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Background: Rufinamide and stiripentol, orphan drugs used in Lennox-Gastaut and Dravet syndromes, respectively, are antiseizure medications (ASMs), often administered to children; however, pharmacokinetic studies are lacking. The authors compared the pharmacokinetic variability of these drugs with respect to the dose, serum concentrations, comedication, age, and duration of treatment., Methods: Children and adolescents (<18 years) whose serum concentrations were measured were retrospectively identified from the therapeutic drug monitoring (TDM) databases at 2 national epilepsy centers in Norway and Denmark (2012-2021)., Results: Data from 165 patients (56% boys/44% girls) treated with rufinamide and 52 patients (50% boys/50% girls) treated with stiripentol were included. For rufinamide, the median age was 10 (range 2-17) years, dose 23 (3-73) mg/d, and serum concentration 34 (3-227) µmol/L [8.1 mg/L (0.71-54.0 mg/L)]. For stiripentol, the median age was 8.5 (range 1-17) years, dose 37 (18-76) mg/d, and serum concentration 33 (4-113) µmol/L [7.7 mg/L (0.93-26.3 mg/L)]. The concomitant use of 1-9 other ASMs during the data collection was noted. Pharmacokinetic variability, calculated as the concentration/(dose/kg) ratio, ranged from 0.26 to 11.31 (µmol/L)/(mg/kg) for rufinamide and 0.17-1.52 (µmol/L)/(mg/kg) for stiripentol. The intraindividual coefficients of variation ranged widely, from 5% to 110% for rufinamide and 11%-117% for stiripentol. The treatment period was at least 5 years in 50% of patients. No statistically significant effects of age, sex, or ASM comedication were observed, possibly due to the small sample size and heterogeneous groups with variable seizure situations, comorbidities, and changes in comedication and physiology., Conclusions: This study demonstrates considerable pharmacokinetic variability in and between patients for both drugs and similar use in terms of age, burden of comedication and retention rates. TDM may be useful in the clinical setting to monitor and optimize treatment in this vulnerable patient group., Competing Interests: C. Johannessen Landmark has received speaker honoraria from Angelini, Eisai, Jazz, and UCB Pharma Nordic, and M. Nikanorova received speaker honoraria from UCB Pharma Nordic. The other authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Lacosamide (LCM) is an antiepileptic drug (AED) with insufficient clinical experience in patients with intellectual disability (ID). They often have more severe epilepsy with comorbidities. The objective was to evaluate the efficacy and tolerability of lacosamide (LCM) in patients with refractory epilepsy with and without ID in a real-life setting, taking drug monitoring (TDM) data into account therapeutic., Methods: Retrospectively, we identified 344 patients using LCM from the TDM service covering the majority of the country, at the National Center for Epilepsy in Norway (2013-2018). Clinical and TDM data were available for 132 patients., Results: Forty-four of the 132 patients (33%) had ID. The retention rate was significantly higher in the ID vs the non-ID group after 1 year (84% vs 68%, P < .05). By combining clinical and TDM data, we demonstrated that 37/38 responding patients had serum concentrations above the lower limit of the reference range (>10 µmol/L), and 16/17 with lower concentrations were non-responders. Mean serum concentration/dose ratios were similar in both groups, 0.06 and 0.07 µmol/L/mg. There were no significant differences regarding efficacy and tolerability. The risk of LCM withdrawal was significantly higher when LCM was added to sodium channel blockers, even if the latter was discontinued., Significance: Lacosamide was generally well tolerated in patients with drug-resistant epilepsy, where one third had ID, and in these patients the retention rate was higher. The combination of clinical and TDM data could possibly facilitate LCM therapy in these vulnerable patients., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Introduction : Antiepileptic drugs (AEDs) are the cornerstone of treatment of patients with epilepsy, and there are presently 27 licensed AEDs making AEDs among the most common medications for which therapeutic drug monitoring (TDM) is performed. The aim of this review is to provide an overview of the current evidence of the use and implementation of AED TDM in patients with epilepsy and other non-epilepsy conditions. Areas covered : The pharmacokinetic variability of AEDs is extensive, resulting in pronounced variability in serum concentrations between patients. TDM may thus be useful to individualize the treatment of patients with epilepsy and also in non-epilepsy conditions. Indications for TDM include settings where pharmacokinetic variability is anticipated (e.g. in children, the elderly, during pregnancy, and patients prescribed polytherapy resulting in drug interactions) and drug adherence. TDM contributes to provide a quality assurance of the treatment. Patient management is, therefore, best guided by the determination of individual therapeutic concentrations. Expert opinion : Because of pharmacokinetic variability is prevalent among AEDs, TDM allows a bespoke approach to epilepsy care allowing dose adjustments based on measured drug concentrations so as to optimize clinical outcome. Future advances include the use of additional markers of toxicity and genetic variability so as to further aid individualization and optimize AED treatment.

Background and Purpose: Patients with juvenile myoclonus epilepsy (JME) may experience uncontrolled seizures and challenges regarding adherence. Implementation of therapeutic drug monitoring (TDM) may contribute to individualization of the therapy with antiepileptic drugs (AEDs). The purpose of this study was to investigate how the treatment of patients with JME is monitored and to demonstrate pharmacokinetic variability within and between patients with a long-term TDM approach., Method: Retrospective data from patients with JME from the TDM-database at Drammen Hospital and the National Center for Epilepsy in Norway (2007-2018) were included., Results: Data from 80 of 90 patients with JME using AEDs with TDM measurements was included (88%, 49/31 women/men aged 14-39). One third (27, 33%) was seizure free, 19 (24%) had generalized tonic-clonic seizures, and 53 (66%) myoclonic seizures during the last year. The most common AEDs measured included lamotrigine, valproate, and levetiracetam. Long-term TDM demonstrated variability over time expressed as intra-patient median values and inter-patient ranges of 19% (7-47) for valproate, 43% (10-83) for lamotrigine and 35% (6-111) for levetiracetam. Fifteen pecent (83/563) of serum concentrations were below the reference ranges and clould be due to variable adherence. Comedication with valproate for lamotrigine and pregnancy contributed to variability. The applicability is illustrated in a case of 10 years' follow-up in a young woman., Conclusion: There was extensive pharmacokinetic variability of AEDs in and between patients with JME. A long-term TDM approach may contribute to closer monitoring of patients with JME and be used as a practical tool during clinical consultations., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

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., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background and Purpose: Use of valproate (VPA) in women of childbearing age is restricted due to dose-dependent risk of teratogenicity. The purpose of this study was to characterise pharmacokinetic variability of VPA in pregnancy, and discuss use of therapeutic drug monitoring (TDM) as guidance to exposure in women., Method: Measurements of trough total and unbound VPA concentrations before, during and after pregnancy, at assumed steady-state were collected from the TDM-database (2006-2016) at the National Center for Epilepsy in Norway. Additional clinical data were obtained from the Oppland county Perinatal Database (1994-2011)., Results: Data from 51 pregnancies in 33 women aged 19-40 years were included. Each woman underwent 1-4 pregnancies, and 1-7 measurements per pregnancy were performed. The variability in total concentration/dose (C/D)-ratios between women was 13-fold, and intra-patient variability extensive. Total C/D-ratios were reduced by 46% from before pregnancy to third trimester (0.48-0.29 μmol/L/mg). Unbound concentrations of VPA were only requested in 10% of the pregnancies. Repeated measurements from two pregnancies in one women revealed increased unbound concentration of VPA during pregnancy. There were 19 with idiopathic generalized epilepsy and two focal based on clinical data from 21 women and 38 pregnancies; 1 major congenital malformation was noted., Conclusion: There is pronounced pharmacokinetic variability of VPA during pregnancy. Unbound concentrations are rarely requested. TDM should be used by measurements of both total and unbound concentrations since total concentrations may be misleading for efficacy and fetal exposure of VPA., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background and Objective: Laboratories 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., Methods: A 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., Results: Reference 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., Conclusion: Updated 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., Competing Interests: Disclosure All authors except EB work at state-owned laboratories that offer measurement of serum concentrations of drugs, including antiepileptic drugs. None of the authors are gaining any financial profit from this paper. The authors report no conflicts of interest in this work.

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.

Although no randomized studies have demonstrated a positive impact of therapeutic drug monitoring (TDM) on clinical outcome in epilepsy, evidence from nonrandomized studies and everyday clinical experience does indicate that measuring serum concentrations of old and new generation antiepileptic drugs (AEDs) can have a valuable role in guiding patient management provided that concentrations are measured with a clear indication and are interpreted critically, taking into account the whole clinical context. Situations in which AED measurements are most likely to be of benefit include (1) when a person has attained the desired clinical outcome, to establish an individual therapeutic concentration which can be used at subsequent times to assess potential causes for a change in drug response; (2) as an aid in the diagnosis of clinical toxicity; (3) to assess compliance, particularly in patients with uncontrolled seizures or breakthrough seizures; (4) to guide dosage adjustment in situations associated with increased pharmacokinetic variability (e.g., children, the elderly, patients with associated diseases, drug formulation changes); (5) when a potentially important pharmacokinetic change is anticipated (e.g., in pregnancy, or when an interacting drug is added or removed); (6) to guide dose adjustments for AEDs with dose-dependent pharmacokinetics, particularly phenytoin.

Therapeutic drug monitoring (TDM) of antiepileptic drugs (AEDs) has made it possible to study the individual variations in drug utilization, to reveal noncompliance in patients and for quality assurance aspects. Even if there is a shortage of data from randomized controlled studies concerning the effectiveness of using TDM as an aid to dosage adjustment, experience from nonrandomized investigations and long-lasting clinical experience have shown that TDM of both older and newer AEDs may be of clinical benefit if used appropriately. The main situations for TDM include: after starting treatment to provide a baseline steady-state concentration for further evaluation of an individual therapeutic concentration; after change in drug dosage, in particular when nonlinear kinetics apply; at therapeutic failure to sort out a pharmacokinetic explanation for uncontrolled seizures or side effects; in case of drug interactions; and when pharmacokinetic changes due to physiological or pathological changes are foreseen (e.g., age-dependent conditions [children, elderly], pregnancy, hepatic disease, renal disease or gastrointestinal conditions potentially affecting drug absorption) and change in drug formulation (brand name/generic). Recently, new terminology and definitions have been suggested by the International League Against Epilepsy. The reference range is a range of drug concentrations quoted by laboratories and is not a therapeutic range. Emphasis should be placed on the concept of an individual therapeutic concentration.

A new generation of antiepileptic drugs (AEDs) has reached the market in recent years with ten new compounds: felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, vigabatrin and zonisamide. The newer AEDs in general have more predictable pharmacokinetics than older AEDs such as phenytoin, carbamazepine and valproic acid (valproate sodium), which have a pronounced inter-individual variability in their pharmacokinetics and a narrow therapeutic range. For these older drugs it has been common practice to adjust the dosage to achieve a serum drug concentration within a predefined 'therapeutic range', representing an interval where most patients are expected to show an optimal response. However, such ranges must be interpreted with caution, since many patients are optimally treated when they have serum concentrations below or above the suggested range. It is often said that there is less need for therapeutic drug monitoring (TDM) with the newer AEDs, although this is partially based on the lack of documented correlation between serum concentration and drug effects. Nevertheless, TDM may be useful despite the shortcomings of existing therapeutic ranges, by utilisation of the concept of 'individual reference concentrations' based on intra-individual comparisons of drug serum concentrations. With this concept, TDM may be indicated regardless of the existence or lack of a well-defined therapeutic range. The ten newer AEDs all have different pharmacological properties, and therefore, the usefulness of TDM for these drugs has to be assessed individually. For vigabatrin, a clear relationship between drug concentration and clinical effect cannot be expected because of its unique mode of action. Therefore, TDM of vigabatrin is mainly to check compliance. The mode of action of the other new AEDs would not preclude the applicability of TDM. For the prodrug oxcarbazepine, TDM is also useful, since the active metabolite licarbazepine is measured. For drugs that are eliminated renally completely unchanged (gabapentin, pregabalin and vigabatrin) or mainly unchanged (levetiracetam and topiramate), the pharmacokinetic variability is less pronounced and more predictable. However, the dose-dependent absorption of gabapentin increases its pharmacokinetic variability. Drug interactions can affect topiramate concentrations markedly, and individual factors such as age, pregnancy and renal function will contribute to the pharmacokinetic variability of all renally eliminated AEDs. For those of the newer AEDs that are metabolised (felbamate, lamotrigine, oxcarbazepine, tiagabine and zonisamide), pharmacokinetic variability is just as relevant as for many of the older AEDs. Therefore, TDM is likely to be useful in many clinical settings for the newer AEDs. The purpose of the present review is to discuss individually the potential value of TDM of these newer AEDs, with emphasis on pharmacokinetic variability.

The aim of this brief communication is to update our recent review on therapeutic drug monitoring (TDM) of the newer antiepileptic drugs (AEDs). The potential value of TDM is discussed in relation to their mode of action and their pharmacokinetic proper-ties. Data on the relationships between serum concentrations and clinical efficacy are limited, and few studies have been designed primarily to study these relationships. As yet there are no generally accepted target ranges for any of the new AEDs. For most drugs a wide range in serum concentration is associated with clinical efficacy,and there is a considerable overlap in serum concentrations related to toxicity and lack of clinical efficacy. Although the available documentation is clearly insufficient, the pharmacological properties of some of the drugs suggest that they may be suitable candidates for TDM. The primary role of TDM for both the newer and established AEDs is to identify an individual's optimum concentration and thus establish a reference value in that patient.

The aim of the present review is to discuss the potential value of therapeutic drug monitoring (TDM) of the newer antiepileptic drugs (AEDs) felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, vigabatrin, and zonisamide. Studies of the relationship between serum concentrations and clinical efficacy of these drugs are reviewed, and the potential value of TDM of the drugs is discussed based on their pharmacokinetic properties and mode of action. Analytical methods for the determination of the serum concentrations of these drugs are also briefly described. There are only some prospective data on the serum concentration-effect relationships, and few studies have been designed primarily to study these relationships. As TDM is not widely practiced for the newer AEDs, there are no generally accepted target ranges for any of these drugs, and for most a wide range in serum concentration is associated with clinical efficacy. Furthermore, a considerable overlap in drug concentrations related to toxicity and nonresponse is reported. Nevertheless, the current tentative target ranges for felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine (10-hydroxy-carbazepine metabolite), tiagabine, topiramate, vigabatrin, and zonisamide are 125 to 250 micromol/L, 70 to 120 micromol/L, 10 to 60 micromol/L, 35 to 120 micromol/L, 50 to 140 micomol/L, 50 to 250 nmol/L, 15 to 60 micromol/L, 6 to 278 micromol/L, and 45 to 180 micromol/L, respectively. Further systematic studies designed specifically to evaluate concentration-effect relationships of the new AEDs are urgently needed. Although routine monitoring in general cannot be recommended at present, measurements of some of the drugs is undoubtedly of help with individualization of treatment in selected cases in a particular clinical setting.

Objective: To discuss the potential value of therapeutic drug monitoring (TDM) of the new antiepileptic drugs gabapentin, lamotrigine, oxcarbazepine, tiagabine, topiramate, vigabatrin and zonisamide., Methods: A review of studies of the relationship between plasma concentrations and effects of new antiepileptic drugs is provided. Furthermore, the potential value of TDM of these drugs is discussed in relation to their mode of action and their pharmacokinetic properties. The various methods that are available for analysing plasma concentrations of the new antiepileptic drugs are also briefly reviewed., Results: The available information on the relationship between plasma concentrations and effects of the new drugs is scarce. For most drugs, wide ranges in concentrations associated with seizure control are reported, and a considerable overlap with drug levels among non-responders and also with concentrations associated with toxicity is often noted. However, very few studies have been designed primarily to explore the relationship between drug plasma concentrations and effects. Consequently, there are no generally accepted target ranges for any of the new antiepileptic drugs. Although the available documentation clearly is insufficient, the pharmacological properties of some of the drugs, in particular lamotrigine, zonisamide and, possibly, oxcarbazepine, topiramate and tiagabine, suggest that they may be suitable candidates for TDM., Conclusion: TDM of some of the new antiepileptic drugs may be of value in selected cases, although routine monitoring in general cannot be recommended at this stage. Further systematic studies designed specifically to investigate concentration-effect relationships of the new antiepileptic drugs are urgently needed.