Decreased serum concentrations of antiseizure medications in children with drug resistant epilepsy following treatment with ketogenic diet.

OBJECTIVE: To examine the potential influence of a ketogenic diet on serum concentrations of antiseizure medications (ASMs) in children with drug resistant epilepsy. METHODS: We investigated the serum concentrations of ASMs in 25 children with drug resistant epilepsy, 2-13 years of age, treated with a classical ketogenic diet for 12 weeks. The patients were recruited from the National Centre for Epilepsy from August 15th, 2017, to January 24th, 2022. Changes in ASM serum concentrations were analyzed using a mixed effect model analysis. Significance level was set at P < 0.05 for all comparisons. RESULTS: The participants used 12 different ASMs during the study. The mean number of ASMs was 2.4 (±SD 0.7). None of the participants changed the type or dose of the ASMs during the intervention period. The serum concentrations of clobazam (n = 9, P = 0.002), desmethylclobazam (n = 9, P = 0.010), and lamotrigine (n = 6, P = 0.016) decreased significantly during the dietary treatment. The analytes with the largest reduction in serum concentration after 12 weeks of dietary treatment were clobazam (mean change -38%) and desmethylclobazam (mean change -37%). We found no significant change in the serum concentrations of levetiracetam, topiramate, and valproic acid. SIGNIFICANCE: We identified a significant decrease in the serum concentrations of clobazam, desmethylclobazam, and lamotrigine following a 12-week ketogenic diet intervention in children with drug resistant epilepsy. An unintended decrease in the serum concentrations of ASMs may render the patient prone to seizures. Measurements of ASM serum concentrations might be useful in patients on a ketogenic diet, especially in patients with lack of efficacy of the dietary treatment.

Efficacy, tolerability and pharmacokinetic variability of brivaracetam in adults with difficult-to-treat epilepsy.

PURPOSE: Brivaracetam (BRV) is one of our latest antiseizure medications (ASMs). It is an analogue of levetiracetam with limited real-life experience. The purpose of this study was to evaluate clinical experience with BRV with focus on efficacy, tolerability and pharmacokinetic variability among adult patients with difficult-to-treat epilepsy. METHODS: We retrospectively collected clinical and laboratory data from patients aged > 18 years who initiated treatment with BRV during 2016-2019 and were followed for > one year or cessation of BRV. RESULTS: The study cohort consisted of 120 adults with drug-resistant epilepsy. Serum concentrations of BRV were available in 72 patients. After one-year follow-up, the retention rate of BRV was 52%. Fifty-seven patients (48%) were responders (>50 reduction of seizure frequency), of whom six became seizure free. Adverse effects were reported in 78 patients (65%); 37 (31%) experienced psychiatric problems like increased irritability, anxiety and depressive symptoms. The mean daily BRV dose was 159 mg (SD 80 mg) and the mean serum concentration 5.4 µmol/L (SD 4.1 µmol/L). In 24 patients, BRV replaced levetiracetam. Pharmacokinetic variability between patients was considerable; 14-fold variation in concentration/dose (C/D)-ratios. Concomitant use of enzyme-inducing ASMs decreased the C/D-ratio by 48%. There were no significant differences in serum concentrations between responders vs. non-responders, or those who experienced adverse effects or not. CONCLUSION: After > 1 year of treatment with BRV, we found a responder rate of 48% in adult patients with difficult-to-treat epilepsy. The drug was largely well tolerated, but one third experienced psychiatric adverse effects. The combination of clinical and pharmacokinetic data provides insight into factors contributing to efficacy and tolerability of new ASMs.

Lamotrigine effects on immune gene expression in larval zebrafish.

PURPOSE: Despite growing evidence that neuroinflammation and pro-inflammatory cytokines are involved in the pathogenesis of seizures and epilepsy, this knowledge has not been incorporated in the proposed mechanism of action of any of the current antiseizure medications (ASMs). Here, we tested the hypothesis by assessing inflammation markers in larval zebrafish (Danio rerio) exposed to lamotrigine (LTG). METHODS: In order to establish the most appropriate LTG concentrations for the transcriptome analysis (RNAseq), we initially assessed for teratogenic (spinal cord deformation, heart oedema, failed inflation of the swim bladder) and behavioural effects (distance moved, time spent active, and average swimming speed during a light/dark test) in zebrafish larvae exposed to 0, 50, 100, 300, 500, 750, and 1000 µM LTG continuously between 5 and 120 h post fertilisation. Subsequently, we repeated the experiment with 0, 50, 100, or 300 µM LTG for transcriptomic analyses. Two databases (Kyoto Encyclopedia of Genes and Genomes; Gene Ontology) were used to interpret changes in gene expression between groups. RESULTS: Major teratogenic effects were observed at concentrations of ≥ 500 µM LTG, whereas behavioural changes were observed at ≥ 300 µM LTG. Transcriptome analysis revealed a non-linear response to LTG. From the suite of differentially expressed genes (DEG), 85% (n = 80 DEGs) were upregulated following exposure to 50 µM LTG, whereas 58% (n = 12 DEGs) and 91% (n = 210 DEGs) were downregulated in response to 100 and 300 µM LTG. The metabolic pathways affected following exposure to 50 and 300 µM LTG were associated with responses to inflammation and pathogens as well development and regulation of the immune system in both groups. Notable genes within the lists of DEGs included component complement 3 (C3.a), which was significantly upregulated in response to 50 µM LTG, whereas interleukin 1ß (IL-1ß) was significantly downregulated in the 300 µM LTG group. The lowest exposure of 50 µM LTG is regarded as clinically relevant to therapeutic exposure. CONCLUSION: We demonstrated that LTG had an impact on the immune system, with a non-monotonic response curve. This dose-dependent relation could indicate that LTG can affect inflammatory responses and also at clinically relevant concentration. Further studies are needed to establish this method as a tool for screening the effects of ASMs on the immune system.

Pharmacokinetic data on brivaracetam, lacosamide and perampanel during pregnancy and lactation.

We present pharmacokinetic data during pregnancy and lactation for brivaracetam, lacosamide and perampanel based on two case studies. Patient 1 used brivaracetam as monotherapy and gave birth to twins. Patient 2 used a combination of brivaracetam, lacosamide and perampanel. In both patients, serum drug concentrations were monitored throughout the pregnancies. Drug concentrations were also analysed in umbilical cord blood at birth, in serum from the offspring and in breastmilk after five days and 3-11 weeks. There were minor changes in concentration/dose-ratios for brivaracetam and lacosamide. The mean milk/serum ratios for brivaracetam and lacosamide were 0.71 and 0.83, respectively, five days and 3-5 weeks after delivery. The perampanel serum concentration increased by up to 80% in Patient 2 during the last part of gestation. The mean milk/serum-ratio for perampanel was 0.13, unchanged from five days to five weeks after delivery. Whereas serum concentrations of brivaracetam and lacosamide remained fairly stable throughout pregnancy, perampanel concentrations seemed to steadily increase towards the end. The distribution to milk was considerable for brivaracetam and lacosamide and low for perampanel. More studies on mother-infant pairs are warranted to confirm these results in larger groups.

Epilepsy and cannabidiol: a guide to treatment.

The growing interest in cannabidiol (CBD), specifically a pure form of CBD, as a treatment for epilepsy, among other conditions, is reflected in recent changes in legislation in some countries. Although there has been much speculation about the therapeutic value of cannabis-based products as an anti-seizure treatment for some time, it is only within the last two years that Class I evidence has been available for a pure form of CBD, based on placebo-controlled RCTs for patients with Lennox-Gastaut syndrome and Dravet syndrome. However, just as we are beginning to understand the significance of CBD as a treatment for epilepsy, in recent years, a broad spectrum of products advertised to contain CBD has emerged on the market. The effects of these products are fundamentally dependent on the purity, preparation, and concentration of CBD and other components, and consensus and standardisation are severely lacking regarding their preparation, composition, usage and effectiveness. This review aims to provide information to neurologists and epileptologists on the therapeutic value of CBD products, principally a purified form, in routine practice for patients with intractable epilepsy.

Pharmacology and drug interactions of cannabinoids.

Cannabinoids include a variety of substances, of which cannabidiol (CBD) is the main substance investigated for the treatment of epilepsy, and this will be the focus in the present review. CBD preparations exist in various forms. There are significant differences in quality control regarding content and reproducibility for an approved drug versus herbal preparations. Cannabidiol has challenging pharmacological properties, and pharmaceutical and pharmacokinetic aspects will depend on the formulation or preparation of a certain product. This article will focus on the characteristics, pharmacokinetic challenges, and interactions of standardised CBD-containing drugs based on evidence from clinical and pharmacokinetic studies.

Safety aspects of antiepileptic drugs-a population-based study of adverse effects relative to changes in utilisation.

PURPOSE: Antiepileptic drugs (AEDs) are increasingly used, and knowledge about adverse effects is scarce based on clinical studies. The purpose of the present study was to characterise adverse effects reports of AEDs in Norway relative to changes in utilisation in various indications from population-based data to elucidate important safety aspects of use of AEDs. METHODS: Aggregated data of adverse effects reported for AEDs in Norway from the EudraVigilance-database (2004-2013) in addition to indication-specific use of AEDs during 2004-2015 from the Norwegian Prescription Database were used. RESULTS: The use of AEDs increased twofold the last decade due to use in psychiatry and neuropathic pain: lamotrigine, pregabalin, gabapentin, valproate, and carbamazepine. There were 1593 adverse effects reported (403 Individual Case Safety Reports, 2/3 women), 0-95 years (mean 46). Most adverse effects were reported for pregabalin (593), carbamazepine (265), lamotrigine (206), gabapentin (144), and valproate (119), where pregabalin had by far the highest reports in relation to the number of users. The most frequently reported adverse drug effects included rash, dizziness, cross-sensitivity reactions, and pyrexia. Overall, nervous system disorders constitute the largest organ class with the majority of the reports. Reporting of fatal outcomes is mandatory, and sudden unexplained death in epilepsy (SUDEP) was reported in 34 occasions. CONCLUSIONS: This study demonstrates that most adverse effects reported concerned AEDs increasingly used in non-epilepsy indications: neuropathic pain (pregabalin, gabapentin, carbamazepine) and psychiatry (lamotrigine, valproate, carbamazepine). Pregabalin had the highest prevalence of adverse effects reported in relation to number of users. This elucidates an important part of pharmacovigilance for improved safety and considerations in clinical practice.

Antiepileptic drug withdrawal in juvenile myoclonic epilepsy.

OBJECTIVES: Withdrawal of antiepileptic drugs (AEDs) has been discouraged in juvenile myoclonic epilepsy (JME). However, impulsivity as a consequence of executive dysfunction in JME may influence treatment adherence. The aim of the present study was to assess how common withdrawal of AEDs is in a large and representative JME group. MATERIALS AND METHODS: Patients with genetic generalized epilepsy (GGE) were identified through a retrospective search of medical records at Drammen Hospital, Norway, and invited to a clinical interview. Information related to AED withdrawal was analyzed in those classified as JME. RESULTS: A total of 132 patients with GGE were interviewed (87 JME). Thirty-five patients with JME (40%) discontinued AEDs, of which 74% did so without consulting a doctor. The rate of self-withdrawal was significantly higher in JME than in other types of GGE. Having a parent with psychosocial difficulties was significantly over-represented in the JME self-withdrawal group. Twelve of those who discontinued AEDs (34%) were free from generalized tonic-clonic seizures (GTCS) and without antiepileptic drugs >1 year. All but one of them withdrew AEDs without consulting a doctor. Age at first motor seizure was significantly higher in those with a favorable outcome of AED withdrawal. CONCLUSIONS: Self-withdrawal of AEDs is common in JME, especially in those with troublesome conditions at home. However, about 1/3 may remain free from GTCS without AEDs. The findings indicate a need for a stronger follow-up with appropriate information about the prognosis of the disorder.

Utilisation and polypharmacy aspects of antiepileptic drugs in elderly versus younger patients with epilepsy: A pharmacoepidemiological study of CNS-active drugs in Norway, 2004-2015.

BACKGROUND AND PURPOSE: Many patients with epilepsy use antiepileptic drugs (AEDs) in combination. The elderly is a vulnerable group regarding polypharmacy. The purpose of this study was to investigate changes in utilisation of AEDs, and the extent of polypharmacy with other CNS-active drugs in elderly versus younger patients in Norway. METHODS: This pharmacoepidemiological study included all prescriptions of antiepileptic, antidepressant and antipsychotic drugs from Norwegian pharmacies in the Norwegian Prescription Database (NorPD) (2004-2015). Variables included number of patients, utilisation in defined daily doses, age, gender, and diagnosis specific reimbursement codes for AEDs. RESULTS: The use of AEDs has increased in all age groups in this population-based study in Norway. In the elderly, AEDs used in neuropathic pain (mainly gabapentin and pregabalin) have increased more than 10-fold (from 0.7 to 9.6 DDDs/1000 elderly/day, 2004-2015), while the prevalence of users is four times more than in younger patients. Polypharmacy between antiepileptic, antidepressant and antipsychotic drugs occurred in 35% of elderly and 38% of younger patients with epilepsy. The use of enzyme-inducers was common, and occurred more often in elderly patients. A total of 42 different interactions that may have clinical implications were identified among these drugs. CONCLUSION: The use of AEDs in elderly compared to younger patients is increasing, especially in neuropathic pain. Polypharmacy with antiepileptic, antidepressant and/or antipsychotic drugs was documented in more than one third of the patients. Awareness of increased drug utilisation, polypharmacy with potential drug interactions, and focus on elderly patients are important for increased patient safety.

Specific Patient Features Affect Antiepileptic Drug Therapy Decisions: Focus on Gender, Age, and Psychiatric Comorbidities.

BACKGROUND: Patient features, apart from the type of seizures/epilepsy, affect markedly antiepileptic drug (AED) choice and dosage. The present review focuses on gender, age and psychiatric comorbidities which play a leading role in influencing antiepileptic treatment. METHODS: Reviews with large population of patients, controlled clinical trials, observational investigations, experimental studies and experimental reviews of experimental data, where appropriated, were analysed and illustrated to produce the most homogeneous indications possible. Different and also contradictory observations have been highlighted to stimulate a critical approach to specific aspects. RESULTS: Women of childbearing age should avoid valproic (VPA), acid, since this drug doubles the risk of major malformations and causes in the exposed offspring reduced intellectual development and disorders of autistic spectrum. The drug is also associated with hormonal disorders, polycystic ovary and reduced fertility. Children treated with valproic acid or phenobarbital can exhibit hyperactivity, nervousness and attention disorders. As a consequence of increased drug elimination, younger children require higher doses as compared to adults and older patients. Elderly patients treated with phenobarbital may face the risk of cognitive disorders and/or falls resulting in bone fractures. Fractures are also facilitated by carbamazepine-induced osteoporosis. Psychiatric disorders are frequently associated with epilepsy and evidence has been gained that common pathological steps underlie these conditions. Depressed patients should avoid drugs like phenobarbital, topiramate, levetiracetam, zonisamide and perampanel since these drugs can induce mood disorders. Although not conclusive, literature data indicate that topiramate and levetiracetam and also tiagabine and vigabatrin, are associated with suicidal thought/behaviour. Conversely, lamotrigine, carbamazepine, VPA and oxcarbazepine exert beneficial effects on mood. Bupropion, clomipramine, amoxapine and maprotyline among antidepressants, and clozapine, olanzapine and quietapine among antipsychotics have been observed to lower seizure threshold. Serum AED concentration monitoring is of help in dosage adjustments, especially in very young children, in patients with cognitive decline and in patients with psychiatric comorbidities. CONCLUSIONS: A careful evaluation of the patient variables analysed in the present review is useful to personalize and optimize AED therapy.

Dosing strategies for antiepileptic drugs: from a standard dose for all to individualised treatment by implementation of therapeutic drug monitoring.

This review focuses on the evolution of approaches to dosing of antiepileptic drugs (AEDs) in clinical practice through history. There has been a shift in the view of treatment of epilepsy, from "one dose fits all patients" in the early days to individualisation of treatment. Over the past 50 years, our knowledge of pharmacological variability of AEDs has markedly increased through implementation of therapeutic drug monitoring (TDM). The use of TDM has demonstrated extensive pharmacokinetic variability for AEDs and a need to individualise the treatment for an optimal outcome. Factors that contribute to pharmacokinetic variability include external factors (including food and comedication), physiological factors (gender, age, and pregnancy), pathological conditions (organ dysfunction), and genetic factors (polymorphisms in metabolising enzymes). Patient groups of children, pregnant women, and the elderly, in whom the most extensive pharmacokinetic changes occur, need special attention and close follow-up of treatment. Patients with complicated and changing combination treatments are also vulnerable. Therapeutic drug monitoring may be particularly helpful in such situations. There are also challenges regarding the use and misuse of therapeutic drug monitoring, such as the use of drug monitoring without a clear indication, misinterpretation of the reference range, and erroneous sampling times.

Therapeutic Drug Monitoring of Clobazam and Its Metabolite-Impact of Age and Comedication on Pharmacokinetic Variability.

BACKGROUND: Clobazam (CLB) has been used as an antiepileptic drug for several decades. There is still insufficient data regarding its pharmacokinetic variability in clinical practice. The purpose of this study was to investigate pharmacokinetic variability of CLB with emphasis on the impact of age and comedication in patients with epilepsy. METHODS: Serum concentration measurements of CLB and its metabolite N-desmethylclobazam (NCLB), as well as demographic and clinical data were retrieved from the routine therapeutic drug monitoring service at the National Center for Epilepsy, Norway, 2009-2013. NCLB/CLB and total (CLB + NCLB), CLB and NCLB concentration/dose (C/D) ratios were calculated. RESULTS: 550 patients (296 women/254 men), average age 27 years (range 1-86), were included. The interindividual pharmacokinetic variability was extensive, as illustrated by a 100-fold variability in serum concentration compared with dose (total C/D ratio 0.03-3.29 µmol·L·mg). The CLB C/D ratio was 36% lower in young children (2-9 years) than in adults (18-64 years), reflecting a higher clearance. In patients receiving phenytoin, felbamate, stiripentol, oxcarbazepine or eslicarbazepine acetate, valproate, phenobarbital, zonisamide or carbamazepine one or more of the calculated ratios were significantly different from that in patients receiving no or neutral comedications. The mean values for the different groups were in the order of 20%-230% of C/D ratios in the neutral group and 200%-950% of the NCLB/CLB ratio. CONCLUSIONS: The pharmacokinetic variability of CLB and its metabolite NCLB in clinical practice is extensive, and is influenced by drug-drug interactions, age, and pharmacogenetics. Therapeutic drug monitoring of CLB and NCLB is therefore valuable in patient management.

Antiepileptic drug treatment in pregnancy: changes in drug disposition and their clinical implications.

Pregnancy is a state where pharmacokinetic changes are more pronounced and more rapid than during any other period of life. The consequences of such changes can be far reaching, not least in the management of epilepsy where the risks with uncontrolled seizures during pregnancy need to be balanced against potential teratogenic effects of antiepileptic drugs (AEDs). This article aims to review the literature on gestational effects on the pharmacokinetics of older and newer generation AEDs and discuss the implications for the treatment of epilepsy in women during pregnancy. Pregnancy can affect the pharmacokinetics of AEDs at any level from absorption, distribution, metabolism, to elimination. The effect varies depending on the type of AED. The most pronounced decline in serum concentrations is seen for AEDs that are eliminated by glucuronidation (UGT), in particular lamotrigine where the effect may be profound. Serum concentrations of AEDs that are cleared mainly through the kidneys, for example, levetiracetam, can also decline significantly. Some AEDs, such as carbamazepine seem to be affected only marginally by pregnancy. Data on pharmacokinetics during pregnancy are lacking completely for some of the newer generation AEDs: pregabalin, lacosamide, retigabine, and eslicarbazepine acetate. Where data are available, the effects of pregnancy on serum concentrations seem to vary considerably individually and are thus difficult to predict. Although large-scale systematic studies of the clinical relevance of the pharmacokinetic alterations are lacking, prospective and retrospective case series have reported an association between declining serum concentrations and deterioration in seizures control. The usefulness of routine monitoring of AED serum concentrations in pregnancy and of dose adjustments based on falling levels, are discussed in this review. We suggest that monitoring could be important, in particular when women have been titrated to the lowest effective AED dose and serum concentration before pregnancy, and when that individual optimal concentration can be used as reference.

Safety aspects of antiepileptic drugs--focus on pharmacovigilance.

PURPOSE: Most patients with epilepsy are dependent on a life-long pharmacological treatment with antiepileptic drugs (AEDs). AEDs include a wide range of substances that possess large pharmacological variability and are often susceptible to drug interactions and adverse drug reactions (ADRs). AEDs are increasingly used in other neurological and psychiatric disorders, and new patient groups are exposed to these drugs. The aim of the present review is to focus upon how pharmacovigilance contributes to improved safety of AEDs. METHODS: The present article is a review based on searches in Pubmed on articles from the last 15 years. Strengths and challenges regarding these aspects will be highlighted and discussed. RESULTS: The concept of pharmacovigilance includes various methods of monitoring of large patient populations with registries and databases of surveillance of ADRs and risk of suicide and sudden unexpected death, drug utilization and prescription patterns, pregnancy and birth registries and therapeutic drug monitoring (TDM) databases for studies on pharmacological variability of AEDs in large sample sizes. Challenges for existing reporting systems and databases include differences in outcome measures and thus international comparison. CONCLUSION: Continuous focus on safety aspects of AEDs and the importance of the implementation of pharmacovigilance contribute to further optimized therapy on a large scale and for the individual patient.

Prescription patterns of antiepileptic drugs in patients with epilepsy in a nation-wide population.

BACKGROUND: Many new antiepileptic drugs (AEDs) have become available in recent years. Investigations of prescription patterns and exposure of AEDs to different patient groups are important regarding drug safety aspects. The aim of this study was to investigate the use of AEDs in epilepsy, with focus on exposure of AEDs, gender and age differences and changes in prescription patterns over time. METHOD: The data consisted of all prescriptions of AEDs from Norwegian pharmacies from the Norwegian Prescription Database (NorPD) (2004-2009), which included 44,000-47,000 patients with epilepsy each year. Variables included age, sex, diagnosis-related reimbursement codes and the use of AEDs (defined daily doses (DDDs)). RESULTS: Twenty two AEDs were in use. There were pronounced age- and gender differences regarding the use of AEDs in epilepsy. The most commonly used drugs were valproate and lamotrigine in children, carbamazepine and lamotrigine in adults, and carbamazepine and phenobarbital in the elderly. Lamotrigine and topiramate were predominantly used in female, and valproate and carbamazepine were predominantly used in male patients, respectively. Eighteen percent used polytherapy with AEDs. Of patients using lamotrigine, 14% received different generic preparations, in spite of the policy of restricted generic substitution. The use of AEDs in 2009 was 6.6 DDDs/1000 inhabitants/day, 49% of the use covered newer AEDs. CONCLUSION: The use of AEDs in epilepsy (2004-2009) was investigated in detail. All AEDs showed pronounced age and gender differences. Newer AEDs covered 49% of the total use in 2009. The study contributes to pharmacovigilance, as it offers a basis of knowledge for national decision-making authorities in the field of drug utilization.