A retrospective review of changes and challenges in the use of antiseizure medicines in Dravet syndrome in Norway.

OBJECTIVE: Dravet syndrome is a developmental and epileptic encephalopathy characterized by severe and drug-resistant seizures in early childhood, followed by developmental delay. The purpose of this study was to investigate aspects of pharmacological treatment of Norwegian patients with Dravet syndrome, focusing on the use of antiseizure medicines (ASMs) and identifying treatment challenges. METHODS: Patients were identified through medical registries at the National Center for Epilepsy in Norway and National Center for Rare Epilepsy Related Disorders during 2008-2018. Additional clinical data were obtained from medical records and laboratory request forms. RESULTS: We identified 53 patients with Dravet syndrome, 30/23 males/females, aged 2-50 years. The majority of patients with known seizure frequency experienced frequent seizures, 80% (n = 35/44). Only two patients were seizure-free. Valproate (n = 48), clobazam (n = 45), levetiracetam (n = 30), and stiripentol (n = 38) were most commonly used, previous or current use. More than one-third (n = 20) had tried sodium channel blockers (including lamotrigine), but these drugs were used less during the last decade. Polytherapy was common, 81% (n = 43) used two or more ASMs, and eight of these patients used 4-5 drugs (15%). Several challenges were identified: high seizure frequency, comorbidities, treatment changes with a wide range of ASMs, common use of oral gastro-tubes, extensive polypharmacy, and drug interactions. SIGNIFICANCE: The use of ASMs has changed over the last decade, in accordance with updated international recommendations. Various treatment challenges were identified. This vulnerable group of patients needs close follow-up for an optimal treatment outcome.

Therapeutic drug monitoring of gabapentin in various indications.

OBJECTIVES: Gabapentin has been increasingly used in various indications in recent years. Despite variable pharmacokinetics, therapeutic drug monitoring (TDM) is scarcely described in other indications than epilepsy. The aim of the study was to investigate the use and pharmacokinetic variability of gabapentin in epilepsy and non-epilepsy indications and to further evaluate the use of TDM in patients with restless legs syndrome (RLS). MATERIALS & METHODS: Population-based data from the Norwegian Prescription Database, retrospective TDM data from the section for Clinical Pharmacology, the National Center for Epilepsy, Norway, and prospective observational data on patients with RLS were used. RESULTS: The use of gabapentin increased by 30% from 2014 to 2017 (32 181 to 42 675 users). TDM data from 120 patients showed a 22-fold pharmacokinetic variability in concentration/dose ratios, and this ratio was elevated in elderly patients (≥65 years). The majority of elderly used gabapentin for non-epilepsy indications. In patients with RLS, intake in the evening/night only was common due to nocturnal symptoms, in contrast to regular dosing regimens in epilepsy. Thus, drug fasting concentrations do not reflect concentrations at the time of required therapeutic effect. TDM was still found useful in most patients to support dosage increase or evaluate adverse effects. CONCLUSION: Due to extensive pharmacokinetic variability, TDM can benefit patients using gabapentin. Challenges with applying TDM in new indications such as RLS include different dosage regimens and consequently different interpretation of serum concentrations. Thus, TDM should be requested on clear clinical grounds and the service tailored according to the therapeutic indication.

Pharmacokinetic Variability and Clinical Use of Lacosamide in Children and Adolescents in Denmark and Norway.

BACKGROUND: The indication for the antiepileptic drug lacosamide (LCM) was recently extended to include children from the age of 4 years. Real-life data on the use and serum concentrations of LCM in children and adolescents are limited. The purpose of this study was to investigate the use of LCM in this patient group in relation to age, comedication, dose, serum concentrations and duration of treatment, and to examine pharmacokinetic variability. METHODS: Children and adolescents (<18 years) who had serum concentrations of LCM measured from January 2012 to June 2018 were retrospectively identified from the therapeutic drug monitoring databases at 2 national epilepsy centers in Norway and Denmark. Clinical data were collected from request forms and medical records. RESULTS: Data from 124 patients were included, 61 girls/63 boys. Weight was available for 76 patients. Median age was 15 years (range 2-17 years), dose of LCM 300 mg/d (76-600 mg/d), and serum concentration 18 µmol/L (5-138 µmol/L) [4.5 mg/L (1.3-34.5 mg/L)]. Pharmacokinetic variability was demonstrated as the concentration/(dose/kg) ratio ranged from 1.3 to 9.4 (µmol/L)/(mg/kg) and was affected by age. Polytherapy with 1-3 other antiepileptic drugs was noted in 107 patients (86%). Treatment was continued beyond 1 year in 71% (n = 45) of the 63 patients where such information was available, and all of these 45 patients had serum concentrations within the defined reference range. The 1-year retention rate was higher in patients not concomitantly using other sodium channel-blocking drugs (82% versus 56%). CONCLUSIONS: The study demonstrates pharmacokinetic variability in and between age groups, which indicates usefulness of therapeutic drug monitoring. More than two-thirds of patients continued treatment beyond 1 year, suggesting reasonable effectiveness.

Pharmacology Portal: An Open Database for Clinical Pharmacologic Laboratory Services.

PURPOSE: More than 50 Norwegian public and private laboratories provide one or more analyses for therapeutic drug monitoring or testing for drugs of abuse. Practices differ among laboratories, and analytical repertoires can change rapidly as new substances become available for analysis. METHODS: The Pharmacology Portal was developed to provide an overview of these activities and to standardize the practices and terminology among laboratories. The Pharmacology Portal is a modern dynamic web database comprising all available analyses within therapeutic drug monitoring and testing for drugs of abuse in Norway. Content can be retrieved by using the search engine or by scrolling through substance lists. The core content is a substance registry updated by a national editorial board of experts within the field of clinical pharmacology. This ensures quality and consistency regarding substance terminologies and classification. FINDINGS: All laboratories publish their own repertoires in a user-friendly workflow, adding laboratory-specific details to the core information in the substance registry. The user management system ensures that laboratories are restricted from editing content in the database core or in repertoires within other laboratory subpages. The portal is for nonprofit use, and has been fully funded by the Norwegian Medical Association, the Norwegian Society of Clinical Pharmacology, and the 8 largest pharmacologic institutions in Norway. IMPLICATIONS: The database server runs an open-source content management system that ensures flexibility with respect to further development projects, including the potential expansion of the Pharmacology Portal to other countries.