbidity scores. No significant effects of body size measures, age, and sex were detected on volume of distribution. Dose-dependent bioavailability of GBP was demonstrated, and the saturable absorption profile was described by a nonlinear hyperbolic function. Prediction-corrected visual predictive check (pc-VPC) suggests adequate fixed- and random-effects models that successfully simulated the mean trend and variability in gabapentin concentration-time profiles. In this analysis, the parameters of the hyperbolic nonlinearity appear to be similar between elderly and younger adults.

Analysis of falls in patients with epilepsy enrolled in the perampanel phase III randomized double-blind studies.

OBJECTIVE: To analyze occurrence of falls among patients with partial seizures, with/without secondarily generalized seizures (SGS), and primary generalized tonic-clonic seizures (PGTCS) in the perampanel phase III clinical studies. METHODS: Studies 304, 305, and 306 randomized subjects (≥12 years) with drug-resistant partial seizures (with/without SGS) to perampanel 2, 4, 8, or 12 mg or placebo for double-blind treatment. The adverse event (AE) of falls was analyzed in the Safety Analysis Set (N = 1480). Study 332 randomized subjects aged ≥12 years with a diagnosis of PGTCS into perampanel 8 mg or placebo groups for double-blind treatment. In a systematic review of reported falls in the study 332 Safety Analysis Set (N = 163), falls were queried to establish whether each was seizure related; subjects with falls resulting from a seizure were not included in this analysis. RESULTS: For studies 304/305/306, treatment-emergent falls occurred in 5.1% perampanel-treated versus 3.4% placebo-treated subjects with partial seizures. Exposure-adjusted rate for falls (falls/subject-month of exposure) was greater for total perampanel than for placebo (0.0175 vs. 0.0093) and was dose related for those receiving perampanel. In subjects with SGS, incidence of treatment-emergent falls was 4.3% in perampanel and 4.0% in placebo groups. Exposure-adjusted rates were 0.0169 and 0.0097 falls per subject-month of exposure in perampanel and placebo, respectively. For study 332, 2.5% perampanel-treated and 1.2% placebo-treated subjects with PGTCS had treatment-emergent falls that were not part of a seizure. Exposure-adjusted rates were 0.0169 and 0.0032 falls per subject-month of exposure in perampanel and placebo, respectively. SIGNIFICANCE: Results of the perampanel studies suggest that patients with epilepsy should be monitored due to the common risk of falls.

Intravenous Topiramate: Pharmacokinetics in Dogs with Naturally Occurring Epilepsy.

RATIONALE: Barriers to developing treatments for human status epilepticus include the inadequacy of experimental animal models. In contrast, naturally occurring canine epilepsy is similar to the human condition and can serve as a platform to translate research from rodents to humans. The objectives of this study were to characterize the pharmacokinetics of an intravenous (IV) dose of topiramate (TPM) in dogs with epilepsy and evaluate its effect on intracranial electroencephalographic (iEEG) features. METHODS: Five dogs with naturally occurring epilepsy were used for this study. Three were getting at least one antiseizure drug as maintenance therapy including phenobarbital (PB). Four (ID 1-4) were used for the 10 mg/kg IV TPM + PO TPM study, and three (ID 3-5) were used for the 20 mg/kg IV TPM study. IV TPM was infused over 5 min at both doses. The animals were observed for vomiting, diarrhea, ataxia, and lethargy. Blood samples were collected at scheduled pre- and post-dose times. Plasma concentrations were measured using a validated high-performance liquid chromatography-mass spectrometry method. Non-compartmental and population compartmental modeling were performed (Phoenix WinNonLin and NLME) using plasma concentrations from all dogs in the study. iEEG was acquired in one dog. The difference between averaged iEEG energy levels at 15 min pre- and post-dose was assessed using a Kruskal-Wallis test. RESULTS: No adverse events were noted. TPM concentration-time profiles were best fit by a two compartment model. PB co-administration was associated with a 5.6-fold greater clearance and a ~4-fold shorter elimination half-life. iEEG data showed that TPM produced a significant energy increase at frequencies >4 Hz across all 16 electrodes within 15 min of dosing. Simulations suggested that dogs on an enzyme inducer would require 25 mg/kg, while dogs on non-inducing drugs would need 20 mg/kg to attain the target concentration (20-30 µg/mL) at 30 min post-dose. CONCLUSION: This study shows that IV TPM has a relatively rapid onset of action, loading doses appear safe, and the presence of PB necessitates a higher dose to attain targeted concentrations. Consequently, it is a good candidate for further evaluation for treatment of seizure emergencies in dogs and people.

Pharmacokinetic-Pharmacodynamic Modeling of Intravenous and Oral Topiramate and Its Effect on the Symbol-Digit Modalities Test in Adult Healthy Volunteers.

A sequential pharmacokinetic-pharmacodynamic (PK-PD) modeling approach was used to quantify the effects of a single dose of topiramate (100 or 200 mg) on working memory, attention, and psychomotor speed as measured by the Symbol-Digit Modalities Test (SDMT). Established on data pooled from 3 randomized, crossover studies in healthy subjects (19-55 years of age), using both oral and a novel stable-labeled intravenous (IV) formulation of topiramate, an inhibitory Emax model was found to characterize the topiramate concentration-SDMT score relationship well. At the EC50 of 2.85 µg/mL, this topiramate plasma concentration value was estimated to be associated with a 25.5% reduction of SDMT score relative to baseline. Age was an important determinant of the baseline SDMT score, with an estimated decrease of 1.13% in baseline SDMT score with every year of age. Moreover, this approach enabled the quantification of the practice effect observed with repeated administration of the neuropsychological test over shorter testing intervals than have previously been reported in the literature. The finding of a significant effect following a single dose of topiramate in the range widely used to treat migraine and epilepsy needs to be evaluated in a broader patient population undergoing chronic treatment, as the narrow range of resultant concentrations limits the generalizability of the findings.

Intravenous and Intramuscular Formulations of Antiseizure Drugs in the Treatment of Epilepsy.

Intravenous and intramuscular antiseizure drugs (ASDs) are essential in the treatment of clinical seizure emergencies as well as in replacement therapy when oral administration is not possible. The parenteral formulations provide rapid delivery and complete (intravenous) or nearly complete (intramuscular) bioavailability. Controlled administration of the ASD is feasible with intravenous but not intramuscular formulations. This article reviews the literature and discusses the chemistry, pharmacology, pharmacokinetics, and clinical use of currently available intravenous and intramuscular ASD formulations as well as the development of new formulations and agents. Intravenous or intramuscular formulations of lorazepam, diazepam, midazolam, and clonazepam are typically used as the initial treatment agents in seizure emergencies. Recent studies also support the use of intramuscular midazolam as easier than the intravenous delivery of lorazepam in the pre-hospital setting. However, benzodiazepines may be associated with hypotension and respiratory depression. Although loading with intravenous phenytoin was an early approach to treatment, it is associated with cardiac arrhythmias, hypotension, and tissue injury at the injection site. This has made it less favored than fosphenytoin, a water-soluble, phosphorylated phenytoin molecule. Other drugs being used for acute seizure emergencies are intravenous formulations of valproic acid, levetiracetam, and lacosamide. However, the comparative effectiveness of these for status epilepticus (SE) has not been evaluated adequately. Consequently, guidelines for the medical management of SE continue to recommend lorazepam followed by fosphenytoin, or phenytoin if fosphenytoin is not available. Intravenous solutions for carbamazepine, lamotrigine, and topiramate have been developed but remain investigational. The current ASDs were not developed for use in emergency situations, but were adapted from ASDs approved for chronic oral use. New approaches for bringing drugs from experimental models to treatment of human SE are needed.