Reference ranges for antiepileptic drugs revisited: a practical approach to establish national guidelines

Abstract

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.

Therapeutic drug monitoring of gabapentin in various indications

“…10,12 The interaction potential is therefore seen as low, even though interactions with some antacids and analgesics have been reported. 15 The reference range for GBP in epilepsy in Norway is 20-120 µmol/L under drug fasting conditions at steady state, 16 similar to international recommendations. 15 The reference range for GBP in epilepsy in Norway is 20-120 µmol/L under drug fasting conditions at steady state, 16 similar to international recommendations.…”

“…13,14 Therapeutic drug monitoring is a commonly used tool to optimize treatment of epilepsy 7 and has been used as a part of the comprehensive care approach in epilepsy for 50 years. 15 The reference range for GBP in epilepsy in Norway is 20-120 µmol/L under drug fasting conditions at steady state, 16 similar to international recommendations. 7 The potential benefits of TDM in chronic pain have not been fully realized, 17 despite the widespread use of drugs such as GBP for this indication.…”

Plasma concentration and clinical effects of perampanel—The Kork experience

“…In a Japanese study the mean PER serum level in responders was 450 ± 361 ng/ml with a range of 85 to 1500 ng/ml [13]. Based on a personal communication from the Dianalund Epilepsy Center in Denmark, a Norwegian report recently proposed a reference range between 86 and 1000 ng/ml [17]. Comparing these reference ranges with our results, our study had one patient with higher plasma concentrations, a good therapy response, and no adverse events at a level of 2436 ng/ml.…”

“…Although reference ranges for PER have been proposed based on the data of the pivotal pilot phase III studies [7] or recommendations of the Dianalund Danish Epilepsy Center [17] it is unclear whether a reliable therapeutic range exists. A linear dose-concentration relationship has been reported earlier [7,12,13] and might suggest such a predictable range.…”

Clinical experience combined with therapeutic drug monitoring of lacosamide

“…The serum concentration measurements were performed as routine analysis of validated methods at the National Center for Epilepsy, measured by HPLC-UV with a measuring range of 10-250 μmol/L for LCM, on an Ultimate 3000 HPLC, Dionex (125 × 3 mm, 3 μm Hypersil BDS C-18 column) based on Greenway et al 22 We used the reference range of 10-40 μmol/L based on the results from drug-fasting samples in the morning as suggested by Contin et al 23 and Svendsen et al 19 and confirmed as a national reference range. 24 The most recent analysis of LCM and other AEDs at assumed steady-state conditions were included. Blood samples were drawn drug-fasting in the morning before intake of the morning dose as a standard procedure; otherwise, the samples were excluded.…”