Assessment of cerebral drug occupancy in humans using a single PET-scan: A [11C]UCB-J PET study.

PURPOSE: Here, we evaluate a PET displacement model with a Single-step and Numerical solution in healthy individuals using the synaptic vesicle glycoprotein (SV2A) PET-tracer [11C]UCB-J and the anti-seizure medication levetiracetam (LEV). We aimed to (1) validate the displacement model by comparing the brain LEV-SV2A occupancy from a single PET scan with the occupancy derived from two PET scans and the Lassen plot and (2) determine the plasma LEV concentration-SV2A occupancy curve in healthy individuals. METHODS: Eleven healthy individuals (five females, mean age 35.5 [range: 25-47] years) underwent two 120-min [11C]UCB-J PET scans where an LEV dose (5-30 mg/kg) was administered intravenously halfway through the first PET scan to partially displace radioligand binding to SV2A. Five individuals were scanned twice on the same day; the remaining six were scanned once on two separate days, receiving two identical LEV doses. Arterial blood samples were acquired to determine the arterial input function and plasma LEV concentrations. Using the displacement model, the SV2A-LEV target engagement was calculated and compared with the Lassen plot method. The resulting data were fitted with a single-site binding model. RESULTS: SV2A occupancies and VND estimates derived from the displacement model were not significantly different from the Lassen plot (p = 0.55 and 0.13, respectively). The coefficient of variation was 14.6% vs. 17.3% for the Numerical and the Single-step solution in Bland-Altman comparisons with the Lassen plot. The average half maximal inhibitory concentration (IC50), as estimated from the area under the curve of the plasma LEV concentration, was 12.5 µg/mL (95% CI: 5-25) for the Single-Step solution, 11.8 µg/mL (95% CI: 4-25) for the Numerical solution, and 6.3 µg/mL (95% CI: 0.08-21) for the Lassen plot. Constraining Emax to 100% did not significantly improve model fits. CONCLUSION: Plasma LEV concentration vs. SV2A occupancy can be determined in humans using a single PET scan displacement model. The average concentration of the three computed IC50 values ranges between 6.3 and 12.5 µg/mL. The next step is to use the displacement model to evaluate LEV occupancy and corresponding plasma concentrations in relation to treatment efficacy. CLINICAL TRIAL REGISTRATION: NCT05450822. Retrospectively registered 5 July 2022 https://clinicaltrials.gov/ct2/results? term=NCT05450822&Search=Search.

A Simulation-Based Assessment of Levetiracetam Concentrations Following Fixed and Weight-Based Loading Doses: A Meta-Regression and Pharmacokinetic Modeling Analysis.

Current recommendations for refractory status epilepticus (SE) unresponsive to benzodiazepines suggest a loading dose of levetiracetam (LEV) of 60 mg/kg to a maximum of 4500 mg. LEV therapeutic drug monitoring can help guide therapy and is garnering increasing attention. The objective of this study is to simulate the probability of target attainment (PTA) of fixed dose and weight-based loading doses of LEV with respect to established therapeutic target concentrations. Meta-regression of the current literature was performed to evaluate the relationship between intravenous LEV loading dose and seizure cessation in refractory SE patients. A previously published pharmacokinetic model was used to simulate the PTA capacity of competing single intravenous dosing schemes (fixed vs weight-based dosing) to achieve maximum (Cpeak) and 12-h (C12h) plasma concentrations that exceed 12 mg/L. The meta-regression indicated that dosage was not a statistically significant modulator of seizure control at dosages between 20 and 60 mg/kg. Stochastic simulations showed all dosing schemes achieved plasma Cpeak >12 mg/L, but C12h levels were <12 mg/L in subjects over 60 kg with a fixed dose ≤2000 mg or in subjects <60 kg with a weight-based dose <30 mg/kg. Dosages of 40 and 60 mg/kg provided ≥90% PTAs across all weights. Using a weight-based loading dose of 40 mg/kg, up to a suggested maximum of 4500 mg, improves the likelihood of achieving a sustained therapeutic drug concentration after the initial LEV dose, whereas fixed <3000 mg may not achieve the desired concentration before maintenance dosing.

Cost-effectiveness analysis of HLA-B*15:02 screening before treatment of epilepsy in Indonesia.

INTRODUCTION: Adverse skin reactions due to drugs such as Stevens Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) occur in 3% of people receiving anti epileptic drugs (AED). Although SJS/TEN has a low incidence, the mortality and morbidity rates are high. Indonesia has not adopted HLA-B*1502 screening prior to administration of carbamazepine (CBZ), although previous studies found a relationship between HLA-B*1502 and SJS/TEN. METHODS: A hybrid decision tree and Markov model was developed to evaluate three strategies for treating newly diagnosed focal epilepsy: CBZ direct therapy, levetiracetam (LEV) direct therapy, and therapy based on HLA-B*15:02 test results. From a societal perspective, base case and sensitivity analyses were carried out over a lifetime. RESULTS: Direct administration of CBZ appears to have a slightly lower average cost than the HLA-B*15:02 allele screening strategy. The increase in quality-adjusted life year (QALY) in HLA-B*15:02 screening before treatment related to the cost difference reached 0.519 with an incremental cost-effectiveness ratio (ICER) of around USD 984 per unit of QALY acquisition. Direct treatment of LEV increased treatment costs by almost USD 2000 on average compared to the standard CBZ strategy. The increase in QALY is 0.834 in direct levetiracetam treatment, with an ICER of around USD 2230 for each QALY processing. CONCLUSION: Calculation of the cost-effectiveness of lifetime epilepsy therapy in this study found that the initial screening strategy with the HLA-B*15:02 test was the most cost-effective.

Psychiatric assessment prior to and after switch from levetiracetam to brivaracetam.

PURPOSE: Brivaracetam is often used as an alternative to levetiracetam in patients with epilepsy (PWE) encountering efficacy issues or adverse events with levetiracetam. This study evaluated the psychological status of PWE who were switched from levetiracetam to brivaracetam due to psychiatric tolerability concerns in comparison to those who remained on levetiracetam. METHODS: We used various psychological assessments including the Symptom Checklist SCL-90-R, the Beck Depression Inventory-II, and the adverse event profile. Eligible participants completed the questionnaires at baseline and again 8 days later. Psychological changes were assessed using standard statistical methods to show differences between a group that immediately switched from levetiracetam to brivaracetam and another group with unchanged levetiracetam. RESULTS: Between May 2020 and May 2021, 63 patients participated in the study, of whom 34 switched from levetiracetam to brivaracetam. At baseline, participants who switched to brivaracetam had fewer antiseizure medications but experienced more monthly seizures. Baseline scores for anxiety (p = 0.020) and psychoticism (p = 0.046) on SCL-90-R in PWE switched to brivaracetam were higher than in the remaining group. In the subsequent assessment, all psychological scores were reduced and were no longer significantly different between both groups. Using multiple regression, initial treatment with a single antiseizure medication and male gender emerged as predictors of psychological improvement. CONCLUSION: Our study found no increased risk of adverse events or psychiatric symptoms after switching from levetiracetam to brivaracetam. Though statistically non-significant, a trend towards improved psychiatric outcomes in the switch group warrants further investigation in future trials with stronger designs for enhanced statistical power.

Comparing the efficacy of anti-seizure medications using matched cohorts on a large insurance claims database.

Epilepsy is a severe chronic neurological disease affecting 60 million people worldwide. Primary treatment is with anti-seizure medicines (ASMs), but many patients continue to experience seizures. We used retrospective insurance claims data on 280,587 patients with uncontrolled epilepsy (UE), defined as status epilepticus, need for a rescue medicine, or admission or emergency visit for an epilepsy code. We conducted a computational risk ratio analysis between pairs of ASMs using a causal inference method, in order to match 1034 clinical factors and simulate randomization. Data was extracted from the MarketScan insurance claims Research Database records from 2011 to 2015. The cohort consisted of individuals over 18 years old with a diagnosis of epilepsy who took one of eight ASMs and had more than a year of history prior to the filling of the drug prescription. Seven ASM exposures were analyzed: topiramate, phenytoin, levetiracetam, gabapentin, lamotrigine, valproate, and carbamazepine or oxcarbazepine (treated as the same exposure). We calculated the risk ratio of UE between pairs of ASM after controlling for bias with inverse propensity weighting applied to 1034 factors, such as demographics, confounding illnesses, non-epileptic conditions treated by ASMs, etc. All ASMs exhibited a significant reduction in the prevalence of UE, but three drugs showed pair-wise differences compared to other ASMs. Topiramate consistently was associated with a lower risk of UE, with a mean risk ratio range of 0.68-0.93 (average 0.82, CI: 0.56-1.08). Phenytoin and levetiracetam were consistently associated with a higher risk of UE with mean risk ratio ranges of 1.11 to 1.47 (average 1.13, CI 0.98-1.65) and 1.15 to 1.43 (average 1.2, CI 0.72-1.69), respectively. Large-scale retrospective insurance claims data - combined with causal inference analysis - provides an opportunity to compare the effect of treatments in real-world data in populations 1,000-fold larger than those in typical randomized trials. Our causal analysis identified the clinically unexpected finding of topiramate as being associated with a lower risk of UE; and phenytoin and levetiracetam as associated with a higher risk of UE (compared to other studied drugs, not to baseline). However, we note that our data set for this study only used insurance claims events, which does not comprise actual seizure frequencies, nor a clear picture of side effects. Our results do not advocate for any change in practice but demonstrate that conclusions from large databases may differ from and supplement those of randomized trials and clinical practice and therefore may guide further investigation.

Evolution of antiseizure medication use and cost in the United States of America 2006-2021.

OBJECTIVE: To describe the evolution in use and cost of antiseizure medications (ASM) in the United States of America (USA). METHODS: Retrospective descriptive study using the IBM MarketScan Commercial Database (data of privately-insured patients) for the years 2006 to 2021. We identified patients with epilepsy who were on ASM. We adjusted cost for inflation with the Gross Domestic Product Implicit Price Deflator. RESULTS: We evaluated 347,158 patients (46.9 % males; median (p25-p75) age: 33 (17-49) years; 28 % with pediatric-onset epilepsy and 72 % with adult-onset epilepsy) with a total of 1,385,382 person-years and 588,285,065 ASM prescription days. The most commonly prescribed (as percentage of prescription days) ASMs in 2006 were valproate (18 %) and lamotrigine (17 %) in pediatric-onset epilepsy and phenytoin (21 %) and carbamazepine (17 %) in adult-onset epilepsy, but starting in the 2010s, levetiracetam and lamotrigine became the most commonly prescribed ASMs in both pediatric-onset (in 2021, levetiracetam 25 %, lamotrigine 16 %) and adult-onset (in 2021, levetiracetam 27 %, lamotrigine 20 %) epilepsy. The proportion of generic ASM use increased 3.6-fold: from 23 % of prescription days in 2006 to 83 % of prescription days in 2021. The median (p25-p75) average wholesale price (AWP) per person-year increased by 102 % from $2,684 ($990-$5,509) in 2006 to $5,417 ($2,858-$12,310) in 2021. The increases were greater in absolute terms for brand-name ASMs by 419 %: $3,109 ($1,564-$5,068 in 2006 and $16,149 ($12,950-$23,377) in 2021 than for generic ASMs by 462 %: $699 ($457-$1,678) in 2006 and $3,931 ($2,618-$6,081) in 2021. The costs directly borne by the patient (copay, coinsurance, deductibles, and pharmacy processing fees) increased by 69 % for brand-name ASMs from $393 ($246-$570) in 2006 to $665 ($335-$1,308) in 2021, but decreased by 37 % for generic ASMs from $147 ($98-$213) in 2006 to $92 ($51-$141) in 2021. CONCLUSIONS: The median cost of ASMs per person-year approximately doubled from 2006 to 2021. The increase in use of generic ASMs probably helped buffer the growing costs of ASMs. However, generic ASMs already represent 83 % of prescription days in 2021, with limited room to further contain costs by just increasing the proportion of generics.

Assessment of the toxic effects of levetiracetam on biochemical, functional, and redox parameters of salivary glands in male Wistar rats.

Levetiracetam (LEV) is an anticonvulsant for epilepsy. The toxic effects of this medication in tissues have been associated with redox state imbalance, which can lead to salivary gland dysfunction. Therefore, the current work investigated the effects of LEV on the biochemical, functional, and redox parameters of the parotid and submandibular glands in rats. For this, male Wistar rats (Rattus norvegicus albinus) were randomly divided into 3 groups (n = 10/group): Control (0.9% saline solution), LEV100 (100 mg/kg), and LEV300 (300 mg/kg). After 21 consecutive days of intragastric gavage treatments, pilocarpine stimulated saliva secretion was collected for salivary biochemical analysis. The extracted salivary glands were utilized for histomorphometry and redox state analyses. Our results showed that LEV300 increased plasma hepatotoxicity markers and reduced salivary amylase activity and the acinar surface area of the parotid gland. Total oxidant capacity and oxidative damage to lipids and proteins were higher in the parotid gland, while total antioxidant capacity and uric acid levels were reduced in the submandibular gland of the LEV100 group compared to Control. On the other hand, total oxidant capacity, oxidative damage to lipids and proteins, total antioxidant capacity, and uric acid levels were lower in both salivary glands of the LEV300 group compared to Control. Superoxide dismutase and glutathione peroxidase activities were lower in the salivary glands of treated animals compared to Control. In conclusion our data suggest that treatment with LEV represents a potentially toxic agent, that contributes to drug-induced salivary gland dysfunction.

Shortages of antiseizure medications in Australia and the association with patient switching, and adherence in a community setting.

PURPOSE: To quantify sponsor-reported shortages of oral antiseizure medications in Australia, estimate the number of patients impacted, and the association between shortages and brand or formulation switching, and changes in adherence. METHODS: A retrospective cohort study of sponsor-reported shortages (defined as where the supply of a medicine will not or will not be likely to meet the demand over a 6-month period) of antiseizure medications reported to the Medicine Shortages Reports Database (Therapeutic Goods Administration, Australia); cross-referencing shortages to the IQVIA-NostraData Dispensing Data (LRx) database, a deidentified, population-level dataset collecting longitudinal dispensation data on individual patients from ∼75% of Australian community pharmacy scripts. RESULTS: Ninety-seven sponsor-reported ASM shortages were identified between 2019 and 2020; of those, 90 (93%) were shortages of generic ASM brands. Of 1,247,787 patients dispensed ≥1 ASMs, 242,947 (19.5%) were impacted by shortages. Sponsor-reported shortages occurred more frequently before the COVID-19 pandemic versus during the pandemic, however, shortages were estimated to affect more patients during the pandemic than before the pandemic. An estimated 330,872 patient-level shortage events were observed, and 98.5% were associated with shortages of generic ASM brands. Shortages occurred at a rate of 41.06 shortages per 100 person-years in patients on generic ASM brands versus 0.83 shortages per 100 person-years in patients on originator ASM brands. In patients taking a formulation of levetiracetam affected by a shortage, 67.6% switched to a different levetiracetam brand or formulation during shortages compared with 46.6% in non-shortage periods. CONCLUSIONS: Approximately 20% of patients on ASMs were estimated to have been impacted by an ASM shortage in Australia. The rate of patient-level shortages was approximately 50 times higher for patients on generic ASM brands versus originator brands. Shortages of levetiracetam were associated with formulation and brand switching. Improved supply chain management amongst sponsors of generic ASMs is needed to maintain the continuity of supply in Australia.

Eficacia y seguridad de lacosamida como tratamiento complementario en pacientes pediátricos con epilepsia focal refractaria / Efficacy and safety of lacosamide as adjunctive treatment in pediatric patients with refractory focal epilepsy

ANTECEDENTES: En el marco de la metodología ad hoc para evaluar solicitudes de tecnologías sanitarias, aprobada mediante Resolución de Institución de Evaluación de Tecnologías en Salud e Investigación N° 97-IETSI-ESSALUD-2022, se ha elaborado el presente dictamen que expone la evaluación de la eficacia y seguridad de lacosamida para el tratamiento de pacientes pediátricos con epilepsia focal refractaria. Así, el médico Dr. Edwin Martín Lazo Rivera, especialista en neurología pediátrica del Hospital Nacional Carlos Alberto Seguín Escobedo - Red Asistencial Arequipa y la Dra. Rebeca Fiorella Valdivia Bravo, especialista en pediatría del Hospital Nacional Alberto Sabogal Sologuren de la Red Prestacional Sabogal, siguiendo la Directiva N° 003-IETSI-ESSALUD-2016, enviaron al Instituto de Evaluación de Tecnologías en Salud e Investigación ­ IETSI sus respectivas solicitudes de autorización de uso del producto farmacéutico lacosamida no incluido en el Petitorio Farmacológico de EsSalud. ASPECTOS GENERALES: La epilepsia es una condición del sistema nervioso central caracterizada por crisis epilépticas recurrentes y no provocadas por desencadenantes inmediatos identificables. Así, la crisis epiléptica es aquel acontecimiento transitorio de signos y/o síntomas originados por una actividad neuronal cerebral sincrónica anormal o excesiva, que puede manifestarse por fenómenos sensitivos, motores, sensoriales o autonómicos con o sin pérdida de la conciencia, ya que dependen del área cerebral donde se originan. En ese sentido, las crisis convulsivas se clasifican según tres posibilidades de origen: las de inicio focal, generalizado y desconocido. Las crisis focales, a su vez, se pueden subclasificar en aquellas que tienen pérdida o no de la consciencia, para posteriormente categorizar si los síntomas son motores o no motores. En consecuencia, los especialistas deciden el abordaje terapéutico de los pacientes con epilepsia focal teniendo en cuenta esta clasificación, adicional a la etiología y a las comorbilidades asociadas (Reséndiz-Aparicio et al.,2019, Fisher et al.,2017, INSN.,2020). En todo el mundo, la epilepsia afecta aproximadamente a 65 millones de personas, reportándose una incidencia de la epilepsia de 67,8 por 100 000 habitantes en los países en desarrollo (Mohammadzadeh et al., 2022). En el Perú, se estima que la prevalencia de epilepsia es de 11,9 a 32,1 por cada 1000 personas (Burneo et al., 2017). Asimismo, es conocido que la incidencia de la epilepsia en la población pediátrica es de aproximadamente 0,5 % a 1 % de la población general. Además, algunos estudios sugieren que hasta el 60 % de los pacientes pediátricos con epilepsia presentarán remisión de su condición, mientras que alrededor del 20 % a 30 % de los pacientes con epilepsia serán refractarios al tratamiento médico (Ortiz de la Rosa et al., 2015). METODOLOGÍA: La búsqueda bibliográfica exhaustiva se llevó a cabo con el objetivo de identificar la mejor evidencia disponible sobre la eficacia y seguridad de lacosamida para el tratamiento de pacientes pediátricos con epilepsia focal refractaria a los FAE disponibles en EsSalud. La búsqueda bibliográfica se realizó en las bases de datos PubMed, The Cochrane Library. Web of Science y LILACS. Adicionalmente, se amplió la búsqueda revisando la evidencia generada por grupos internacionales que realizan revisiones sistemáticas (RS), evaluaciones de tecnologías sanitarias (ETS) y guías de práctica clínica (GPC) de: la National Institute for Health and Care Excellence (NICE), la American Academy of Neurology (ANN), la American Epilepsy Society (AES), la Scottish Intercollegiate Guidelines Network (SIGN), la Internacional Database of GRADE Guideline (BIGG), la Canadian Agency for Drugs and Technologies in Health (CADTH), la Comissáo Nacional de Incorporadáo de Tecnologias no Sistema Único de Saúde (CONITEC) y el Ministerio de Salud del Perú (MINSA). Adicionalmente, se realizó una búsqueda manual en las bases el portal de la Base Regional de Informes de Evaluación de Tecnologías en Salud de las Américas (BRISA), y el repositorio institucional de la Dirección General de Medicamentos, Insumos y Drogas (DIGEMID). Finalmente, se realizó una búsqueda en el portal ClinicalTrials.govdel National Institutes of Health (NIH) para identificar ensayos clínicos en desarrollo o que aún no hayan sido publicados. La metodología de tipo escalonada fue utilizada para la selección de documentos a ser incluidos en el presente dictamen. De acuerdo con los criterios de elegibilidad, se priorizaron durante la selección: GPC, ETS, RS de ensayos clínicos (EC) con o sin metaanálisis (MA), y ensayos clínicos aleatorizados (ECA) de fase III. Se elaboraron estrategias de búsqueda sensibles en bases de datos bibliográficas y sitios web para obtener la evidencia científica que permita responder a la pregunta PICO. Las estrategias de búsqueda incluyeron términos relacionados con la intervención y población de interés. Se emplearon términos MeSH4, así como términos de lenguaje libre, junto con operadores booleanos para cada una de las bases de datos elegidas para la búsqueda. Los registros obtenidos de la búsqueda bibliográfica fueron importados al aplicativo web Rayyan (http://rayyan.qcri.org/) para una revisión manual por título y resumen. La selección de los estudios se realizó en una primera fase por dos evaluadores del Equipo Técnico del IETSI de manera independiente (búsqueda par); evaluando los títulos y resúmenes en relación con la pregunta PICO y seleccionando aquellos que serían evaluados a texto completo en una segunda fase por un único evaluador. En la segunda fase, uno de los evaluadores revisó los documentos a texto completo incluidos en la primera fase y realizó la selección final de los estudios. RESULTADOS: Luego de la búsqueda bibliográfica, se incluyó una GPC elaborada por la National Institute for Health and Care Excellence (NICE 2022), y un ECA de fase III, NCT01921205 (Farkas et al., 2019). CONCLUSIÓN: Por lo expuesto, el Instituto de Evaluación de Tecnologías en Salud e Investigación aprueba el uso de lacosamida para el tratamiento complementario en pacientes pediátricos con epilepsia focal refractaria, como producto farmacéutico no incluido en el Petitorio Farmacológico de EsSalud, según lo establecido en el Anexo N° 1. La vigencia del presente informe preliminar es de un año a partir de la fecha de publicación. Así, la continuación de dicha aprobación estará sujeta a la evaluación de los resultados obtenidos y de mayor evidencia que pueda surgir en el tiempo.

Population pharmacokinetics and dosing regimen optimization of levetiracetam in epilepsy during pregnancy.

AIMS: The pharmacokinetics of levetiracetam (LEV) significantly changed during pregnancy. It is a great challenge to predict the adjusted doses of LEV to reach the preconception target concentrations. This study aimed to establish a population pharmacokinetic model of LEV in women with epilepsy (WWE) during pregnancy to analyse the factors of pharmacokinetic variability and to develop a model-based individualized dosing regimen. METHODS: A total of 166 concentration-time points from 37 WWE during pregnancy treated with LEV were collected to analyse LEV pharmacokinetics with nonlinear mixed-effects modelling. The dosing regimen was optimized by Monte Carlo simulations based on the final model. RESULTS: The LEV pharmacokinetics in pregnant WWE were best described by a 1-compartment model of first-order absorption and elimination. The population typical value of apparent clearance (CL/F) in the final model was estimated to be 3.82 L/h (95% confidence interval 3.283-4.357 L/h) with a relative standard error of 7.2%. Both total body weight (TBW) and trimester of pregnancy were significantly associated with LEV-CL/F during pregnancy; LEV-CL/F increased by 42.72% when TBW increased from 55 to 65 kg from the first trimester to the second trimester. Monte Carlo simulations showed that dosing regimens for LEV should be individualized based on the patient's TBW and trimester of pregnancy to maximize the likelihood of achieving the therapeutic range. CONCLUSION: This first population pharmacokinetic study of LEV in WWE during pregnancy supports the use of a weight-based and pregnancy-based dosing regimen and can lay a foundation for further optimizing the individualized dosing regimens.

Assessment of asymmetric dimethylarginine and homocysteine in epileptic children receiving antiepileptic drugs.

BACKGROUND: Epilepsy is a neurological disease that requires long-term antiepileptic drugs (AEDs). The old generation of AEDs may affect serum homocysteine and asymmetric dimethylarginine (ADMA) and disturb lipid levels. The aim of the study was to evaluate serum ADMA, homocysteine, lipid profile, and carotid intima-media thickness (CIMT) in epileptic children. METHODS: This study was implemented on 159 epileptic children who were subdivided into 3 subgroups, with 53 receiving sodium valproate, 53 receiving levetiracetam, and 53 receiving polytherapy, for over 6 months and 53 healthy children. RESULTS: Low-density lipoprotein, triglycerides, and cholesterol levels were increased in epileptic children (p < 0.001), which were higher in those receiving multidrug followed by a valproate receiver. While high-density lipoprotein was lower in those receiving multidrug more than those receiving valproate. ADMA and homocysteine levels increased in epileptic patients than in controls (p < 0.001). Higher ADMA was also observed in the multidrug receiver (5.78 ± 0.62), followed by the levetiracetam group (5.56 ± 0.61). Homocysteine levels were significantly higher in multidrug and valproate-treated children than those treated with levetiracetam. CIMT was significantly higher in multidrug and valproate-treated patients (p < 0.001). CONCLUSIONS: Long-term use of AEDs, especially old-generation polytherapy, can elevate lipid profiles, homocysteine, ADMA levels, and carotid intima-media thickness compared to the minimal effect of new AEDs. IMPACT: The long-term use of antiepileptic drugs, especially old-generation polytherapy, can increase lipid profiles, homocysteine levels, ADMA, and carotid intima thickness compared to the minimal effect of new antiepileptic generation. A routine follow-up of these markers and a lifestyle modification are recommended to avoid cerebrovascular events as much as possible.

Effect of Nonadherence on Levetiracetam Pharmacokinetics and Remedial Dose Recommendations Using Monte Carlo Simulations.

BACKGROUND AND OBJECTIVE: Nonadherence to levetiracetam (LEV) use can result in subtherapeutic concentrations and increase the risk of the occurrence of seizures. The impact of missing LEV doses on its pharmacokinetics and evidence of the appropriate remedial dose is lacking. This study has determined the influence of missed LEV doses on its pharmacokinetics and has explored the appropriate remedial dosage regimens. METHODS: Monte Carlo simulation was used to assess the impacts of different remedial dosage regimens on LEV concentrations. Simulated LEV concentrations outside the individual therapeutic range were calculated for the compliance scenario and for each of the remedial dosage regimens. The percentage of deviation from the full compliance scenario was also calculated. The regimen with the lowest percentage of deviation was considered the most appropriate. RESULTS: The suitable LEV remedial dose varied across the delay times. For one missed dose, a remedial regimen with a regular dose followed by the usual dose was suitable for a delay time of less than 6 h, while a replacement with a regular dose followed by a partial dose appeared to be appropriate for a delay time of 6 h and longer. This was justified based on the concerns of LEV toxicity when the remedial dose is close to the next scheduled dose. For two consecutive missed doses, a remedial dose with one and a half of the regular dose was suitable if the gap between that and the next dose was greater than 6 h. CONCLUSIONS: The appropriate remedial dosage regimen for one and two consecutive missed doses of LEV have been proposed. These remedial regimens, however, should be applied with clinicians' judgment based on the clinical status of the patients.

A pharmacogenomic assessment of psychiatric adverse drug reactions to levetiracetam.

OBJECTIVE: Levetiracetam (LEV) is an effective antiseizure medicine, but 10%-20% of people treated with LEV report psychiatric side-effects, and up to 1% may have psychotic episodes. Pharmacogenomic predictors of these adverse drug reactions (ADRs) have yet to be identified. We sought to determine the contribution of both common and rare genetic variation to psychiatric and behavioral ADRs associated with LEV. METHODS: This case-control study compared cases of LEV-associated behavioral disorder (n = 149) or psychotic reaction (n = 37) to LEV-exposed people with no history of psychiatric ADRs (n = 920). All samples were of European ancestry. We performed genome-wide association study (GWAS) analysis comparing those with LEV ADRs to controls. We estimated the polygenic risk scores (PRS) for schizophrenia and compared cases with LEV-associated psychotic reaction to controls. Rare variant burden analysis was performed using exome sequence data of cases with psychotic reactions (n = 18) and controls (n = 122). RESULTS: Univariate GWAS found no significant associations with either LEV-associated behavioural disorder or LEV-psychotic reaction. PRS analysis showed that cases of LEV-associated psychotic reaction had an increased PRS for schizophrenia relative to contr ols (p = .0097, estimate = .4886). The rare-variant analysis found no evidence of an increased burden of rare genetic variants in people who had experienced LEV-associated psychotic reaction relative to controls. SIGNIFICANCE: The polygenic burden for schizophrenia is a risk factor for LEV-associated psychotic reaction. To assess the clinical utility of PRS as a predictor, it should be tested in an independent and ideally prospective cohort. Larger sample sizes are required for the identification of significant univariate common genetic signals or rare genetic signals associated with psychiatric LEV ADRs.

Antiseizure medication treatment pathways for US Medicare beneficiaries with newly treated epilepsy.

OBJECTIVE: This study was undertaken to characterize antiseizure medication (ASM) treatment pathways in Medicare beneficiaries with newly treated epilepsy. METHODS: This was a retrospective cohort study using Medicare claims. Medicare is the United States' federal health insurance program for people aged 65 years and older plus younger people with disabilities or end-stage renal disease. We included beneficiaries with newly treated epilepsy (International Classification of Diseases codes for epilepsy/convulsions 2014-2017, no ASM in the previous 2 years). We displayed the sequence of ASM fills using sunburst plots overall, then stratified by mood disorder, age, and neurologist prescriber. We tabulated drug costs for each pathway. RESULTS: We included 21 458 beneficiaries. Levetiracetam comprised the greatest number of pill days (56%), followed by gabapentin (11%) and valproate (8%). There were 22 288 unique treatment pathways. The most common pathways were levetiracetam monotherapy (43%), gabapentin monotherapy (10%), and valproate monotherapy (5%). Gabapentin was the most common second- and third-line ASM. Whereas only 2% of pathways involved first-line lacosamide, those pathways accounted for 19% of cost. Gabapentin and valproate use was increased and levetiracetam use was decreased in beneficiaries with mood disorders compared to beneficiaries without mood disorders. Levetiracetam use was increased and gabapentin, valproate, lamotrigine, and topiramate use was decreased in beneficiaries aged >65 years compared with those aged 65 years or less. Lamotrigine, levetiracetam, and lacosamide use was increased and gabapentin use was decreased in beneficiaries whose initial prescriber was a neurologist compared to those whose prescriber was not a neurologist. SIGNIFICANCE: Levetiracetam monotherapy was the most common pathway, although substantial heterogeneity existed. Lacosamide accounted for a small percentage of ASMs but a disproportionately large share of cost. Neurologists were more likely to prescribe lamotrigine compared with nonneurologists, and lamotrigine was prescribed far less frequently than may be endorsed by guidelines. Future work may explore patient- and physician-driven factors underlying ASM choices.

Cost-Effectiveness of Zonisamide Versus Levetiracetam in Newly Diagnosed Focal Onset Epilepsy in Serbia.

OBJECTIVES: When choosing initial therapy for epilepsy, the decision should be supported by studies that include both treatment outcome and costs. This is especially important for developing countries with restricted budgets because such circumstances are also characterized by higher epilepsy prevalence rates. The aim of this study was to compare cost-utility of zonisamide (ZNS) and levetiracetam (LEV) in patients with newly diagnosed focal-onset epilepsy in the Republic of Serbia. METHODS: A 5-state, 3-month-cycle Markov model was created to compare ZNS and LEV. The model assumed that patients whose seizures were not controlled by treatment with either ZNS or LEV would be continued on carbamazepine in controlled-release form in the second cycle and would then be treated with a pregabalin add-on if still not adequately controlled. The perspective of the Serbian Republic Health Insurance Fund was chosen, and the time horizon was 15 years. Model results were obtained after Monte Carlo microsimulation of a sample with 1000 virtual patients. Both multiple one-way and probabilistic sensitivity analyses were performed. RESULTS: After base-case analysis, LEV was dominated by ZNS because the net monetary benefit was positive (16 940.78 ± 22 572.26 Serbian dinars; €144.09 ± €191.99) and the incremental cost-effectiveness ratio was below the willingness-to-pay threshold of 3 Serbian gross domestic products per capita per quality-adjusted life-year gained. Multiple one-way and probabilistic sensitivity analyses confirmed the results of the base-case simulation. CONCLUSIONS: ZNS has a more beneficial cost-effectiveness ratio than LEV for the treatment of newly diagnosed focal epilepsy in Serbian milieu.

Lamotrigine versus levetiracetam or zonisamide for focal epilepsy and valproate versus levetiracetam for generalised and unclassified epilepsy: two SANAD II non-inferiority RCTs.

BACKGROUND: Levetiracetam (Keppra®, UCB Pharma Ltd, Slough, UK) and zonisamide (Zonegran®, Eisai Co. Ltd, Tokyo, Japan) are licensed as monotherapy for focal epilepsy, and levetiracetam is increasingly used as a first-line treatment for generalised epilepsy, particularly for women of childbearing age. However, there is uncertainty as to whether or not they should be recommended as first-line treatments owing to a lack of evidence of clinical effectiveness and cost-effectiveness. OBJECTIVES: To compare the clinical effectiveness and cost-effectiveness of lamotrigine (Lamictal®, GlaxoSmithKline plc, Brentford, UK) (standard treatment) with levetiracetam and zonisamide (new treatments) for focal epilepsy, and to compare valproate (Epilim®, Sanofi SA, Paris, France) (standard treatment) with levetiracetam (new treatment) for generalised and unclassified epilepsy. DESIGN: Two pragmatic randomised unblinded non-inferiority trials run in parallel. SETTING: Outpatient services in NHS hospitals throughout the UK. PARTICIPANTS: Those aged ≥ 5 years with two or more spontaneous seizures that require anti-seizure medication. INTERVENTIONS: Participants with focal epilepsy were randomised to receive lamotrigine, levetiracetam or zonisamide. Participants with generalised or unclassifiable epilepsy were randomised to receive valproate or levetiracetam. The randomisation method was minimisation using a web-based program. MAIN OUTCOME MEASURES: The primary outcome was time to 12-month remission from seizures. For this outcome, and all other time-to-event outcomes, we report hazard ratios for the standard treatment compared with the new treatment. For the focal epilepsy trial, the non-inferiority limit (lamotrigine vs. new treatments) was 1.329. For the generalised and unclassified epilepsy trial, the non-inferiority limit (valproate vs. new treatments) was 1.314. Secondary outcomes included time to treatment failure, time to first seizure, time to 24-month remission, adverse reactions, quality of life and cost-effectiveness. RESULTS: Focal epilepsy. A total of 990 participants were recruited, of whom 330 were randomised to receive lamotrigine, 332 were randomised to receive levetiracetam and 328 were randomised to receive zonisamide. Levetiracetam did not meet the criteria for non-inferiority (hazard ratio 1.329) in the primary intention-to-treat analysis of time to 12-month remission (hazard ratio vs. lamotrigine 1.18, 97.5% confidence interval 0.95 to 1.47), but zonisamide did meet the criteria (hazard ratio vs. lamotrigine 1.03, 97.5% confidence interval 0.83 to 1.28). In the per-protocol analysis, lamotrigine was superior to both levetiracetam (hazard ratio 1.32, 95% confidence interval 1.05 to 1.66) and zonisamide (hazard ratio 1.37, 95% confidence interval 1.08 to 1.73). For time to treatment failure, lamotrigine was superior to levetiracetam (hazard ratio 0.60, 95% confidence interval 0.46 to 0.77) and zonisamide (hazard ratio 0.46, 95% confidence interval 0.36 to 0.60). Adverse reactions were reported by 33% of participants starting lamotrigine, 44% starting levetiracetam and 45% starting zonisamide. In the economic analysis, both levetiracetam and zonisamide were more costly and less effective than lamotrigine and were therefore dominated. Generalised and unclassifiable epilepsy. Of 520 patients recruited, 260 were randomised to receive valproate and 260 were randomised to receive to levetiracetam. A total of 397 patients had generalised epilepsy and 123 had unclassified epilepsy. Levetiracetam did not meet the criteria for non-inferiority in the primary intention-to-treat analysis of time to 12-month remission (hazard ratio 1.19, 95% confidence interval 0.96 to 1.47; non-inferiority margin 1.314). In the per-protocol analysis of time to 12-month remission, valproate was superior to levetiracetam (hazard ratio 1.68, 95% confidence interval 1.30 to 2.15). Valproate was superior to levetiracetam for time to treatment failure (hazard ratio 0.65, 95% confidence interval 0.50 to 0.83). Adverse reactions were reported by 37.4% of participants receiving valproate and 41.5% of those receiving levetiracetam. Levetiracetam was both more costly (incremental cost of £104, 95% central range -£587 to £1234) and less effective (incremental quality-adjusted life-year of -0.035, 95% central range -0.137 to 0.032) than valproate, and was therefore dominated. At a cost-effectiveness threshold of £20,000 per quality-adjusted life-year, levetiracetam was associated with a probability of 0.17 of being cost-effective. LIMITATIONS: The SANAD II trial was unblinded, which could have biased results by influencing decisions about dosing, treatment failure and the attribution of adverse reactions. FUTURE WORK: SANAD II data could now be included in an individual participant meta-analysis of similar trials, and future similar trials are required to assess the clinical effectiveness and cost-effectiveness of other new treatments, including lacosamide and perampanel. CONCLUSIONS: Focal epilepsy - The SANAD II findings do not support the use of levetiracetam or zonisamide as first-line treatments in focal epilepsy. Generalised and unclassifiable epilepsy - The SANAD II findings do not support the use of levetiracetam as a first-line treatment for newly diagnosed generalised epilepsy. For women of childbearing potential, these results inform discussions about the benefit (lower teratogenicity) and harm (worse seizure outcomes and higher treatment failure rate) of levetiracetam compared with valproate. TRIAL REGISTRATION: Current Controlled Trials ISRCTN30294119 and EudraCT 2012-001884-64. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 75. See the NIHR Journals Library website for further project information.

BACKGROUND AND METHODS: The SANAD II trial was a clinical trial designed to identify the most clinically effective and cost-effective treatment for adults and children aged > 5 years with newly diagnosed epilepsy. There are two main epilepsy types: focal and generalised. In focal epilepsy, seizures start at a single place in the brain (a focus), whereas in generalised epilepsy seizures start in both sides of the brain at the same time. Anti-seizure medications are the main treatment. For people with newly diagnosed epilepsy, the first anti-seizure medication should control the seizures as quickly as possible while avoiding side effects. The first-choice treatments are lamotrigine (Lamictal®, GlaxoSmithKline plc, Brentford, UK) for focal epilepsy and valproate (Epilim®, Sanofi SA, Paris, France) for generalised epilepsy (however, the latter should be avoided in women who could become pregnant). A number of newer anti-seizure medications have been approved for NHS use, but it is unclear whether or not they should be used as first-line treatments. The SANAD II trial focused on the new medicines levetiracetam (Keppra®, UCB Pharma Ltd, Slough, UK) and zonisamide (Zonegran®, Eisai Co. Ltd, Tokyo, Japan). We recruited 1510 people aged ≥ 5 years with newly diagnosed epilepsy: 990 with focal epilepsy and 520 with generalised or unclassified epilepsy. FINDINGS: FOCAL EPILEPSY: People starting treatment with levetiracetam or zonisamide were significantly less likely to have a 12-month remission from seizures than people starting treatment with lamotrigine, unless they were changed to another anti-seizure medication. Side effects that were thought to be caused by anti-seizure medications were reported by 33% of participants starting lamotrigine, 44% of those starting levetiracetam and 45% of those starting zonisamide. The cost-effectiveness analyses showed that neither levetiracetam nor zonisamide is value for money for the NHS when compared with lamotrigine. The SANAD II findings do not support the use of levetiracetam or zonisamide as first-line treatments in focal epilepsy. FINDINGS: GENERALISED AND UNCLASSIFIABLE EPILEPSY: People starting treatment with levetiracetam were significantly less likely to have a 12-month remission from seizures than people starting valproate, unless they were changed to another anti-seizure medication. Side effects that were thought to be caused by anti-seizure medications were reported by 37% of participants starting valproate and 42% of participants starting levetiracetam. The cost-effectiveness analyses showed that levetiracetam is not good value for money for the NHS when compared with valproate. The SANAD II findings do not support the use of levetiracetam as a first-line treatment for newly diagnosed generalised epilepsy. Importantly, our results will inform treatment decisions for women, who may choose a less effective treatment that is safer in pregnancy.

Adherence to levetiracetam for management of epilepsy: Assessment with electronic monitors.

INTRODUCTION: Anti-seizure medications are used to manage epilepsy and require long-term adherence to maintain therapeutic drug levels. We assessed adherence to levetiracetam and the use of a digital intervention to improve adherence in patients with epilepsy. METHODS: 30 participants with epilepsy were randomized 1:1 either to a digital email adherence intervention or control group. All patients were provided levetiracetam equipped with electronic monitoring caps to assess patient adherence to medication. Patients were followed for 6 months, with return visits at 1 month, 3 months, and 6 months. RESULTS: Subjects randomized to the control arm (n = 15) took 66% of the prescribed doses compared to the intervention group, who took 65% of prescribed doses (n = 15). Nine participants did not complete the study. Of the twenty-one participants that completed the study, the overall rate of adherence was 72% of prescribed doses taken. Two subjects in the control group and three subjects in the intervention group were adherent every month of the study-taking at least 80% of prescribed doses. Those randomized to the control group took the correct number of doses 44% of days in the study, and those in the intervention group took the correct number of doses 37% of days. DISCUSSION: Poor adherence to levetiracetam is common. An internet-based email survey intervention did not improve adherence to levetiracetam in epilepsy patients. Further advances in adherence are needed to help patients receive the maximum benefit of their medical treatments.

Inclusão de novas apresentações de comprimidos de levetiracetam (500 mg e 1000 mg) como tratamento adjuvante para epilepsia / Inclusion of new presentations of levetiracetam tablets (500 mg and 1000 mg) as adjuvant treatment for epilepsy

INTRODUÇÃO: levetiracetam na forma farmacêutica comprimido é ofertado pelo SUS e consta no PCDT de epilepsia nas concentrações de 250 mg e 750 mg para as indicações previamente mencionadas, em dose diária para adultos variando de 1000 a 3000 mg e para crianças e adolescentes entre 500 e 3000 mg, com administração dos comprimidos a cada 12 horas. A demanda avaliada neste documento se refere à adição dos comprimidos de 500 mg e 1000 mg de levetiracetam ao arsenal terapêutico de tratamento para epilepsia, sem modificação do esquema posológico atualmente praticado e recomendado em PCDT. TECNOLOGIA: levetiracetam em comprimidos de 500 mg e 1000 mg. PERGUNTAS: levetiracetam em comprimidos de 500 mg e 1000 mg é clinicamente equivalente a levetiracetam em comprimidos de 250 mg e 750 mg? A adição dos comprimidos de 500 mg e 1000 mg como opções de tratamento adjuvante para epilepsia geraria economia ao Sistema Único de Saúde? EVIDÊNCIAS CLÍNICAS: o estudo de bioequivalência entre levetiracetam 1000 mg (Etira®) e 750 mg (Keppra®) foi considerado como evidência clínica. O estudo concluiu pela comparabilidade entre os comprimidos após normalização pela dose. Dessa forma, os comprimidos nas concentrações de 500 mg e 1000 mg poderiam se tornar opções de tratamento em adição aos comprimidos já listados em PCDT de 250 mg e 750 mg, sem prejuízo da eficácia clínica. AVALIAÇÃO ECONÔMICA: a análise de custo-minimização foi refeita pela Secretaria Executiva da Conitec. Nesta análise, foram explorados diversos cenários comparando o cenário atual (levetiracetam em comprimidos de 250 mg e 750 mg) com o cenário proposto (levetiracetam em comprimidos de 250 mg, 500 mg, 750 mg e 1000 mg). No cenário caso base foram considerados custos médios de compras públicas e o menor número possível de comprimidos por tomada (maior conforto ao paciente). Esta análise resultou em economia em 4 das 6 doses diárias avaliadas: 1500 mg (-R$ 460 por paciente ao ano), 2000 mg (-R$ 124), 2500 mg (-R$ 124) e 3000 mg (-R$ 584), mas não para a de 1000 mg (+R$ 854). No caso da dose diária de 500 mg, como o paciente recebe apenas 1 comprimido de 250 mg por tomada, não haveria alteração nos custos anuais por paciente. Em cenários alternativos, foram avaliados custos mínimos e máximos de compras públicas bem como custos da tabela CMED PMVG 18%. Além disso, foram exploradas todas as combinações possíveis entre comprimidos para se atingir a dose por tomada. As análises com todos os cenários mostraram que, em geral, os cenários com os comprimidos atualmente disponíveis são mais econômicos, menos quando o comprimido de 750 mg (preço médio) é substituído. Considerando todos os cenários explorados, a incorporação dos comprimidos de 500 mg e 1000 mg poderia gerar desde uma economia anual por paciente de R$1.854 até um ônus de R$3.548. ANÁLISE DE IMPACTO ORÇAMENTÁRIO: a análise de impacto orçamentário foi refeita pela Secretaria Executiva da Conitec, considerando dados de consumo real de levetiracetam no SUS. No cenário caso base, foram considerados custos médios de compras públicas e as mesmas combinações de comprimidos utilizadas na análise de custo-minimização. Além disso, foi considerado que 50% da população usaria combinações envolvendo os comprimidos de 500 mg e 1000 mg. Este cenário resultou em um impacto acumulado ao longo de 5 anos de R$ 10.219.437 (aumento de 2,6% nos gastos com levetiracetam). Em cenários alternativos, foram explorados custos mínimos e máximos de compras públicas e da lista CMED, bem como utilização dos comprimidos de 500 mg e 1000 mg por 50% ou 100% da população. As análises de cenários alternativos estimaram incrementos no orçamento com a incorporação dos comprimidos de 500 mg e 1000 mg variando de R$ 10.219.437 a R$ 248.709.722 acumulados em 5 anos. Como essa análise é realizada em nível populacional, ponderando as doses diárias, a potencial economia observada para algumas doses na análise de custo-minimização acaba dominada pelo ônus das doses mais caras na análise de impacto orçamentário. CONSIDERAÇÕES FINAIS: o estudo de bioequivalência comprovou que os comprimidos de 500 mg e 1000 mg podem ser adicionados às opções de levetiracetam citados em PCDT (atualmente, comprimidos de 250 mg e 750 mg), sendo mantido o benefício clínico. Em relação às análises econômicas, a análise caso base, na qual foram considerados custos médios de compras públicas, mostrou potencial economia com a incorporação dos comprimidos de 500 mg e 1000 mg para as doses diárias entre 1500 mg e 3000 mg, mas não para a dose de 1000 mg. Análises alternativas sugerem que possa haver desde economia até ônus. Economia é observada geralmente quando o comprimido de 750 mg (preço médio) é substituído. A análise de impacto orçamentário mostrou para todos os cenários incremento no orçamento ao longo de 5 anos, quando ponderadas todas as doses simultaneamente no consumo populacional. RECOMENDAÇÃO PRELIMINAR DA CONITEC: Diante do exposto, a Conitec, em sua 98ª reunião ordinária, realizada no dia 09 de junho de 2021, deliberou que a matéria fosse disponibilizada em consulta pública com recomendação preliminar não favorável à incorporação no SUS de novas apresentações de comprimidos de levetiracetam nas concentrações de 500 mg e 1000 mg como terapia adjuvante de epilepsia para tratamento de crises focais/parciais com ou sem generalização secundária, de crises tônico-clônicas primárias generalizadas em pacientes com epilepsia idiopática generalizada, e de crises mioclônicas secundárias em pacientes com epilepsia mioclônica juvenil. Considerou-se após apreciação inicial do parecer técnico-científico que é previsto incremento nos gastos com levetiracetam sem vantagens significativas aos pacientes. CONSULTA PÚBLICA: A Consulta Pública nº 58 foi realizada entre os dias 30/06/2021 e 19/07/2021. Foram recebidas 452 contribuições, sendo 62 pelo formulário para contribuições técnico-científicas e 390 pelo formulário para contribuições sobre experiência ou opinião de pacientes, de familiares, amigos ou cuidadores de pacientes, de profissionais de saúde ou de pessoas interessadas no tema. As contribuições enviadas foram majoritariamente (>99%) favoráveis à incorporação, destacando pontos positivos como comodidade posológica e adesão ao tratamento devido à possibilidade de ingerir um menor número de comprimidos por tomada. O demandante do pedido de incorporação (Aché Laboratórios Farmacêuticos SA) apresentou uma nova proposta de preço para os comprimidos de 500 e 1000 mg e, após atualização dos modelos de custo-minimização e de impacto orçamentário pelo DGITIS, há previsão de economia para todas as doses previstas em PCDT e redução orçamentária estimada em R$ 45.992.096 acumulados em 5 anos. RECOMENDAÇÃO FINAL DA CONITEC: o plenário da Conitec, em sua 101ª Reunião Ordinária, no dia 01 de setembro de 2021, deliberou por unanimidade recomendar a incorporação de novas apresentações de comprimidos de levetiracetam (500 mg e 1000 mg) como tratamento adjuvante para epilepsia. Considerou-se após proposta de preço enviada pelo demandante durante a consulta pública que é previsto economia para o SUS com a disponibilização destas apresentações como opção terapêutica. Por fim, foi assinado o Registro de Deliberação nº 661/2021. Decisão: Incorporar novas apresentações de comprimidos de levetiracetam (500 mg e 1000 mg) como tratamento adjuvante para epilepsia, no âmbito do Sistema Único de Saúde ­ SUS, conforme a Portaria nº 67, publicada no Diário Oficial da União nº 185, seção 1, página 113, em 29 de setembro de 2021.

Levetiracetam dosing in patients receiving continuous renal replacement therapy.

OBJECTIVE: The study was aimed to define appropriate levetiracetam dosing regimens from available published pharmacokinetics (PK) studies in critically ill patients with and without cirrhosis receiving continuous renal replacement therapy (CRRT) via Monte Carlo simulation (MCS). METHODS: Mathematical pharmacokinetic models were developed using published demographic and PK data in adult critically ill patients with known variability and correlations between PK parameters. CRRT modalities (continuous venovenous hemofiltration and continuous venovenous hemodialysis) with different effluent rates were modeled. Levetiracetam regimens from available clinical resources were evaluated on the probability of target attainment (PTA) using pharmacodynamics (PD) target of the trough concentrations and area under the time-concentration curve within a range of 6-20 mg/L and 222-666 mg × hour/L for the initial 72 hours of therapy, respectively. Optimal regimens were defined from regimens that yielded the highest PTA. Each regimen was tested in a group of different 10,000 virtual patients. RESULTS: Our results showed the optimal levetiracetam dosing regimen of 750-1000 mg every 12 hours is recommended for adult patients receiving both CRRT modalities with two different effluent rates of 25 and 35 mL/kg/h. Child-Pugh class C cirrhotic patients undergoing CRRT required lower dosing regimens of 500-750 mg every 12 ours due to smaller non-renal clearance. Of interest, some of literature-based dosing regimens were not able to attain the PK and PD targets. SIGNIFICANCE: Volume of distribution, non-renal clearance, CRRT clearance, and body weight were significantly correlated with the PTA targets. Dosing adaptation in this vulnerable population should be concerned. Clinical validation of our finding is absolutely needed.