RESUMEN
INTRODUCTION: Cannabidiol (CBD) is one of the main components of the cannabis plant that has demonstrated anti-epileptic seizure effect. Following its clinical development, in September 2019 the European Medicines Agency approved its indication for the adjunctive therapy of epileptic seizures associated with Lennox-Gastaut syndrome (LGS) and Dravet syndrome (DS), combined with clobazam (CLB), in patients of 2 years of age and older. AIM: To establish recommendations on the use of plant-derived highly purified CBD on which Spanish experts have reached consensus for the treatment of epilepsy in patients with DS and LGS based on their clinical experience and the scientific evidence. DEVELOPMENT: Consensus meeting with the participation of four Spanish neurologists and neuropediatric who are experts in epilepsy secondary to DS and LGS and with clinical experience in the use and management of CBD. They discussed on several topics, including posology (starting dose, dose escalation schema), efficacy (assessment of outcomes and indications for treatment withdrawal), and safety (evaluation, drug-drug interactions, adverse events management). CONCLUSIONS: In order to optimise CBD treatment, a slow dose escalation (= 4 weeks) is recommended until the maximum recommended dose or the desire effect is reached. It is also recommended that the concomitant antiseizure medications (ASMs) be reduced in case of adverse events due to interactions, and that the treatment continues for at least 6 months if it is well tolerated. The efficacy and safety of CBD must be assessed individually, considering the benefits and risks for individual patients.
TITLE: Cannabidiol para el tratamiento del síndrome de Lennox-Gastaut y del síndrome de Dravet: recomendaciones de expertos sobre su uso en la práctica clínica en España.Introducción. El cannabidiol (CBD) es uno de los componentes principales de la planta del cannabis que ha demostrado efecto ante las crisis epilépticas. Tras su desarrollo clínico, obtuvo su aprobación por la Agencia Europea del Medicamento en septiembre de 2019 para el tratamiento de las crisis epilépticas asociadas con el síndrome de Lennox-Gastaut (SLG) y el síndrome de Dravet (SD), en combinación con el clobazam (CLB), en pacientes a partir de los dos años. Objetivo. Establecer unas recomendaciones de manejo del CBD derivado de la planta altamente purificado consensuadas por expertos españoles en el tratamiento de la epilepsia para su uso en pacientes con SD y SLG, basándose en su experiencia clínica y en la evidencia científica. Desarrollo. Reunión de consenso de un grupo de cuatro neurólogos y neuropediatras españoles expertos en el manejo de la epilepsia asociada al SD y el SLG y con experiencia clínica en el uso de CBD. Se debatió sobre diferentes áreas, incluyendo la posología (dosis de inicio, pauta de escalada), la eficacia (valoración de resultados e indicaciones para la suspensión del tratamiento) y la seguridad (evaluación, interacciones entre fármacos, manejo de efectos adversos). Conclusiones. Para optimizar el tratamiento con CBD, se recomienda una pauta lenta de escalada de dosis (de cuatro semanas o más) hasta alcanzar la dosis máxima recomendada o el efecto deseado, reducir los fármacos anticrisis epilépticas concomitantes si aparecen efectos adversos por interacciones y mantener el tratamiento al menos seis meses si se tolera. La eficacia y la seguridad del CBD deben evaluarse de forma individual, considerando el beneficio y el riesgo para cada paciente.
Asunto(s)
Anticonvulsivantes/uso terapéutico , Cannabidiol/uso terapéutico , Epilepsias Mioclónicas/tratamiento farmacológico , Síndrome de Lennox-Gastaut/tratamiento farmacológico , Guías de Práctica Clínica como Asunto , Anticonvulsivantes/administración & dosificación , Anticonvulsivantes/efectos adversos , Cannabidiol/administración & dosificación , Cannabidiol/efectos adversos , Clobazam/administración & dosificación , Clobazam/uso terapéutico , Clonazepam/administración & dosificación , Clonazepam/uso terapéutico , Diazepam/administración & dosificación , Diazepam/uso terapéutico , Dioxolanos/administración & dosificación , Dioxolanos/uso terapéutico , Esquema de Medicación , Sinergismo Farmacológico , Quimioterapia Combinada , Humanos , Fenobarbital/administración & dosificación , Fenobarbital/uso terapéutico , Pirrolidinonas/administración & dosificación , Pirrolidinonas/uso terapéutico , España , Triazoles/administración & dosificación , Triazoles/uso terapéutico , Ácido Valproico/administración & dosificación , Ácido Valproico/uso terapéuticoRESUMEN
BACKGROUND: Lennox-Gastaut syndrome (LGS) is an age-specific epilepsy syndrome characterised by multiple seizure types, including drop seizures. LGS has a characteristic electroencephalogram, an onset before age eight years and an association with drug resistance. This is an updated version of the Cochrane Review published in 2013. OBJECTIVES: To assess the efficacy and tolerability of anti-seizure medications (ASMs) for LGS. SEARCH METHODS: We searched the Cochrane Register of Studies (CRS Web) and MEDLINE (Ovid, 1946 to 28 February 2020) on 2 March 2020. CRS Web includes randomised controlled trials (RCTs) or quasi-RCTs from the Cochrane Central Register of Controlled Trials (CENTRAL); the Specialised Registers of Cochrane Review Groups, including Cochrane Epilepsy; PubMed; Embase; ClinicalTrials.gov; and the World Health Organization's International Clinical Trials Registry Platform (ICTRP). We imposed no language restrictions. We contacted pharmaceutical companies and colleagues in the field to seek any unpublished or ongoing studies. SELECTION CRITERIA: We considered RCTs, including cross-over trials, of ASMs for LGS in children and adults. We included studies of ASMs used as either monotherapy or as an add-on (adjunctive) therapy. We excluded studies comparing different doses of the same ASM. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodological procedures, including independent, dual assessment for risk of bias and application of the GRADE approach to rate the evidence certainty for outcomes. MAIN RESULTS: We found no trials of ASM monotherapy. The review included 11 trials (1277 participants; approximately 11 weeks to 112 weeks follow-up after randomisation) using add-on ASMs for LGS in children, adolescents and adults. Two studies compared add-on cannabidiol (two doses) with add-on placebo in children and adolescents only. Neither study reported overall seizure cessation or reduction. We found high-certainty evidence that 72 more people per 1000 (confidence interval (CI) 4 more to 351 more) had adverse events (AE) leading to study discontinuation with add-on cannabidiol, compared to add-on placebo (two studies; 396 participants; risk ratio (RR) 4.90, 95% CI 1.21 to 19.87). One study compared add-on cinromide with add-on placebo in children and adolescents only. We found very low-certainty evidence that 35 more people per 1000 (CI 123 fewer to 434 more) had 50% or greater average reduction of overall seizures with add-on cinromide compared to add-on placebo (one study; 56 participants; RR 1.15, 95% CI 0.47 to 2.86). This study did not report participants with AE leading to study discontinuation. One study compared add-on clobazam (three doses) with add-on placebo. This study did not report overall seizure cessation or reduction. We found high-certainty evidence that 106 more people per 1000 (CI 0 more to 538 more) had AE leading to study discontinuation with add-on clobazam compared to add-on placebo (one study; 238 participants; RR 4.12, 95% CI 1.01 to 16.87). One study compared add-on felbamate with add-on placebo. No cases of seizure cessation occurred in either regimen during the treatment phase (one study; 73 participants; low-certainty evidence). There was low-certainty evidence that 53 more people per 1000 (CI 19 fewer to 716 more) with add-on felbamate were seizure-free during an EEG recording at the end of the treatment phase, compared to add-on placebo (RR 2.92, 95% CI 0.32 to 26.77). The study did not report overall seizure reduction. We found low-certainty evidence that one fewer person per 1000 (CI 26 fewer to 388 more) with add-on felbamate had AE leading to study discontinuation compared to add-on placebo (one study, 73 participants; RR 0.97, 95% CI 0.06 to 14.97). Two studies compared add-on lamotrigine with add-on placebo. Neither study reported overall seizure cessation. We found high-certainty evidence that 176 more people per 1000 (CI 30 more to 434 more) had ≥ 50% average seizure reduction with add-on lamotrigine compared to add-on placebo (one study; 167 participants; RR 2.12, 95% CI 1.19 to 3.76). We found low-certainty evidence that 40 fewer people per 1000 (CI 68 fewer to 64 more) had AE leading to study-discontinuation with add-on lamotrigine compared to add-on placebo (one study; 169 participants; RR 0.49, 95% CI 0.13 to 1.82). Two studies compared add-on rufinamide with add-on placebo. Neither study reported seizure cessation. We found high-certainty evidence that 202 more people per 1000 (CI 34 to 567 more) had ≥ 50% average seizure reduction (one study; 138 participants; RR 2.84, 95% CI 1.31 to 6.18). We found low-certainty evidence that 105 more people per 1000 (CI 17 fewer to 967 more) had AE leading to study discontinuation with add-on rufinamide compared to add-on placebo (one study; 59 participants; RR 4.14, 95% CI 0.49 to 34.86). One study compared add-on rufinamide with another add-on ASM. This study did not report overall seizure cessation or reduction. We found low-certainty evidence that three fewer people per 1000 (CI 75 fewer to 715 more) had AE leading to study discontinuation with add-on rufinamide compared to another add-on ASM (one study; 37 participants; RR 0.96, 95% CI 0.10 to 9.57). One study compared add-on topiramate with add-on placebo. This study did not report overall seizure cessation. We found low-certainty evidence for ≥ 75% average seizure reduction with add-on topiramate (one study; 98 participants; Peto odds ratio (Peto OR) 8.22, 99% CI 0.60 to 112.62) and little or no difference to AE leading to study discontinuation compared to add-on placebo; no participants experienced AE leading to study discontinuation (one study; 98 participants; low-certainty evidence). AUTHORS' CONCLUSIONS: RCTs of monotherapy and head-to-head comparison of add-on ASMs are currently lacking. However, we found high-certainty evidence for overall seizure reduction with add-on lamotrigine and rufinamide, with low-certainty evidence for AE leading to study discontinuation compared with add-on placebo or another add-on ASM. The evidence for other add-on ASMs for overall seizure cessation or reduction was low to very low with high- to low-certainty evidence for AE leading to study discontinuation. Future research should consider outcome reporting of overall seizure reduction (applying automated seizure detection devices), impact on development, cognition and behaviour; future research should also investigate age-specific efficacy of ASMs and target underlying aetiologies.
Asunto(s)
Síndrome de Lennox-Gastaut/tratamiento farmacológico , Adolescente , Adulto , Edad de Inicio , Anticonvulsivantes/administración & dosificación , Anticonvulsivantes/efectos adversos , Cannabidiol/administración & dosificación , Cannabidiol/efectos adversos , Niño , Preescolar , Cinamatos/administración & dosificación , Cinamatos/efectos adversos , Clobazam/administración & dosificación , Electroencefalografía , Felbamato/administración & dosificación , Humanos , Lamotrigina/administración & dosificación , Persona de Mediana Edad , Placebos/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Topiramato/administración & dosificación , Triazoles/administración & dosificación , Vigilia/fisiología , Adulto JovenRESUMEN
INTRODUCTION: Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS) are two serious epileptic syndromes with paediatric onset which are refractory to therapy and are associated with an important increase in mortality rates and comorbidities compared to the general population. These pathologies have a strong impact on the lives of patients and their families, because they undergo multiple pharmacological therapies (many of them without specific indication), with frequent changes due to poor efficacy and associated adverse effects. The specialists who care for these patients highlight unmet needs and the lack of specific, safe and effective treatments for better management of the syndrome. DEVELOPMENT: A group of four neurologists specializing in epilepsy has met to review the scientific literature and evaluate the efficacy and safety of oral solution cannabidiol in the treatment of these syndromes, both in randomized clinical trials (CT) and in some observational studies. CONCLUSIONS: Cannabidiol is positioned as an innovative therapy that allows better control of epileptic seizures and comorbidities of DS and LGS, furthermore its efficacy and safety have been evaluated in more than 700 patients. In CTs, cannabidiol significantly reduced the percentage of convulsive seizures and drop seizures compared to placebo in patients with DS and LGS respectively, which could improve their quality of life and that of their family members. The most frequent adverse effects reported were somnolence and decreased appetite. Elevated liver aminotransferase levels were also reported, especially in patients given concomitant sodium valproate. This therapy may allow better control of the epileptic seizures associated with these syndromes.
TITLE: Cannabidiol en los síndromes de Dravet y Lennox-Gastaut: un nuevo abordaje terapéutico.Introducción. Los síndromes de Dravet (SD) y Lennox-Gastaut (SLG) son dos síndromes epilépticos graves y de inicio en la edad pediátrica, refractarios al tratamiento, asociados a un notable incremento en las tasas de mortalidad y comorbilidades respecto a la población general. Suponen un fuerte impacto en la vida de los pacientes y sus familiares, ya que los pacientes están sometidos a múltiples terapias farmacológicas (muchas sin indicación específica), con cambios frecuentes debido a la escasa eficacia y a los efectos adversos. Los especialistas que les atienden destacan las necesidades no cubiertas y la falta de tratamientos específicos, seguros y eficaces para un mejor manejo de la enfermedad. Desarrollo. Se ha reunido un grupo formado por cuatro neurólogos especialistas en epilepsia para hacer una revisión de la literatura científica y evaluar los resultados de eficacia y seguridad de la solución oral de cannabidiol en el tratamiento de estos síndromes, tanto en ensayos clínicos aleatorizados como en diversos estudios observacionales. Conclusiones. El cannabidiol se sitúa como una terapia innovadora que permite un mejor control de las crisis epilépticas y comorbilidades del SD y el SLG; además, su eficacia y seguridad han sido evaluadas en más de 700 pacientes. En los ensayos clínicos redujo significativamente el porcentaje de crisis convulsivas y de caída en comparación con placebo en los pacientes con SD y SLG, respectivamente, y puede mejorar su calidad de vida y la de sus familiares. Los efectos adversos más frecuentes fueron la somnolencia y la disminución del apetito. También se notificaron niveles elevados de aminotransferasas hepáticas, especialmente en pacientes tratados concomitantemente con ácido valproico. Esta terapia podría permitir un mejor control de las crisis epilépticas asociadas a estas patologías.
Asunto(s)
Anticonvulsivantes/uso terapéutico , Cannabidiol/uso terapéutico , Epilepsias Mioclónicas/tratamiento farmacológico , Síndrome de Lennox-Gastaut/tratamiento farmacológico , Administración Oral , Adolescente , Algoritmos , Anticonvulsivantes/efectos adversos , Anticonvulsivantes/farmacocinética , Cannabidiol/administración & dosificación , Cannabidiol/efectos adversos , Cannabidiol/farmacocinética , Niño , Preescolar , Ensayos Clínicos Fase III como Asunto , Clobazam/administración & dosificación , Clobazam/farmacocinética , Clobazam/uso terapéutico , Ensayos de Uso Compasivo , Método Doble Ciego , Epilepsia Refractaria/tratamiento farmacológico , Sinergismo Farmacológico , Humanos , Lactante , Resultado del TratamientoRESUMEN
OBJECTIVES: To assess the efficacy and safety profile of add-on cannabidiol (CBD) in patients with Lennox-Gastaut syndrome (LGS) and Dravet syndrome (DS) on clobazam and in the overall population of four randomized, controlled phase 3 trials. METHODS: Patients received plant-derived, highly purified CBD medicine (Epidiolex® in the USA; Epidyolex® in Europe; 100 mg/ml oral solution) at a dose of 10 or 20 mg/kg/day, or placebo for 14 weeks. A subgroup analysis of patients on clobazam and meta-analysis by syndrome were conducted. The primary endpoint was percentage reduction in primary seizure type during the treatment period. RESULTS: 396 patients with LGS (49% on clobazam) and 318 patients with DS (64% on clobazam) were included. CBD treatment resulted in a reduction in primary seizure frequency vs placebo in the overall population (treatment ratio [95% confidence interval]: LGS, 0.70 [0.62-0.80]; DS, 0.71 [0.60-0.83]) and in patients receiving clobazam (LGS, 0.56 [0.47-0.67]; DS, 0.63 [0.52-0.77]). The antiseizure efficacy of CBD was also demonstrated across other endpoints vs placebo (≥50% responder rate, total seizure frequency, number of seizure-free days, and Subject/Caregiver Global Impression of Change scores) in the overall populations and in patients receiving clobazam. There were higher incidences of somnolence and sedation in patients on CBD and clobazam. Most incidences of elevated transaminases occurred in patients on concomitant valproate and, to a lesser extent, clobazam. CONCLUSIONS: Add-on CBD was effective in reducing seizures in the overall populations and in conjunction with clobazam. Somnolence and sedation occurred more frequently in patients on CBD and clobazam.
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Anticonvulsivantes/uso terapéutico , Cannabidiol/uso terapéutico , Clobazam/uso terapéutico , Epilepsias Mioclónicas/tratamiento farmacológico , Síndrome de Lennox-Gastaut/tratamiento farmacológico , Adulto , Anticonvulsivantes/administración & dosificación , Anticonvulsivantes/efectos adversos , Cannabidiol/administración & dosificación , Cannabidiol/efectos adversos , Clobazam/administración & dosificación , Clobazam/efectos adversos , Femenino , Humanos , Masculino , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
OBJETIVO: El objetivo del presente trabajo es brindar una revisión sistemática y actualizada acerca de la farmacología de cannabidiol, con especial énfasis en la farmacocinética, eventos adversos e interacciones, vinculada al uso de este fármaco en epilepsias refractarias. MÉTODO: Se realizó una revisión de los trabajos publicados y relaciona-dos con la farmacocinética y los eventos adversos e interacciones farmacológicas de cannabidiol utilizado para el tratamiento de las epilepsias refractarias mediante una búsqueda en PubMed y LILACS. RESULTADOS: Los estudios originales que describen la farmacocinética de cannabidiol de manera exhaustiva son limitados aunque informativos. La absorción de cannabidiol es rápida y se incrementa la biodisponibilidad por la ingesta conjunta de comidas ricas en grasas. El cannabidiol presenta farmacocinética lineal hasta dosis de 3.000 mg/día y se acumula por la administración continua. La semivida de eliminación se referencia entre 14 y 60 horas dependiendo de los tiempos de toma de muestra del estudio farmacocinético y no se descartan modificaciones en la eliminación por la administración en dosis múltiples. De las interacciones farmacológicas entre cannabidiol con otros fármacos antiepilépticos referenciadas hasta el momento, aquella con clobazam es la que presenta mayor evidencia científica. Los eventos adversos más frecuentes asociados al uso de cannabidiol fueron de gravedad leve o moderada e incluyeron somnolencia, principalmente por el uso conjunto de clobazam, y alteraciones gastrointestinales. Se evidenciaron asimismo anormalidades en la función hepática concomitantes con el uso de ácido valproico. CONCLUSIONES: Ante la creciente demanda de la utilización de cannabidiol en epilepsias refractarias, es fundamental el conocimiento de su farmacología por parte del equipo de salud. En especial, el farmacéutico clínico juega un papel primordial en la monitorización de su seguridad y eficacia. Esto permite la optimización del tratamiento clínico del cannabidiol administrado conjuntamente con otros fármacos antiepilépticos de mayor uso, lo que conduce a maximizar la actividad farmacológica y minimizar la aparición de eventos adversos al igual que de interacciones farmacológicas. El seguimiento clínico del paciente resulta fundamental para evitar la discontinuación del tratamiento o exacerbación de eventos adversos que afecten la calidad de vida del paciente
OBJECTIVE: The aim of this article is to provide a systematic and updated review on the pharmacology of cannabidiol in the context of refractory epilepsy, with special emphasis on its pharmacokinetics, adverse drug reactions and drug-drug interactions. METHOD: A review of the literature related to cannabidiol pharmacokinetics, adverse drug reactions and drug-drug interactions was carried out in the context of refractory epilepsy, through a search in PubMed and LILACS. RESULTS: Original studies that exhaustively describe the pharmacokinetics of cannabidiol are limited but informative. Cannabidiol is rapidly absorbed and its bioavailability increases when administered with high fat meals. Cannabidiol exhibits a linear pharmacokinetic profile for doses up to 3,000 mg/day and accumulates after multiple administrations. Elimination half-life has been reported between 14 h and 60 h depending on the sampling times of each study; changes in cannabidiol elimination due to continuous administration cannot be discarded. Of all reported drug-drug interactions with anticonvulsants or other co-administered drugs in patients with epilepsy, the strongest evidence is provided with clobazam. The most frequent cannabidiol-related adverse drug reactions were low to moderate and included somnolence, mainly related to concomitant administration of clobazam, and gastrointestinal alterations. Also, liver function abnormalities were reported during the use of cannabidiol and valproic acid. CONCLUSIONS: Given the increased use of cannabidiol in refractory epilepsy, a comprehensive understanding of its pharmacological profile is essential for the clinical team. Specifically, clinical pharmacists play an important role in monitoring cannabidiol's safety and efficacy. This approach leads to treatment optimization, allowing to maximizing the pharmacological activity and minimizing the occurrence of adverse events as well as drug-to-drug interactions. Clinical follow-up is essential to avoid discontinuation of treatment or exacerbation of adverse events, which may impair the patients' quality of life
Asunto(s)
Humanos , Animales , Epilepsia Refractaria/tratamiento farmacológico , Cannabidiol/farmacocinética , Cannabidiol/efectos adversos , Cannabidiol/administración & dosificación , Clobazam/administración & dosificación , Calidad de VidaRESUMEN
We investigated the effects of cannabidiol (CBD; 21-day maintenance dose) on the pharmacokinetics (PK) of clobazam (CLB) and monitored the safety of CBD (or placebo) plus CLB in 20 patients with uncontrolled epilepsy on stable doses of CLB. Blood samples collected until 24 hours postdose were evaluated by liquid chromatography tandem mass spectrometry. PK parameters of CLB and major metabolite N-desmethylclobazam (N-CLB), valproic acid, stiripentol, levetiracetam, topiramate, plant-derived highly purified CBD (Epidiolex in the United States; 100 mg/mL oral solution) and its major metabolites were derived using noncompartmental analysis. There was no evidence of a drug-drug interaction (DDI) between CBD and CLB: geometric mean ratio (GMR) of day 33:day 1 CLB was 1.0 (90%CI, 0.8-1.2) for Cmax and 1.1 (90%CI, 0.9-1.2) for AUCtau . There was a significant DDI between CBD and N-CLB: the GMR of day 33:day 1 N-CLB was 2.2 (90%CI, 1.4-3.5) for Cmax and 2.6 (90%CI, 2.0-3.6) for AUCtau . Placebo had no effect on CLB or N-CLB; CBD had no effect on levetiracetam. Data were insufficient regarding DDIs with other antiepileptic drugs. The safety profile of CBD (20 mg/kg/day) with CLB was acceptable; all but 1 adverse events (AEs) were mild or moderate. One serious AE (seizure cluster) led to CBD discontinuation. One patient withdrew after intolerable AEs. Although there was no evidence of a CBD and CLB DDI, there was a significant DDI between CBD and N-CLB. The safety profile of GW Pharmaceuticals' CBD formulation with CLB was consistent with other GW-sponsored trials.
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Anticonvulsivantes/farmacocinética , Cannabidiol/farmacocinética , Clobazam/farmacocinética , Adulto , Anticonvulsivantes/administración & dosificación , Anticonvulsivantes/efectos adversos , Anticonvulsivantes/sangre , Cannabidiol/administración & dosificación , Cannabidiol/efectos adversos , Cannabidiol/sangre , Clobazam/administración & dosificación , Clobazam/efectos adversos , Clobazam/sangre , Método Doble Ciego , Interacciones Farmacológicas , Quimioterapia Combinada/efectos adversos , Epilepsia/sangre , Epilepsia/tratamiento farmacológico , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
OBJECTIVE: The efficacy of cannabidiol (CBD) with and without concomitant clobazam (CLB) was evaluated in stratified analyses of four large randomized controlled trials, two in Lennox-Gastaut syndrome, and two in Dravet syndrome. METHODS: Each trial of CBD (Epidiolex® in the US; Epidyolex® in the EU; 10 and 20 mg/kg/day) was evaluated by CLB use. The treatment ratio was analyzed using negative binomial regression for changes in seizure frequency and logistic regression for the 50% responder rate, where the principle analysis combined both indications and CBD doses in a stratified meta-analysis. Pharmacokinetic data were examined for an exposure/response relationship based on CLB presence/absence. Safety data were analyzed using descriptive statistics. RESULTS: The meta-analysis favored CBD vs. placebo regardless of CLB use. The treatment ratio (95% CI) of CBD over placebo for the average reduction in seizure frequency was 0.59 (0.52, 0.68; P < .0001) with CLB and 0.85 (0.73, 0.98; P = .0226) without CLB, and the 50% responder rate odds ratio (95% CI) was 2.51 (1.69, 3.71; P < .0001) with CLB and 2.40 (1.38, 4.16; P = .0020) without CLB. Adverse events (AEs) related to somnolence, rash, pneumonia, or aggression were more common in patients with concomitant CLB. There was a significant exposure/response relationship for CBD and its active metabolite. CONCLUSIONS: These results indicate CBD is efficacious with and without CLB, but do not exclude the possibility of a synergistic effect associated with the combination of agents. The safety and tolerability profile of CBD without CLB show a lower rate of certain AEs than with CLB.
Asunto(s)
Anticonvulsivantes/administración & dosificación , Cannabidiol/administración & dosificación , Clobazam/administración & dosificación , Epilepsias Mioclónicas/tratamiento farmacológico , Síndrome de Lennox-Gastaut/tratamiento farmacológico , Cannabidiol/efectos adversos , Clobazam/efectos adversos , Quimioterapia Combinada , Epilepsias Mioclónicas/complicaciones , Humanos , Síndrome de Lennox-Gastaut/complicaciones , Ensayos Clínicos Controlados Aleatorios como Asunto , Convulsiones/tratamiento farmacológico , Convulsiones/etiologíaRESUMEN
OBJECTIVE: To evaluate the potential impact of concomitant clobazam (CLB) use on the efficacy of cannabidiol (CBD) treatment in patients with Dravet syndrome and Lennox-Gastaut syndrome using meta-analytical techniques. METHODS: We searched for randomized, placebo-controlled, single- or double-blinded trials. The proportion of patients who achieved ≥50% reduction from baseline in seizure frequency during the treatment period was assessed according to CLB status. Risk ratios (RRs) with 95% confidence intervals (CIs) were estimated. RESULTS: Four trials were included and enrolled 714 participants, 429 for the add-on CBD group and 285 for the add-on placebo group. Among CBD-treated patients, 240 (55.9%) were taking concomitant CLB (CLB-On) and 189 (44.1%) were not taking concomitant CLB (CLB-Off); in placebo-treated patients, 158 (55.4%) were CLB-On and 127 (44.6%) CLB-Off. The percentages of patients who had at least 50% reduction in seizure frequency during the treatment period were 29.1% in the CBD arm and 15.7% in the placebo group among CLB-Off patients (RR = 1.80, 95% CI = 1.12-2.90, P = .015). Among CBL-On patients, the ≥50% reduction in seizure frequency was found in 52.9% and 27.8% in the CBD and placebo groups, respectively (RR = 1.85, 95% CI = 1.40-2.44, P < .001). SIGNIFICANCE: CBD was associated with a higher rate of seizure response in comparison to placebo when added to the existing antiepileptic regimen both in patients taking and in those not taking concomitant CLB. The lack of randomization for CLB status and the limited sample size need to be considered in the interpretation of the findings.
Asunto(s)
Anticonvulsivantes/administración & dosificación , Cannabidiol/administración & dosificación , Clobazam/administración & dosificación , Convulsiones/tratamiento farmacológico , Anticonvulsivantes/sangre , Cannabidiol/sangre , Clobazam/sangre , Quimioterapia Combinada , Epilepsias Mioclónicas/sangre , Epilepsias Mioclónicas/tratamiento farmacológico , Humanos , Síndrome de Lennox-Gastaut/sangre , Síndrome de Lennox-Gastaut/tratamiento farmacológico , Ensayos Clínicos Controlados Aleatorios como Asunto/métodos , Convulsiones/sangre , Resultado del TratamientoRESUMEN
Four pivotal randomized placebo-controlled trials have demonstrated that adjunctive therapy with cannabidiol (CBD) improves seizure control in patients with Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS). Between 47% and 68% of patients allocated to CBD treatment in these trials were receiving clobazam (CLB), which shows complex interactions with CBD resulting, in particular, in a 3.4- to 5-fold increase in plasma concentration of the active metabolite norclobazam. This raises concern as to the role played by these interactions in determining the reduction in seizure frequency in CBD-treated patients, and the question of whether CBD per se has clinically evident antiseizure effects. We appraised available evidence on the clinical consequences of the CBD-CLB interaction, focusing on subgroup analyses of seizure outcomes in patients on and off CLB comedication in the pivotal CBD trials, as provided by the European Medicines Agency Public Assessment Report. Evaluation of the results of individual trials clearly showed that improvement in seizure control over placebo was greater when CBD was added on to CLB than when it was added on to other medications. However, seizure control was also improved in patients off CLB, and despite the small sample size the difference vs placebo was statistically significant for the 10 mg/kg/d dose in one of the two LGS trials. Stronger evidence for an antiseizure effect of CBD independent of an interaction with CLB emerges from meta-analyses of seizure outcomes in the pooled population of LGS and DS patients not receiving CLB comedication. Although these results need to be interpreted taking into account methodological limitations, they provide the best clinical evidence to date that CBD exerts therapeutic effects in patients with epilepsy that are independent of its interaction with CLB. Greater antiseizure effects, and a greater burden of adverse effects, are observed when CBD is combined with CLB.
Asunto(s)
Anticonvulsivantes/administración & dosificación , Cannabidiol/administración & dosificación , Clobazam/administración & dosificación , Medicina Basada en la Evidencia/métodos , Ensayos Clínicos Controlados Aleatorios como Asunto/métodos , Convulsiones/tratamiento farmacológico , Anticonvulsivantes/sangre , Cannabidiol/sangre , Clobazam/sangre , Interacciones Farmacológicas/fisiología , Quimioterapia Combinada , Epilepsias Mioclónicas/sangre , Epilepsias Mioclónicas/tratamiento farmacológico , Humanos , Síndrome de Lennox-Gastaut/sangre , Síndrome de Lennox-Gastaut/tratamiento farmacológico , Convulsiones/sangreRESUMEN
OBJECTIVE: Cannabidiol (CBD) has been approved by the US Food and Drug Administration (FDA) to treat intractable childhood epilepsies, such as Dravet syndrome and Lennox-Gastaut syndrome. However, the intrinsic anticonvulsant activity of CBD has been questioned due to a pharmacokinetic interaction between CBD and a first-line medication, clobazam. This recognized interaction has led to speculation that the anticonvulsant efficacy of CBD may simply reflect CBD augmenting clobazam exposure. The present study aimed to address the nature of the interaction between CBD and clobazam. METHODS: We examined whether CBD inhibits human CYP3A4 and CYP2C19 mediated metabolism of clobazam and N-desmethylclobazam (N-CLB), respectively, and performed studies assessing the effects of CBD on brain and plasma pharmacokinetics of clobazam in mice. We then used the Scn1a+/- mouse model of Dravet syndrome to examine how CBD and clobazam interact. We compared anticonvulsant effects of CBD-clobazam combination therapy to monotherapy against thermally-induced seizures, spontaneous seizures and mortality in Scn1a+/- mice. In addition, we used Xenopus oocytes expressing γ-aminobutyric acid (GABA)A receptors to investigate the activity of GABAA receptors when treated with CBD and clobazam together. RESULTS: CBD potently inhibited CYP3A4 mediated metabolism of clobazam and CYP2C19 mediated metabolism of N-CLB. Combination CBD-clobazam treatment resulted in greater anticonvulsant efficacy in Scn1a+/- mice, but only when an anticonvulsant dose of CBD was used. It is important to note that a sub-anticonvulsant dose of CBD did not promote greater anticonvulsant effects despite increasing plasma clobazam concentrations. In addition, we delineated a novel pharmacodynamic mechanism where CBD and clobazam together enhanced inhibitory GABAA receptor activation. SIGNIFICANCE: Our study highlights the involvement of both pharmacodynamic and pharmacokinetic interactions between CBD and clobazam that may contribute to its efficacy in Dravet syndrome.
Asunto(s)
Anticonvulsivantes/farmacocinética , Cannabidiol/farmacocinética , Clobazam/farmacocinética , Epilepsias Mioclónicas/metabolismo , Animales , Anticonvulsivantes/administración & dosificación , Cannabidiol/administración & dosificación , Clobazam/administración & dosificación , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos/métodos , Interacciones Farmacológicas/fisiología , Quimioterapia Combinada , Epilepsias Mioclónicas/tratamiento farmacológico , Epilepsias Mioclónicas/genética , Humanos , Ratones , Ratones Transgénicos , Canal de Sodio Activado por Voltaje NAV1.1/genéticaRESUMEN
Pharmacometrics is the mathematical study of pharmacokinetics, disease progression, and clinical outcomes. One objective of pharmacometrics is to facilitate rational drug treatment in patients, also termed clinical pharmacometrics. In this review, our clinical pharmacometric studies conducted over the last 10 years are discussed. Population pharmacokinetic analysis using therapeutic monitoring data for levetiracetam revealed that oral clearance allometrically scaled to both body weight and estimated glomerular filtration rate can accurately predict clinical data from patients of various ages (pediatric to elderly) with varying renal function. Dosage adjustments based on renal function in the package information are effective in controlling the trough and peak concentrations in similar ranges. In addition, a retrospective pharmacokinetic and pharmacodynamic study revealed that the efficacy of low-dose clobazam therapy was significantly influenced by CYP2C19 polymorphisms. Pharmacokinetic and pharmacodynamic models were successfully built using electronic medical information to explain retrospective international normalized ratio values of prothrombin time before and after catheter ablation in warfarin-treated patients. Simulation studies suggest that more than 20 mg of vitamin K2 is unnecessary in the preoperative period of catheter ablation. A physiologically based pharmacokinetic model adapted to tacrolimus pharmacokinetic data in patients who underwent living-donor liver transplantation was constructed, and clarified that oral clearance of this drug was affected by CYP3A5 genotypes in both the liver and intestine to the same extent. In conclusion, pharmacometrics is a useful methodology for individualized and optimized drug therapy.
Asunto(s)
Monitoreo de Drogas , Quimioterapia , Asignación de Recursos para la Atención de Salud , Farmacocinética , Anticoagulantes/administración & dosificación , Anticoagulantes/farmacocinética , Anticonvulsivantes/administración & dosificación , Anticonvulsivantes/farmacocinética , Clobazam/administración & dosificación , Clobazam/farmacocinética , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP3A/genética , Cálculo de Dosificación de Drogas , Genotipo , Humanos , Inmunosupresores/administración & dosificación , Inmunosupresores/farmacocinética , Polimorfismo Genético , Medicina de Precisión , Tacrolimus/administración & dosificación , Tacrolimus/farmacocinética , Vitamina K 2/administración & dosificación , Vitamina K 2/farmacocinética , Warfarina/administración & dosificación , Warfarina/farmacocinéticaRESUMEN
BACKGROUND: Patients undergoing epilepsy surgery are on polytherapy. Drug tapering is usually done after 1 year in adults and after 6 months in children. Sometimes, drugs have to be altered during the perioperative period, which is more commonly seen in hemispherotomy (HS) patients. The present study was done to compare perioperative drug alterations between HS and temporal (TL) lobectomy patients. MATERIALS AND METHODS: Prospective analysis of postoperative HS and TL patients was done. Primary outcomes were drug number, dosage changes, and seizure outcome. Secondary outcome studied was a change in intelligence quotient (IQ) in the two groups. RESULTS: At total of 71 patients were included. Perioperative drug stopping (clobazam - CLB) was needed in 3/38 patients in the HS group, due to sedation. Dosage was reduced in 23/38 (60.52%) in HS group, and in 2/33 (6%) in TL group P < 0.001. The most common drug was CLB, with reduction in 21/27 (77.77%) patients, with a mean reduction of 41.21 ± 4.01%. Two patients required drug substitution in the HS group. About 64/71 (90.1%) patients achieved Class I outcome at a 1-year postoperative time point (TL - 90.9%, HS - 89.47%). There was no change in IQ in any of the groups. CONCLUSION: Perioperative drug alteration is often needed in the HS patients as compared to TL patients. Benzodiazepines have to be reduced to maintain alertness in the HS patients. The increased sedation postoperatively can be due to decreased cortical drive over the reticular activating system, gamma-aminobutyric acid (GABA) receptor denervation hypersensitivity, or increased activity of drugs over the remaining active hemisphere.
Asunto(s)
Lobectomía Temporal Anterior , Anticonvulsivantes/administración & dosificación , Benzodiazepinas/administración & dosificación , Clobazam/administración & dosificación , Epilepsia/tratamiento farmacológico , Epilepsia/cirugía , Hemisferectomía , Evaluación de Resultado en la Atención de Salud , Atención Perioperativa , Cuidados Posoperatorios , Adolescente , Adulto , Niño , Preescolar , Epilepsia del Lóbulo Temporal/tratamiento farmacológico , Epilepsia del Lóbulo Temporal/cirugía , Femenino , Humanos , Masculino , Estudios Prospectivos , Adulto JovenRESUMEN
OBJECTIVE: To describe the use of a population pharmacokinetic (PopPK) model incorporating weight and ontogeny to identify effective clobazam (CLB) dosing for use in a clinical trial in pediatric patients with Dravet syndrome. METHODS: Pharmacokinetic data were combined from 3 CLB trials (OV-1012, OV-1017, and study 301) and a simulated study (study 401) for a total of 1306 CLB and 1305 N-desmethyl clobazam (N-CLB) samples from 193 Lennox-Gastaut syndrome patients and healthy subjects aged 6 months to 45 years. A structured approach based on US Food and Drug Administration guidance and pharmacometric knowledge discovery was developed using a nonlinear mixed-effects approach. Graphing and fitting using logistical weight regression were used to identify covariates for inclusion in the final model, which was evaluated using goodness-of-fit criteria and validated using prediction-corrected visual predictive check (pcVPC). Using the final PopPK model, a simulation study determined CLB and N-CLB distributions after 4 weeks of 1.5 and 2.0 mg/kg CLB. RESULTS: The parameters of the final PopPK model were similar to previous reports. Fixed-effect parameters were precisely estimated, with no significant increase in NONMEM objective function value. Intersubject variability estimates were similar to previous reports, with <35% shrinkage associated with parameter variability, except for intercompartmental clearance and apparent volumes of distribution of peripheral compartments. Goodness-of-fit plots and pcVPC show that the model adequately described CLB and N-CLB data. The CLB/N-CLB ratio in virtual study subjects aged <3 years was 0.23 for 1.5 and 2.0 mg/kg and was 0.14 for subjects aged ≥3 years, which is 2 to 3 times those reported in a previous stiripentol/CLB/valproate study in which seizure improvement was reported. SIGNIFICANCE: The PopPK model dosing parameters of 1.5 and 2.0 mg/kg are likely to result in efficacious concentrations of CLB and N-CLB in pediatric patients as young as 16 months. Dosages exceeding 1.5 mg/kg should be monitored for tolerability, particularly in patients aged <2 years, as there may be a higher incidence of sedation.
Asunto(s)
Anticonvulsivantes/uso terapéutico , Clobazam/uso terapéutico , Epilepsias Mioclónicas/tratamiento farmacológico , Síndrome de Lennox-Gastaut/tratamiento farmacológico , Adolescente , Adulto , Anticonvulsivantes/administración & dosificación , Niño , Preescolar , Clobazam/administración & dosificación , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Adulto JovenRESUMEN
Introduction: Lennox-Gastaut syndrome (LGS) is a chronic, epileptic encephalopathy, characterized by multiple seizure types, distinctive slow spike-wave patterns in the electroencephalogram (EEG), and severe cognitive and behavioral comorbidities. Seizures are typically refractory and long-term prognosis is poor. No antiseizure drug (ASD) is fully effective as a monotherapy. Clobazam (CLB) was licensed in the United States in 2011 as an adjunctive therapy for seizures in LGS. In 2018, a new formulation, CLB oral soluble film (COSF) (AQST-120), was approved by the Federal Drug Administration (FDA) for the same indication. Areas covered: The authors summarize current pharmacological options and guidelines for the management of seizures in LGS and efficacy and safety findings from phase II and III randomized controlled trials of adjunctive CLB in patients with LGS. An open-label extension trial is also considered. A pharmacokinetic comparison of COSF and CLB tablets is also undertaken. Expert opinion: CLB is partly effective as an add-on therapy in treating seizures in LGS. Adverse effects, pharmacokinetic interactions and the potential for tolerance with long-term treatment should be weighed against the clinical benefit when considering the introduction of CLB in this population. COSF has a similar pharmacokinetic profile to CLB tablets and may help to improve adherence to treatment.
Asunto(s)
Anticonvulsivantes/administración & dosificación , Clobazam/administración & dosificación , Síndrome de Lennox-Gastaut/tratamiento farmacológico , Anticonvulsivantes/efectos adversos , Anticonvulsivantes/uso terapéutico , Clobazam/efectos adversos , Tolerancia a Medicamentos , Humanos , Ensayos Clínicos Controlados Aleatorios como Asunto , Convulsiones/tratamiento farmacológico , ComprimidosRESUMEN
OBJECTIVE: The aim of this study was to describe the treatment pattern of patients with Dravet syndrome (DS) in Germany with routine antiepileptic drugs (AEDs) and emergency medication, and to review the literature of real-world evidence on medicine utilization of patients with DS in Europe. METHODS: Patient use of routine AEDs and emergency medications over 3-6â¯months was analyzed from a 2018 multicenter survey of 93 caregivers of patients with DS throughout Germany. Results were contextualized in a review of real-world evidence on medicine utilization of patients with DS in Europe. RESULTS: The variety of medications and the most frequent combinations routinely used by patients with DS (AEDs and others) are described. Patients use a large number of pharmaceutical treatments to manage seizures. The five most commonly used AEDs were sodium valproate (66% of the patients; mean daily dose: 660â¯mg; 24.5â¯mg per kg bodyweight), bromide (44%; 1462â¯mg; 51.2â¯mg per kg), clobazam (41%; 10.4â¯mg; 0.32â¯mg per kg), stiripentol (35%; 797â¯mg; 27.6â¯mg per kg), and topiramate (24%; 107â¯mg; 3.5â¯mg per kg). Ninety percent had reported using emergency medications in the last 3â¯months;, with the most common medications being Buccolam (40%, an oromucosal form of midazolam) and diazepam (20%, mostly rectal application). No discernable relationships between current medication and age or seizure frequency were observed. SIGNIFICANCE: This is the first comprehensive report of routine AEDs and emergency medication use in a large sample of patients with DS in Germany over a period of 3-6â¯months and shows that despite the most common AED combinations being in line with clinical guidelines/best practice, there is no discernable impact of best treatment on seizure frequency. We find a higher use of bromide in Germany compared with other real-world evidence in Europe.
Asunto(s)
Anticonvulsivantes/administración & dosificación , Prescripciones de Medicamentos , Epilepsias Mioclónicas/tratamiento farmacológico , Epilepsias Mioclónicas/epidemiología , Convulsiones/tratamiento farmacológico , Convulsiones/epidemiología , Clobazam/administración & dosificación , Estudios de Cohortes , Quimioterapia Combinada , Femenino , Alemania/epidemiología , Humanos , Masculino , Topiramato/administración & dosificación , Ácido Valproico/administración & dosificaciónRESUMEN
Clobazam is a commonly used long-acting benzodiazepine approved by the US Food and Drug Administration (FDA) to treat seizures associated with Lennox Gastaut syndrome. The FDA approved maximum dosage of clobazam is 1 mg/kg/d or a total of 40 mg a day. Many providers exceed this dosage but there is limited data on the safety, tolerability, and efficacy of supratherapeutic doses. We reviewed retrospective data at our institution and compared patients on supratherapeutic doses to patients on therapeutic doses. A total of 133 patients met inclusion criteria (65 supratherapeutic, 67 therapeutic). There was no statistically significant difference in terms of seizure control, health care utilization, or side effects between patients on supratherapeutic doses and those on therapeutic doses. This study lends further support to the safety and tolerability of supratherapuetic doses of clobazam.
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Anticonvulsivantes/uso terapéutico , Clobazam/uso terapéutico , Síndrome de Lennox-Gastaut/tratamiento farmacológico , Convulsiones/tratamiento farmacológico , Adolescente , Anticonvulsivantes/administración & dosificación , Anticonvulsivantes/efectos adversos , Niño , Preescolar , Clobazam/administración & dosificación , Clobazam/efectos adversos , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Infantile spasms constitute a catastrophic epileptic condition. Seizures in approximately half of children with infantile spasms fail to improve with initial treatment attempts; at present, data regarding alternative treatments are limited. We assessed the efficacy of clobazam as an adjunctive therapy in patients whose seizures failed to respond to initial regimens of standard treatment for infantile spasms. All patients from Severance Children's Hospital who received clobazam as adjunctive therapy for infantile spasms were selected for the study. The efficacy of clobazam was evaluated by assessing the daily spasm frequency. Patients were categorized as complete responders if the spasms disappeared within 2â¯weeks of introducing clobazam, and the patients became spasm-free during weeks 3 and 4. Tolerability was gauged by analyzing adverse events and discontinuation rates. In all, 171 patients qualified for the analysis. Clobazam was introduced after the administration of 2.6 (median; interquartile range [IQR], 1.0-4.0) failed antiepileptic drugs (AEDs), at the age of 8.2â¯months (IQR, 6.0-10.0â¯months). After clobazam therapy was initiated, 38 (22.2%) patients became spasm-free for ≥2â¯weeks. Thirteen out of the 38 complete responders remained spasm-free until the last follow-up and did not require the administration of other AEDs. In 10 patients, the electroencephalogram (EEG) tracings were also within normal limits. These patients were successfully weaned off of all AEDs. Patients with conditions of unknown etiology, who had fewer prior exposures to AEDs, and had not received prior adrenocorticotropic hormone (ACTH)/steroids were more likely to have complete spasm control than the others. Adverse effects were minor, and only 6 of 101 (6%) patients who experienced adverse events had their treatments discontinued during the 3-month follow-up period. The most common adverse events observed were hypersalivation, sedation, and sleep disturbance. Thus, clobazam might be an effective and safe alternative therapeutic option in patients whose seizures failed to respond to initial regimens of standard treatment for infantile spasms. Further prospective studies on clobazam for infantile spasms, focusing on specific good response groups, dosing protocols, and long-term outcome are needed.
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Anticonvulsivantes/farmacología , Clobazam/farmacología , Espasmos Infantiles/tratamiento farmacológico , Anticonvulsivantes/efectos adversos , Clobazam/administración & dosificación , Quimioterapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Lactante , Masculino , Estudios RetrospectivosRESUMEN
GW Pharmaceuticals' formulation of highly purified cannabidiol oral solution is approved in the United States for seizures associated with Lennox-Gastaut and Dravet syndromes in patients aged ≥2 years, for which clobazam, stiripentol, and valproate are commonly used antiepileptic drugs. This open-label, fixed-sequence, drug-drug interaction, healthy volunteer trial investigated the impact of cannabidiol on steady-state pharmacokinetics of clobazam (and N-desmethylclobazam), stiripentol, and valproate; the reciprocal effect of clobazam, stiripentol, and valproate on cannabidiol and its major metabolites (7-hydroxy-cannabidiol [7-OH-CBD] and 7-carboxy-cannabidiol [7-COOH-CBD]); and cannabidiol safety and tolerability when coadministered with each antiepileptic drug. Concomitant cannabidiol had little effect on clobazam exposure (maximum concentration [Cmax ] and area under the concentration-time curve [AUC], 1.2-fold), N-desmethylclobazam exposure increased (Cmax and AUC, 3.4-fold), stiripentol exposure increased slightly (Cmax , 1.3-fold; AUC, 1.6-fold), while no clinically relevant effect on valproate exposure was observed. Concomitant clobazam with cannabidiol increased 7-OH-CBD exposure (Cmax , 1.7-fold; AUC, 1.5-fold), without notable 7-COOH-CBD or cannabidiol increases. Stiripentol decreased 7-OH-CBD exposure by 29% and 7-COOH-CBD exposure by 13%. There was no effect of valproate on cannabidiol or its metabolites. Cannabidiol was moderately well tolerated, with similar incidences of adverse events reported when coadministered with clobazam, stiripentol, or valproate. There were no deaths, serious adverse events, pregnancies, or other clinically significant safety findings.
Asunto(s)
Anticonvulsivantes/farmacocinética , Cannabidiol/efectos adversos , Clobazam/farmacocinética , Dioxolanos/farmacocinética , Ácido Valproico/farmacocinética , Adulto , Anticonvulsivantes/administración & dosificación , Anticonvulsivantes/sangre , Cannabidiol/administración & dosificación , Cannabidiol/farmacocinética , Clobazam/administración & dosificación , Clobazam/sangre , Citocromo P-450 CYP2C19/genética , Dioxolanos/administración & dosificación , Dioxolanos/sangre , Interacciones Farmacológicas , Femenino , Genotipo , Voluntarios Sanos , Humanos , Masculino , Ácido Valproico/administración & dosificación , Ácido Valproico/sangreRESUMEN
Clobazam (CLB) is a 1,5-benzodiazepine that has been widely used as an anxiolytic and antiseizure drug (ASD) since it was first synthesized over 50 years ago. CLB was approved in the United States in 2011 as adjunctive therapy for seizures in patients ≥2 years old with Lennox-Gastaut syndrome. CLB pharmacokinetics (PK) have been studied in single- and multiple-dose administrations in healthy subjects. Salient features include high bioavailability, linear PK, and negligible effects from coadministration of other ASDs. CLB is highly and extensively absorbed, with little effect from food; time to maximum plasma concentration is 0.5 to 4 hours following the dose. After CLB doses of 20 to 40 mg/day, the volume of distribution is 99 to 120 L, with oral clearance ranging from 1.9 to 2.3 L/h. CLB is lipophilic and distributes throughout the body after oral administration. It is metabolized in the liver by cytochrome P450 (CYP) isoenzymes CYP3A, CYP2C19, and CYP2B6, and its main active metabolite is N-desmethylclobazam. The half-life of CLB after a single oral dose ranges from 36 to 42 hours; the half-life of N-desmethylclobazam ranges from 59 to 74 hours. The metabolites of CLB are primarily excreted renally. Population PK modeling using data from healthy subjects and patients with Lennox-Gastaut syndrome indicates that race, sex, age, weight, and renal function do not influence CLB PK. As CLB has been extensively studied since the 1970s, this review is meant to provide a consolidated and comprehensive resource on CLB PK for both prescribers and scientists alike.
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Ansiolíticos/farmacocinética , Anticonvulsivantes/farmacocinética , Clobazam/farmacocinética , Ansiolíticos/administración & dosificación , Ansiolíticos/química , Anticonvulsivantes/administración & dosificación , Anticonvulsivantes/química , Clobazam/administración & dosificación , Clobazam/química , Interacciones Farmacológicas , Humanos , Modelos BiológicosRESUMEN
BACKGROUND: Drugs are prescribed for chronic low back pain without knowing in advance whether a patient will respond to them or not. Quantitative sensory tests (QST) can discriminate patients according to sensory phenotype, possibly reflecting underlying mechanisms of pain processing. QST may therefore be a screening tool to identify potential responders to a certain drug. The aim of this study was to investigate whether QST can predict analgesic effects of oxycodone, imipramine and clobazam in chronic low back pain. METHODS: Oxycodone 15 mg (n = 50), imipramine 75 mg (n = 50) and clobazam 20 mg (n = 49) were compared to active placebo tolterodine 1 mg in a randomized, double-blinded, crossover fashion. Electrical, pressure and thermal QST were performed at baseline and after 1 and 2 h. Pain intensity was assessed on a 0-10 numeric rating scale every 30 min for up to 2 h. The ability of baseline QST to predict pain reduction after 2 h was analysed using linear mixed models. Genetic variants of drug-metabolizing enzymes and genes affecting pain sensitivity were examined as covariables. RESULTS: No predictor of analgesic effect was found for oxycodone and clobazam. Thermal QST was associated with analgesic effect of imipramine: patients more sensitive to heat or cold were more likely to experience an effect of imipramine. Pharmacogenetic variants and pain-related candidate genes were not associated with drug efficacy. CONCLUSIONS: Thermal QST have the potential to predict imipramine effect in chronic low back pain. Oxycodone and clobazam effects could not be predicted by any of the selected QST or genetic variants. SIGNIFICANCE: Predicting drug efficacy in chronic low back pain remains difficult. There is some evidence that patients more sensitive to heat and cold pain respond better to imipramine.