Pharmacokinetic Variability of Sulthiame: The Impact of Age, Drug-Drug Interactions, and Biochemical Markers of Toxicity in Patients with Epilepsy.

PURPOSE: Sulthiame is an antiseizure medication increasingly used for epilepsy. The aim of this study was to investigate the pharmacokinetic variability of sulthiame in children and adults with epilepsy with respect to age, comedication, dose, serum concentration, and biochemical markers of toxicity in a clinical setting. METHOD: Retrospective quantitative data from the therapeutic drug monitoring (TDM) database at the Section for Clinical Pharmacology, the National Center for Epilepsy, Norway (2015-2021), were used. RESULTS: TDM data from 326 patients (127 female/199 male) were included [mean age, 11.4 (range 2-44) years; mean weight, 41 (range 14-109) kg]. Interindividual pharmacokinetic variability in the concentration/(dose/body weight) (C/(D/kg)) ratio was 16-fold; intraindividual variability was up to 8-fold (coefficient of variation = 10%-78%). Young children (younger than 6 years) had a significantly lower C/(D/kg) ratio than older age groups ( P < 0.05). Various comedications did not significantly affect the C/(D/kg) ratio, possibly owing to the small sample size. However, CYP2C19-mediated inhibition by sulthiame was indicated because patients using clobazam and sulthiame (n = 28) had a 3.5-fold higher N-desmethylclobazam C/(D/kg) ratio than those using neutral comedication (n = 45; P < 0.001). Patients with pH values below the adjusted normal range (7.32-7.42; n = 15) had a 33% higher sulthiame concentration than those with normal pH values (n = 22; P < 0.05). Blood gas measurements, especially pH, may serve as markers of toxicity and can be used in combination with clinical data when toxicity is suspected. CONCLUSIONS: This study revealed the extensive intraindividual and interindividual pharmacokinetic variability of sulthiame, with age as a contributing factor. Sulthiame has clinically relevant interactions with clobazam. The use of TDM and pH as a biochemical marker may contribute to individualized and safe sulthiame treatment.

Seizure control and complications in patients switching from clobazam to clonazepam due to drug shortage.

BACKGROUND: Antiseizure medication (ASM) shortages are a global problem that have a negative impact on outcomes such as seizure control in patients with epilepsy (PWE). In the case of clobazam (CLB) shortage, there is no study regarding the management strategy. This study aims to investigate the alteration in seizure frequency and the occurrence of side effects in PWE undergoing an abrupt switch from clobazam (CLB) to clonazepam (CLZ), during CLB shortage. MATERIAL AND METHODS: A retrospective study was conducted from electronic health records at our neurology outpatient clinic from January to July 2022. Change in seizure frequency and percentage of CLZ-associated side effects were determined as primary and secondary outcomes, respectively. Potential drug-drug interactions (Level C and above) were evaluated by using Lexicomp Drug Interaction Checker. RESULTS: The analysis included a total of 29 adult patients (15F, median age: 29). The switching ratio was 10 mg CLB for every 1 mg CLZ (10:1). Seizure frequency was higher during the CLZ period compared to the CLB period (p < 0.05), but no status epilepticus cases were observed. All patients exhibited potential drug-drug interactions, leading to reduced CLZ levels in 12 cases. A total of 36 CLZ-associated side effects were identified, with fatigue (19.4 %), drowsiness (16.6 %), and somnolence (13.8 %) being the most prevalent. A positive and strong correlation was found between CLZ dose and the number of side effects (r: 0.556; p: 0.002). CONCLUSION: The abrupt switch from CLB to CLZ was observed to increase seizure frequency without leading to status epilepticus in PWE. CLZ-associated side effects were found to be tolerable despite the abrupt switch. Future studies may explore the effect of alternative switching ratios.

Is adjunctive Cannabidiol effective in controlling seizures for adult patients with Lennox-Gastaut Syndrome? - A single centre long term follow up study.

Epileptic encephalopathies are a disabling and life-limiting cause of childhood-onset epilepsy. Lennox Gastaut syndrome (LGS) is a characteristic example. In spite of the development of multiple medical and surgical therapies, many patients with these conditions remain treatment refractory Cannabidiol was licenced by The National Institute for Health and Care Excellence (NICE) in December 2019 for the adjunctive treatment of seizures associated with Lennox Gastaut syndrome [TA 615]. As the largest complex epilepsy centre in the Midlands, we describe our findings from a single centre retrospective study in 50 adults (aged 16 and over) with LGS- associated epilepsy. Our outcome measure was the efficacy of Cannabidiol on seizures of differing types over a 6-24-month period. Patients were treated with adjunctive Cannabidiol (with Clobazam, as per NICE recommendations). Each patient's usual anti-seizure medications (ASMs) were continued. Patients with a Vagal Nerve Stimulator (VNS) in situ remained on this treatment. Gradual titration of Cannabidiol from 1 mg/kg/day up to 10 mg/ kg/ day reduced the frequency of both focal and generalised seizures with ≥ 50 % seizure reduction in 76 % of the cohort. No patients became seizure free. Cannabidiol was well tolerated; 94 % of the cohort remained on the drug at last follow up.

Metabolic Disposition of Triazolam and Clobazam in Humanized CYP3A Mice with a Double-Knockout Background of Mouse Cyp2c and Cyp3a Genes.

Knockout (KO) of mouse Cyp3a genes increases the expression of hepatic CYP2C enzymes, which can metabolize triazolam, a typical substrate of human CYP3A. There is still marked formation of 1'-hydroxytriazolam in Cyp3a-KO (3aKO) mice after triazolam dosing. Here, we generated a new model of humanized CYP3A (hCYP3A) mice with a double-KO background of Cyp3a and Cyp2c genes (2c3aKO), and we examined the metabolic profiles of triazolam in wild-type (WT), 2c3aKO, and hCYP3A/2c3aKO mice in vitro and in vivo In vitro studies using liver microsomes showed that the formation of 1'-hydroxytriazolam in 2c3aKO mice was less than 8% of that in WT mice. The formation rate of 1'-hydroxytriazolam in hCYP3A/2c3aKO mice was eightfold higher than that in 2c3aKO mice. In vivo studies showed that area under the curve (AUC) of 1'-hydroxytriazolam in 2c3aKO mice was less than 3% of that in WT mice. The AUC of 1'-hydroxytriazolam in hCYP3A/2c3aKO mice was sixfold higher than that in 2c3aKO mice. These results showed that formation of 1'-hydroxytriazolam was significantly decreased in 2c3aKO mice. Metabolic functions of human CYP3A enzymes were distinctly found in hCYP3A mice with the 2c3aKO background. Moreover, hCYP3A/2c3aKO mice treated with clobazam showed human CYP3A-mediated formation of desmethylclobazam and prolonged elimination of desmethylclobazam, which is found in poor metabolizers of CYP2C19. The novel hCYP3A mouse model without mouse Cyp2c and Cyp3a genes (hCYP3A/2c3aKO) is expected to be useful to evaluate human CYP3A-mediated metabolism in vivo SIGNIFICANT STATEMENT: Humanized CYP3A (hCYP3A/2c3aKO) mice with a background of double knockout (KO) for mouse Cyp2c and Cyp3a genes were generated. Although CYP2C enzymes played a compensatory role in the metabolism of triazolam to 1'-hydroxytriazolam in the previous hCYP3A/3aKO mice with Cyp2c genes, the novel hCYP3A/2c3aKO mice clearly showed functions of human CYP3A enzymes introduced by chromosome engineering technology.

A retrospective non-interventional study evaluating the pharmacokinetic interactions between cenobamate and clobazam.

Cenobamate is an antiseizure medication (ASM) approved for the treatment of partial-onset seizures in adults. As both an inductor and an inhibitor of hepatic enzymes, cenobamate affects the metabolism of other ASMs, among which is clobazam. To our knowledge, the extent of interaction between cenobamate and clobazam and its clinical significance have not been studied yet. In this retrospective study we assessed serum concentrations of clobazam and N-desmethylclobazam (NCLB)in five patients before and after co-medication with cenobamate and calculated the percentage increase in concentration-to-dose ratio (CDR) of both. We were able to demonstrate that the addition of cenobamate resulted in an increase in serum concentration and consequently in CDR of NCLB in all patients. However this occurred in variable degrees: NCLB concentration showed an increase of 1208 µg/L (CDR145%) in one patient and between 1691 µ/L (CDR 819%) and 3995 µ/L (CDR 1852%) in the other four. This resulted in fatigue, which improved after dose reduction of CLB. Therefore, it is to be concluded that concomitant administration of cenobamate and clobazam can lead to a substantial increase in serum concentrations of NCLB. This can have a positive therapeutic effect on one hand; however, on the other hand, this can lead to unwanted fatigue.

The cenobamate-clobazam interaction- evidence of synergy in addition to pharmacokinetic interaction.

OBJECTIVES: Report insights into the pharmacokinetic and pharmacodynamic interaction between cenobamate (CNB) and clobazam (CLB), derived from data in patients enrolled at our center in a global multicenter open-label safety study of CNB. MATERIALS & METHODS: Patients in this study either took CLB at baseline (n = 6) or had CLB added after CNB titration to maximal dose (n = 5) in addition to other antiseizure medications. Clobazam was always administered as a single bedtime dose. Random serum concentrations of CLB and N-desmethylclobazam (N-CLB) were obtained. RESULTS: Baseline daily CLB doses were 20-50 mg. Sedation began in the six baseline CLB patients at CNB doses of 25-100 mg. The N-CLB/ CLB ratio increased proportionally to the CNB dose. CLB was stopped in all six patients, five of whom were ≥50% responders. Seizure control deteriorated after stopping CLB, with only one remaining responder. Clobazam was restarted at 5 mg/d in five of the six patients. At the last follow-up, four of these patients were continuing CLB; two were seizure-free and 2 were ≥50% responders. Among the five patients that added 5 mg/d CLB de novo, three were responders. All patients were still on CNB at the end of the study. DISCUSSION: Data suggest starting CLB dose reduction at CNB doses of 25-100 mg/d. Due to possible synergy, the addition of low-dose CLB could be considered in patients with incomplete response to CNB.

Real-world, long-term evaluation of the tolerability and therapy retention of Epidiolex® (cannabidiol) in patients with refractory epilepsy.

OBJECTIVE: Epidiolex® (CBD) is FDA-approved for seizures associated with Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS), and tuberous sclerosis complex (TSC). Phase III studies suggest that certain adverse effects (AEs), possibly linked to pharmacokinetic/pharmacodynamic (PK/PD) interactions may be therapy-limiting. We sought to identify these factors that contribute to treatment success and retention of therapy. METHODS: A single-center, retrospective review of patients with refractory epilepsy taking Epidiolex® was performed. Kaplan-Meier analysis was performed to describe Epidiolex® retention, as a measure of overall effectiveness. RESULTS: One hundred and twelve patients were screened; 4 were excluded due to loss to follow-up or never starting Epidiolex®. Of 108 patients, mean age was 20.3 years (13.1, range 2 to 63), and 52.8% were female. Mean initial and maintenance doses were 5.3 mg/kg/day (1.3) and 15.3 mg/kg/day (5.8), respectively. At the final evaluation, 75% of patients remained on Epidiolex®. The 25th percentile for discontinuation was 19 months. 46.3% of patients experienced at least one treatment-emergent adverse effect (TEAE) with 14.5% d/c Epidiolex® due to treatment emerging adverse effects (TEAE). The most common reasons for discontinuation were lack of efficacy (37%), increased seizure activity (22%), worsened behavior (22%), and sedation (22%). One out of 27 discontinuations was due to liver function test (LFT) elevations (3.7%). At initiation, 47.2% were concurrently taking clobazam, and 39.2% of those patients had an initial clobazam dose decrease. 53% of patients were able to either discontinue or lower the dose of at least one other antiseizure medication. SIGNIFICANCE: Epidiolex® is generally well-tolerated and the majority continued long-term treatment. Patterns of adverse effects were similar to clinical trials, however gastrointestinal complaints, and significant LFT elevations were less common. Our data suggest most patients discontinue within the first several months of treatment and suggest that further studies designed to evaluate early identification and potential mitigation of adverse effects and including drug interactions are warranted.

Tolerability of clobazam as add-on therapy in patients aged 50 years and older with drug-resistant epilepsy.

OBJECTIVE: To evaluate the tolerability of clobazam in patients with drug-resistant epilepsy aged 50 years and older. METHODS: We performed a single center, retrospective chart review of patients at least 50 years of age with drug resistant epilepsy of any type who started clobazam as an add on therapy. Retention rate, safety, and tolerability at 6 and 12 months and last follow-up, and the discontinuation rate due to side effects were analyzed. RESULTS: A total of 26 patients met inclusion criteria. Mean age was 62 ± 7.1 years, and 69.2% of patients were female. The mean baseline seizure frequency before initiation of clobazam was 2 (range 1-30) seizures per month. The mean total daily dose of clobazam administered was 13 (range 5 to 30) mg/day. At the 12-month follow-up visit after clobazam initiation, 40% of patients were seizure-free and an additional 45% of patients had > 50% reduction in seizure frequency. The mean seizure frequency at 12-month follow-up was 1.5 (range 0-24) seizures per month. The mean total dose of clobazam at 12-month follow-up was 14.25 (range 5 to 25) mg/day. The mean duration of clobazam at last follow was 55.2 ± 27.02 (mean ± SD months) and 18 (69.2%) patients remained on clobazam. Twenty out of 26 (76.9%) patients reported at least one side effect and 6/26 (23%) discontinued the medication within a month of initiation. At last follow-up, 40% remained seizure free on stable dosing. CONCLUSION: Clobazam can be a safe and tolerable, add-on treatment older adults with drug-resistant epilepsy. Those who responded tolerated the medication well. Discontinuation due to side effects occurred soon after initiation of therapy.

Distinct Biomarkers of ANT Stimulation and Seizure Freedom in an Epilepsy Patient with Ambulatory Hippocampal Electrocorticography.

INTRODUCTION: Deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) and responsive neurostimulation (RNS) of the hippocampus are the predominant approaches to brain stimulation for treating mesial temporal lobe epilepsy (MTLE). Both are similarly effective at reducing seizures in drug-resistant patients, but the underlying mechanisms are poorly understood. In rare cases where it is clinically indicated to use RNS and DBS simultaneously, ambulatory electrophysiology from RNS may provide the opportunity to measure the effects of ANT DBS in the putative seizure onset zone and identify biomarkers associated with clinical improvement. Here, one such patient became seizure free, allowing us to identify and compare the changes in hippocampal electrophysiology associated with ANT stimulation and seizure freedom. METHODS: Ambulatory electrocorticography and clinical history were retrospectively analyzed for a patient treated with RNS and DBS for MTLE. DBS artifacts were used to identify ANT stimulation periods on RNS recordings and measure peri-stimulus electrographic changes. Clinical history was used to determine the chronic electrographic changes associated with seizure freedom. RESULTS: ANT stimulation acutely suppressed hippocampal gamma (25-90Hz) power, with minimal theta (4-8Hz) suppression and without clear effects on seizure frequency. Eventually, the patient became seizure free alongside the emergence of chronic gamma increase and theta suppression, which started at the same time as clobazam was introduced. Both seizure freedom and the associated electrophysiology persisted after inadvertent DBS discontinuation, further implicating the clobazam relationship. Unexpectedly, RNS detections and long episodes increased, although they were not considered to be electrographic seizures, and the patient remained clinically seizure free. CONCLUSION: ANT stimulation and seizure freedom were associated with distinct, dissimilar spectral changes in RNS-derived electrophysiology. The time course of these changes supported a new medication as the most likely cause of clinical improvement. Broadly, this work showcases the use of RNS recordings to interpret the effects of multimodal therapy. Specifically, it lends additional credence to hippocampal theta suppression as a biomarker previously associated with seizure reduction in RNS patients.

[Measurement of benzodiazepine receptor agonists metabolites and their concentration in urine]. / Opredelenie metabolitov agonistov benzodiazepinovykh retseptorov i ustanovlenie ikh protsentnogo soderzhaniya v moche.

The study objective was to detect and measure the ratio of metabolites of benzodiazepine receptor agonists in urine during forensic chemical and chemical and toxicological studies, as well as to characterize the main metabolites to use them to confirm the oral intake of the test substances. Data on the presence of metabolites in the urine will allow us to reliably confirm the intake of zaleplon, zopiclone, clobazam, and phenazepam and determine the routes of administration (intake) into the body of the victim. Benzodiazepine derivatives (clobazam and phenazepam) and non-benzodiazepines (zaleplon and zopiclone) have different chemical structures and similar mechanisms of action resulting in a similar clinical presentation of side effects and the need for forensic chemical study according to poisoning symptoms. Metabolites of benzodiazepine receptor agonists and their ratio in urine after oral administration were measured: zaleplon (parent compound), deethylzaleplon, 5-oxozaleplon, 5-oxodeethylzaleplon, oxozaleplon glucuronide; zopiclone (parent compound), zopiclone-N-oxide, N-desmethylzopiclone; clobazam (parent compound), N-desmethylclobazam, 4-hydroxyclobazam, hydroxydesmethylclobazam; phenazepam (parent compound) and 3-hydroxyphenazepam. It is advisable to determine zaleplon in urine by the presence of 5-oxaleplon (97% of the total amount of metabolites), zopiclone by zopiclone-N-oxide (86% in urine), clobazam by the parent compound (61% in urine), phenazepam by the parent compound (90-100% in urine).

Evaluating the efficacy of prototype antiseizure drugs using a preclinical pharmacokinetic approach.

OBJECTIVE: Pharmacokinetics (PK) of a drug drive its exposure, efficacy, and tolerability. A thorough preclinical PK assessment of antiseizure medications (ASMs) is therefore essential to evaluate the clinical potential. We tested protection against evoked seizures of prototype ASMs in conjunction with analysis of plasma and brain PK as a proof-of-principle study to enhance our understanding of drug efficacy and duration of action using rodent seizure models. METHODS: In vivo seizure protection assays were performed in adult male CF-1 mice and Sprague Dawley rats. Clobazam (CLB), N-desmethyl CLB (NCLB), carbamazepine (CBZ), CBZ-10,11-epoxide (CBZE), sodium valproate (VPA), and levetiracetam (LEV) concentrations were quantified in plasma and brain using liquid chromatography-tandem mass spectrometry. Mean concentrations of each analyte were calculated and used to determine PK parameters via noncompartmental analysis in Phoenix WinNonLin. RESULTS: NCLB concentrations were approximately 10-fold greater than CLB in mice. The antiseizure profile of CLB was partially sustained by NCLB in mice. CLB concentrations were lower in rats than in mice. CBZE plasma exposures were approximately 70% of CBZ in both mice and rats, likely contributing to the antiseizure effect of CBZ. VPA showed a relatively short half-life in both mice and rats, which correlated with a sharp decline in efficacy. LEV had a prolonged brain and plasma half-life, associated with a prolonged duration of action in mice. SIGNIFICANCE: The study demonstrates the utility of PK analyses for understanding the seizure protection time course in mice and rats. The data indicate that distinct PK profiles of ASMs between mice and rats likely drive differences in drug efficacy between rodent models.

Identification of novel signal of clobazam-associated drug reaction with eosinophilia and systemic symptoms syndrome: A disproportionality analysis.

OBJECTIVES: Clobazam is a well-known benzodiazepine used as an anti-anxiety drug as well as an anti-epileptic, particularly for patients who are not responding to first-line treatments. Recent case reports have indicated the association of clobazam with drug reaction with eosinophilia systemic symptoms syndrome (DRESS Syndrome). However, DRESS syndrome is not known to be associated with clobazam. Thus, the main objective of the current study was to identify the potential signal of clobazam-associated DRESS Syndrome. MATERIALS & METHODS: US FDA Adverse event reporting system (US FAERS), pharmacovigilance data 2004Q1-2021Q3 was extracted using OpenVigil 2.1-MedDRA-v24. The Proportional Reporting Ratio (PRR), Reporting Odds Ratio (ROR) with a Chi-Square value (95% confidence interval), and number of cases (≥3) were used as disproportionality analysis parameters. RESULTS: A total of 141 drug-event combinations were reported and results of disproportionality analysis indicate the positive signal of DRESS syndrome with clobazam. The signal strength was decreased after removing the cases of concomitantly administered drugs (phenytoin, levetiracetam, and valproic acid); however, the association of clobazam with DRESS syndrome remains statistically significant. The subgroup analysis results have shown a greater number of cases in the age group (18-64 years) as compared to other age groups whereas the number of cases in the male and female groups is almost similar. CONCLUSION: The DRESS syndrome is identified as a novel signal with clobazam. However, further causality assessment is required.

Evaluation of one-year effectiveness of clobazam as an add-on therapy to anticonvulsant monotherapy in participants with epilepsy having uncontrolled seizure episodes: An Indian experience.

OBJECTIVES: To prospectively study the effectiveness and safety of clobazam as an add-on therapy in patients with epilepsy whose seizures are not adequately controlled with antiseizure medicine (ASM) monotherapy. METHODS: We conducted a prospective, observational study at 28 neurology outpatient clinics in India from June 2017 to October 2019. Consecutive patients with epilepsy (older than 3 years) with inadequate seizure control with ASM monotherapy were initiated on clobazam. Patients were followed up at 1, 3, 6, 9, and 12 months. Seizure control and adverse events were assessed through personal interviews and seizure diaries. RESULTS: Out of 475 eligible patients, data of 429 patients (men: 65.5%) were evaluated (46 excluded due to protocol deviations). The median age was 25 (range, 3-80 years) years and the median duration of epilepsy was 3 (0.1-30) years. The majority of patients had focal epilepsy (55.0%) and genetic generalized epilepsy (40.1%). The one-year follow-up was completed by 380 (88.5%) patients. At one-year follow-up, 317 (83.4%; N = 380) patients in the study remained seizure free. These 317 patients who were seizure free at 12 months comprised 73.9% of the evaluable population (N = 429). In 98.8% of patients, the primary reason for adding clobazam was inadequate control of seizures with treatment. During one-year follow-up, a total of 113 (22.6%) patients experienced at least one adverse event which included 103 (20.6%) patients who experienced 386 episodes of seizures. CONCLUSION: The study provides preliminary evidence that clobazam is effective and well-tolerated as add-on therapy for a period of one year among patients with epilepsy inadequately stabilized with monotherapy. TRIAL REGISTRATION NUMBER: CTRI/2017/12/010906.

COVID-19 and antiepileptic drugs: an approach to guide practices when nirmatrelvir/ritonavir is co-prescribed.

Management and dose adjustment are a major concern for clinicians in the absence of specific clinical outcome data for patients on antiepileptic drugs (AEDs), in the event of short-term (5 days) nirmatrelvir/ritonavir co-exposure. Therefore, in this report, we identified drugs that require dose adjustment because of drug-drug interactions (DDIs) between nirmatrelvir/ritonavir and AEDs. We hereby used four databases (Micromedex Drug Interaction, Liverpool Drug Interaction Group for COVID-19 Therapies, Medscape Drug Interaction Checker, and Lexicomp Drug Interactions) and DDI-Predictor.In the light of applying the DDI-Predictor, for carbamazepine, clobazam, oxcarbazepine, eslicarbazepine, phenytoin, phenobarbital, pentobarbital, rufinamide, and valproate as CYP3A4 inducers, we recommend that a dose adjustment of short-term nirmatrelvir/ritonavir as a substrate (victim) drug would be more appropriate instead of these AEDs to avoid impending DDI-related threats in patients with epilepsy.

[Determination of zaleplon and clobazam by high performance liquid chromatography - high resolution tandem mass spectrometry using Orbitrap technology]. / Opredelenie zaleplona i klobazama metodom vysokoeffektivnoi zhidkostnoi khromatografii ­ tandemnoi mass-spektrometrii s vysokim razresheniem s ispol'zovaniem tekhnologii Orbitrap.

THE AIM OF THE STUDY: Was to develop a method for the qualitative and quantitative determination of benzodiazepine receptor agonists (zaleplon and clobazam), taking into account different chemical structures, by high-performance liquid chromatography-high-resolution tandem mass spectrometry using Orbitrap technology for the purposes and tasks of forensic medical examination. A method has been developed for the identification and quantitative determination of zaleplon and clobazam by high-performance liquid chromatography-high-resolution tandem mass spectrometry using Orbitrap technology. The proposed identification method can be used in the future to form a database of domestic mass spectra for potent and narcotic substances.

[Analysis of the feasibility of a forensic chemical investigation in clobazam poisoning]. / Analiz vozmozhnosti provedeniya sudebno-khimicheskogo issledovaniya pri otravlenii klobazamom.

The study objective was to determine the relevance of methods to detect clobazam poisoning during the forensic and chemical toxicological examination. The lack of a systematic approach to clobazam identification and assay as a part of forensic chemical and chemical toxicological analyses was demonstrated. The published data on the study of clobazam in biological objects are inconsistent and incomplete, precluding the conduction of focused forensic chemical and toxicological investigations on biological objects with required validity. Various methods of forensic chemical and toxicological investigation of clobazam in biological objects were studied and presented. Data are presented on various physicochemical test methods (TLC, HPLC, UV spectrometry, GC, and GC-MS) for clobazam detection.

Evaluation of diazepam nasal spray in patients with epilepsy concomitantly using maintenance benzodiazepines: An interim subgroup analysis from a phase 3, long-term, open-label safety study.

OBJECTIVE: Diazepam nasal spray (Valtoco), indicated for acute treatment of frequent seizure activity (seizure clusters) in patients with epilepsy ≥6 years of age, is designed to be a rapid, noninvasive, socially acceptable route of administration. This interim analysis evaluated the safety profile of diazepam nasal spray in patients with and without concomitant use of benzodiazepines, with use of a second dose for a seizure cluster as a proxy for effectiveness. METHODS: A long-term, phase 3, open-label safety study enrolled patients with epilepsy who had seizures despite a stable antiseizure medication regimen. RESULTS: Among 175 patients enrolled by October 31, 2019, a total of 158 were treated with diazepam nasal spray (aged 6-65 years; 53.8% female). Of those, 119 (75.3%) received concomitant benzodiazepines (60, chronic; 59, intermittent); 39 (24.7%) did not. Use of a second dose was similar in patients using chronic concomitant benzodiazepines (second dose in 11.1% [144/1299]) and those with no concomitant benzodiazepines (second dose in 10.3% [41/398]). Treatment emergent adverse events (TEAEs) occurred for 80.0% with chronic use of concomitant benzodiazepines and 61.5% without. Cardiorespiratory depression was not reported, and no serious TEAEs were treatment related. Study retention was high: 83.3% in the chronic benzodiazepine group and 76.9% in the no-benzodiazepine group. Findings were similar in a sub-analysis of patients who were (n = 44) or were not (n = 75) taking clobazam. SIGNIFICANCE: This analysis of patients from a long-term study shows a similar safety profile of diazepam nasal spray in patients with and without concomitant benzodiazepines, and consistent with the established profile for diazepam. Use of a single dose of diazepam nasal spray and high study retention rates suggest the effectiveness of diazepam nasal spray in patients irrespective of chronic daily benzodiazepine use. Results were similar in the clobazam sub-analysis. These results support the safety and effectiveness of diazepam nasal spray in patients with concomitant benzodiazepine use.

The long-term efficacy of cannabidiol in the treatment of refractory epilepsy.

OBJECTIVE: Cannabidiol (CBD) has been shown to reduce seizures among patients with refractory epilepsies of various etiologies in recent clinical trials and an expanded access program (EAP). Most studies report efficacy over short time periods (<1 year), with little published on longer term efficacy. Here, we investigate the efficacy of CBD for a treatment period of up to 60 months (median = 45.5 months). METHODS: We conducted a retrospective review of patient-reported seizure logs and medical records for 54 subjects with refractory epilepsy who enrolled in the Massachusetts General Hospital's open-label EAP for CBD as a new treatment for epilepsy. We analyzed the effect of CBD on seizure frequencies and concomitant antiepileptic drug (AED) use at 1 year after starting treatment and the most recent study visit. RESULTS: Our results indicate that CBD maintains its efficacy for controlling seizures from Year 1 to the most recent study visit. The percentage of seizure responders remained similar at these time points (41.7%-42.6%), and the seizure response rate was also maintained (p = .12). Efficacy was also seen over a broad dose range, and up to 50 mg/kg/day. CBD was particularly effective for controlling seizures in the setting of tuberous sclerosis complex and for reducing epileptic spasms and absence seizures. Although CBD use did not lead to an overall decrease in concomitant AEDs, most subjects reduced the dose of at least one concomitant AED compared to baseline. CBD was generally well tolerated, with drowsiness and diarrhea as the primary adverse reactions. SIGNIFICANCE: This study demonstrates CBD does not lose its efficacy in controlling seizures over a treatment period of up to 60 months. Taken alongside other results on the efficacy and tolerability of CBD in the treatment of refractory epilepsies, our results provide evidence that CBD is an effective, safe, and well-tolerated AED for long-term use.

Efficacy of clobazam as add-on therapy in brain tumor-related epilepsy.

PURPOSE: Brain tumor-related epilepsy (TRE) is often resistant to currently available antiepileptic medications (AEDs). Clobazam was initially approved as adjunctive AED for patients with Lennox Gastaut syndrome but has been used in TRE, despite limited evidence in this context. This observational study aims to examine the effect of clobazam on seizure frequency on patients who have a primary CNS tumor and continued seizures despite their current AEDs. METHODS: A retrospective review of patients with histologically-confirmed primary brain tumors seen in the neuro-oncology interdisciplinary clinic from April 2016-2019 was completed, and patients on clobazam were identified. Response to clobazam was defined as a greater than 50% reduction in seizure frequency. Additional data including patient and tumor characteristics, treatment course, tolerability, AEDs used prior to addition of clobazam, and AEDs concomitantly used with clobazam were collected. RESULTS: A total of 35 patients with TRE on clobazam were identified, with 2 patients unable to tolerate the medication due to side effects. Of the 33 remaining patients, a total of 31 (93.9%) of patients were deemed responders. Ten patients (30.3%) were seizure free within 6 months of clobazam initiation and 21 (63.6%) reported a significant reduction in seizure frequency. This reduction also allowed several patients to modify concurrent AEDs. CONCLUSIONS: Clobazam is an effective agent to use as add-on AED in TRE, with 94% of patients showing a significant response within 6 months. Furthermore, the addition of clobazam may yield a reduction in polypharmacy, as concomitant AEDs can be reduced and potentially withdrawn.

Cannabidiol in conjunction with clobazam: analysis of four randomized controlled trials.

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.