Reductions in concomitant antiseizure medication drug load during adjunctive cenobamate therapy: Post-hoc analysis of a subset of patients from a phase 3, multicenter, open-label study.

OBJECTIVE: Many patients with epilepsy require polytherapy, which increases their antiseizure medication (ASM) drug load, a measure that considers the doses of all ASMs a patient is taking. Changes in concomitant ASM drug load after adding cenobamate were evaluated post-hoc in a subset of the open-label, phase 3 study. METHODS: Patients 18-70 years old with uncontrolled focal seizures taking 1-3 ASMs were enrolled. Total concomitant ASM drug load (not including cenobamate) was calculated by dividing the patient's prescribed dose for each ASM by its defined daily dose, per the World Health Organization, then summing the ratios. Changes in concomitant ASM drug load were measured from baseline in 3-month intervals up to 24 months by both total and class-specific ASM drug load. Subgroups of interest included: older adults (65-70 years), prior epilepsy-related surgery vs none, and baseline seizure frequency < 3 vs ≥ 3 seizures/28 days. RESULTS: Data from 240 patients were available (mean age 41.8 years, mean baseline drug load 3.57). Following cenobamate initiation, the mean concomitant ASM drug load was reduced by 29.4 % at Month 12 % and 31.8 % at Month 24. Reductions occurred in all assessed ASM drug classes, with the largest reduction in benzodiazepines (55.2 % at Month 24). Each assessed subgroup exceeded a 30 % reduction in concomitant ASM drug load at Month 24. Over 24 months, maintenance of ≥ 50 % response occurred in 89.3 %, 86.4 %, and 90.6 % of patients with low (-0.25 to <0), moderate (-0.59 to -0.25), or high (-3.3 to -0.59) numerical reductions in concomitant ASM drug load from baseline, respectively, compared with 86.0 % in patients with no change in drug load; maintenance of 100 % response occurred in 80.7 %, 84.3 %, and 70.0 % of patients with low, moderate, or high numerical reductions in concomitant ASM drug load, compared with 82.0 % in patients with no change. CONCLUSIONS: Adding cenobamate led to reduced mean concomitant ASM drug loads during 1 and 2 years of treatment. Reductions occurred regardless of ASM drug class, patient age, or epilepsy disease characteristics and did not impact maintenance of response rates.

Greater need for treatment optimization in patients with epilepsy initiating adjunctive therapy: Results of a retrospective claims analysis of antiseizure medication drug load in the United States.

BACKGROUND: This retrospective, observational study used US claims data to assess changes in antiseizure medication (ASM) drug load for a cohort of patients with epilepsy. METHODS: Adults (≥18 years) with a diagnosis of epilepsy (ICD-10 code G40.xxx) who started new adjunctive ASM treatment with one of 4 branded (brivaracetam, eslicarbazepine, lacosamide, perampanel) or 4 unbranded (carbamazepine, lamotrigine, levetiracetam, topiramate) ASMs between January 1, 2016 and December 31, 2020 were identified from IBM MarketScan® research databases (primary study population). Patients must have been continuously enrolled 360 days before the start of the new ASM (eligibility period). Follow-up was from the start of new ASM until Day 540 (∼18 months). The primary endpoint was concomitant ASM drug load, which included all ASMs except the new (comparator) ASM. A sensitivity analysis population included adults with epilepsy who were continuously enrolled for ≥ 180 days during at least one calendar year in the study period (2016-2020), whether or not the comparator ASM was new or existing during that period. Total ASM drug load, which included comparator ASM and concomitant ASMs, was assessed in the sensitivity analysis population. RESULTS: In total, 21,332 patients were included in the primary study population, of which 5767 initiated branded ASMs and 15,565 initiated unbranded ASMs. A total of 392,426 patients were included in the sensitivity analysis population during at least one calendar year 2016-2020. Concomitant ASM drug load increased in the 360 days prior to new ASM start and slightly declined thereafter. Mean concomitant ASM drug load for the primary population was 1.6 (SD 1.8) at new ASM start. Concomitant drug load was higher among those starting branded ASM comparators compared to those starting unbranded comparators. Mean total ASM drug load for patients increased over time and was approximately double for patients exposed to branded ASMs (mean range 2.1 to 2.7) compared to that of patients exposed to any unbranded ASM (mean range 1.0 to 1.3). CONCLUSION: Concomitant ASM drug load increased prior to addition of new ASM, with higher increases observed among patients starting branded vs unbranded ASMs, followed by slight decreases thereafter. Total drug load increased linearly among all patients. These findings underscore the need for ongoing ASM regimen evaluation and treatment optimization in patients with epilepsy.

Real-world analysis of retention on cenobamate in patients with epilepsy in the United States.

BACKGROUND: This retrospective, observational study used US claims data to assess retention rates on cenobamate compared with four branded antiseizure medications (ASMs) in patients with epilepsy. METHODS: Adults (≥18 years) with prevalent epilepsy (ICD-10 code G40.xx) and ≥ 1 prescription for cenobamate or any of the newer branded ASMs (brivaracetam, eslicarbazepine, lacosamide, or perampanel) between May 1, 2020 and December 31, 2021 were identified from the HealthVerity Marketplace database. At least 360 days of continuous enrollment was required before and after the index date (Day 1 of initiating cenobamate or branded ASM). Patients were followed until cessation of cenobamate or branded ASM or the end of data collection using Kaplan-Meier methods. Retention was compared between cenobamate and the branded ASMs (both as a group and individually) using Chi-square tests. RESULTS: In total, 4109 patients were included (195 cenobamate; 3914 branded ASMs). A higher proportion of patients in the cenobamate group compared with the branded ASMs group had concurrent focal and generalized epilepsy (65.6% vs 40.0%) and were on ≥ 3 concomitant ASMs (48.2% vs 12.8%) at the index date. Median time to discontinuation (i.e., the time that half the patients discontinued) was not quite reached after 12 months in the cenobamate group (50.3% of patients remained on cenobamate) and was 7.7 months in the branded ASMs group. Retention was significantly higher with cenobamate vs the branded ASMs group (p = 0.04545) and vs the individual ASMs lacosamide (p = 0.03044) and perampanel (p = 0.01558). Twelve-month retention rates (95% confidence intervals) were 50.3% (43.1%-57.0%) for cenobamate, 40.5% (38.9%-42.0%) for branded ASMs overall, 42.3% (38.6%-46.0%) for brivaracetam, 44.1% (39.2%-49.0%) for eslicarbazepine, 39.9% (38.0%-41.8%) for lacosamide, and 36.8% (31.9%-41.8%) for perampanel. CONCLUSIONS: In this real-world analysis, retention was significantly higher with cenobamate vs a pooled group of four branded ASMs despite a greater frequency of patients in the cenobamate group having characteristics of more difficult-to-treat epilepsy.

Trends and Costs Associated With the Diagnosis and Treatment of Infantile Spasms: A 10-Year Multicenter Retrospective Review.

OBJECTIVE: Early treatment of infantile spasms (IS) may be imperative for improvement of neurodevelopmental outcomes. Existing studies have led to inconclusive recommendations with variation in treatment. Our objective was to determine the national average cost, initial diagnostic workup, treatments, and hospital length of stay for patients with IS. METHODS: This retrospective cohort study was designed to review data of patients < 2 years from 43 non-profit institutions. Data obtained included patient demographics, length of stay, admission cost, and treatments used from 2004 to 2014. Cost data were collected and adjusted to 2014 dollars, the year data were analyzed. RESULTS: A total of 6183 patients met study criteria (n = 3382, 55% male). Three-quarters of patients (n = 4684, 76%) had an electroencephalogram, 56.4% had brain imaging (n = 3487), and 17% (n = 1050) underwent a lumbar puncture. Medication for IS was initiated during inpatient hospital stay in two-thirds of all patients (n = 4139, 67%). Most patients were initiated on corticotropin (n = 2066, 33%) or topiramate (n = 1804, 29%). Average length of stay was 5.8 days with an average adjusted cost of $18,348. Over time there was an 86.6% increase in cost from an average $12,534.54 (2004) to $23,391.20 (2014), a significant change (p < 0.01). This correlated with an increase in average length of stay. CONCLUSIONS: Variability exists in diagnostic workup and pharmacotherapy initiated for IS, which may lead to differences in the cost of hospital stay. Further studies may help determine contributing factors to increased cost and improve health care utilization for IS patients.

Fosphenytoin Population Pharmacokinetics in the Acutely Ill Pediatric Population.

OBJECTIVE: The purpose of this study is to describe the pharmacokinetics of phenytoin in pediatric patients receiving fosphenytoin. DESIGN: Retrospective, population pharmacokinetic analysis. SETTING: Emergency department or PICU of a large tertiary care children's hospital. PATIENTS: Patients less than 19 years old who received fosphenytoin in the PICU or emergency center for treatment of seizures from January 2011 to June 2017 were included. INTERVENTIONS: Population pharmacokinetic analysis was performed with NONMEM v7.3 (Icon Plc, Dublin, Ireland). Simulation was performed to determine optimal loading dose and maintenance dosing regimens. MEASUREMENTS AND MAIN RESULTS: A total of 536 patients (55.4% male; median age, 3.4 yr [interquartile range, 0.92-8.5 yr]) met study criteria. Fosphenytoin was administered at median 15.1 mg/kg/dose (interquartile range, 6.3-20.7 mg/kg/dose). Mean serum concentrations of 17.5 ± 7.8 mg/L were at a median 4.2 hours (interquartile range, 2.5-7.8 hr) after a dose. A pharmacokinetic model with two compartments, allometrically scaled fat-free mass on all parameters, and serum creatinine and concomitant phenobarbital use on clearance had the best fit. Simulation demonstrated that a 20 mg/kg loading dose followed by 6 mg/kg/dose every 8 hours had the greatest percentage of concentrations in the 10-20 mg/L range, with reduced doses to achieve therapeutic in patients with reduced kidney function. CONCLUSIONS: A loading dose of 20 mg/kg followed by 6 mg/kg/dose every 8 hours based on fat-free mass is a reasonable empiric strategy for attainment and maintenance of therapeutic trough concentrations. Concomitant phenobarbital use may increase clearance of phenytoin and fosphenytoin dose reductions should occur in patients with reduced kidney function.

Phenobarbital population pharmacokinetics across the pediatric age spectrum.

OBJECTIVE: Phenobarbital is frequently used in pediatric patients for treatment and prophylaxis of seizures. Pharmacokinetic data for this patient population is lacking and would assist in dosing decisions. METHODS: A retrospective population pharmacokinetic analysis was designed for all pediatric patients <19 years of age initiated on phenobarbital at our institution from January 2011 to June 2017. Patients were included if they were initiated on intravenous or enteral phenobarbital for treatment or prophylaxis of seizures and had a serum phenobarbital concentration monitored while an inpatient. Data collection included the following: age, weight, height, gestational age, core body temperature, serum creatinine, blood urea nitrogen, aspartase aminotransferase, alanine aminotransferase, urine output over the prior 12 hours, phenobarbital doses and serum concentrations, and potential drug-drug interactions. Descriptive statistical methods were used to summarize the data. Pharmacokinetic analysis was performed with NONMEM and simulation was performed for doses of 10, 20, 30, and 40 mg kg-1  dose-1 , iv, followed by enteral doses of 3, 4, 5, and 6 mg kg-1  d-1 . RESULTS: A total of 355 patients (50.3% male, median gestational age 39 weeks (interquartile range [IQR] 35, 40), median age 0.28 years (IQR 0.06, 0.82). Median phenobarbital dose was enteral = 2.6 (IQR 1.9, 3.9) mg kg-1  dose-1 ; intravenous = 2.6 (IQR 2.2, 4.9) mg kg-1  dose-1 ) and mean serum concentration was 41.1 ± 23.9 mg/L at median 6.5 (IQR 2.9, 11.1) hours after a dose. A one-compartment proportional error model best fit the data where clearance and volume of distribution were allometrically scaled using fat-free mass. Significant covariates included serum creatinine, postmenstrual age, and drug-drug interactions on clearance, and age in years on volume of distribution. SIGNIFICANCE: Phenobarbital dosing of 30 mg kg-1  dose-1 ,iv, followed by 4 mg kg-1  d-1 had the highest probability of attaining a therapeutic concentration at 7 days. Postmenstrual age and drug-drug interactions should be incorporated into dosing decisions.