Background and objectiveLaboratories sometimes use different reference ranges for the same antiepileptic drug (AED), particularly for new and poorly investigated drugs. This may contribute to misunderstandings, concerns or inappropriate dose changes, which in turn may affect therapeutic effect, drug safety or treatment adherence. Therefore, the Norwegian Association of Clinical Pharmacology wished to update and harmonize the reference ranges for AEDs and establish national guidelines for Norway.MethodsA working group collected information on the reference ranges used by Norwegian laboratories for all commonly used AEDs. These reference ranges were compared to recent recommendations by the International League Against Epilepsy, current literature, applicable clinical studies, reference ranges used by leading Northern European epilepsy centers outside of Norway, and routine data derived from Norwegian laboratory databases.ResultsReference ranges varied between laboratories for four of 23 available AEDs (lamotrigine, valproate, eslicarbazepine and oxcarbazepine). For four AEDs (brivaracetam, perampanel, stiripentol and sulthiame), reference ranges had not previously been established. In total, 13 reference ranges were either harmonized, updated or newly established. No changes were applied to the remaining 10 AEDs.ConclusionUpdated and harmonized reference ranges are now available for 22 of the 23 AEDs available in Norway. The exception is vigabatrin (reference range not applicable). Revision of reference ranges is an important part of pharmacovigilance of AEDs and must be a continuous process based on current literature and clinical experience.

Lacosamide (LCM) is a new antiepileptic drug (AED). Experience from therapeutic drug monitoring (TDM) in clinical practice is limited. The purpose of this study is to evaluate the pharmacokinetic variability of LCM in relation to efficacy and tolerability in patients with refractory epilepsy in a real-life setting. Variables included age, gender, daily doses and serum concentrations of LCM and other AEDs from the TDM-database at the National Center for Epilepsy in Norway. Clinical data regarding efficacy and tolerability were collected from medical records. The Norwegian Prescription Database (NorPD) was used to include population-based numbers of users. TDM-data from 344 patients were included. The median dose, serum concentration, and concentration/dose (C/D)-ratio of LCM was 350 (range 25-700) mg/day, 19.7 (range 8.1-56.2) µmol/L, and 0.06 (0.02-0.82) µmol/L/mg, respectively. Serum concentrations were reduced by 28% by concomitant use of enzyme inducers and increased by 30% in patients aged >65 years. Efficacy and tolerability were assessed in 227 patients: 29% had >50% seizure reduction (eight seizure free), 30% had no effect, and 44% reported adverse effects. In Norway, there were on average 500 patients per year using LCM in this period based on NorPD. The study demonstrated pharmacokinetic variability and use of TDM of LCM in Norway. Data were collected from multiple sources for improved pharmacovigilance. Serum concentrations were influenced by enzyme inducers and ageing, indicating the usefulness of TDM. Effect and tolerability were favorable within a suggested reference range of 10-40 µmol/L given drug-fasting conditions.

No abstract

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.

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.

Gabapentin and pregabalin are more used in women than in men, and routine use of TDM is most common in patients with epilepsy. Pharmacokinetic variability is extensive, highlighting a need for individualisation of therapy regardless of indication.

This comprehensive epidemiologic study indicates that less than 0.3% of newborns receive inotropic support in the neonatal period. Dopamine was the most commonly used drug. Relating inotrope use to clinical condition, gestational age, and postnatal age may be useful for clinicians and helpful in delineating relevant patient populations for future clinical trials.

Possible pharmacokinetic interactions have been studied for ESL as compared to OXC and CBZ. The pharmacokinetics of ESL is not affected by enzyme-inducing AEDs or VPA and does not affect the metabolism of LTG in contrast to OXC and CBZ. The study demonstrates the value of using TDM databases to explore the potential for pharmacokinetic interactions of new AEDs.