Harmonised reference ranges for antiepileptic drugs

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    Antiepileptic drugs are the cornerstone of epilepsy treatment and are also used in a range of other indications. Measurement of the serum concentrations of antiepileptic drugs has a long tradition as a tool in the treatment of epilepsy in Norway. New and updated national reference ranges for serum concentration measurements of antiepileptic drugs in the treatment of epilepsy are now available.

    In 2016, according to the Norwegian Prescription Database, there were 127 138 users of antiepileptic drugs in Norway, equivalent to 24 users per 1 000 inhabitants (1). The use of these drugs increases every year, with the most extensive increase related to the treatment of neuropathic pain and psychiatric disorders (2, 3). The use of these drugs to treat epilepsy is stable at approximately 7 DDD/1 000 inhabitants/day (2).

    Owing to unfavourable pharmacokinetic properties, marked interaction potential and narrow therapeutic windows, measurement of the serum concentration of antiepileptic drugs is a useful tool in the management of epilepsy (4, 5). The reference ranges for first-generation antiepileptic drugs (those introduced up to and including in 1984) are well established and fairly consistent worldwide, with only few and minor differences between laboratories (5).

    Since 1984, 15 new antiepileptic drugs have entered the market. The reference ranges for some of these drugs may be considered to be equally well established as those of the first-generation drugs. For the newer drugs, however, there is little published evidence. Only in a few cases are there clinical data available that may form a basis for defining reference ranges. As a consequence, greater variation is observed both between laboratories and in scientific articles. For some of the latest antiepileptic drugs, even preliminary suggestions for reference ranges are not yet available.

    Updated harmonised reference ranges in Norway

    Updated harmonised reference ranges in Norway

    In February 2015, the Norwegian Association of Clinical Pharmacology launched the Pharmacology Portal as a nationwide web portal for pharmacological and toxicological analyses (6, 7). It is thus naturally desirable for the laboratories represented in the portal to use the same reference ranges. This allows for better collaboration between laboratories and ensures that those who request the analyses receive unambiguous results. Harmonised national reference ranges have so far been established for benzodiazepines, z-hypnotics, opioids and anticoagulants (8–10).

    The working group on antiepileptic drugs has recently submitted its report to the Board of the Norwegian Association of Clinical Pharmacology. The report is based on existing reference ranges in Norway and on an international consensus report on the use of therapeutic drug monitoring (5), as well as updated information from the literature and from epilepsy centres in other countries. The working group has used this information to perform an overall evaluation of existing reference ranges, prioritised according to the level of clinical evidence. A detailed description of the methods can be found in the report (11), which has been approved by the Board of the Norwegian Association of Clinical Pharmacology. The new reference ranges can therefore be considered valid, and entries for relevant drugs have been updated in the Pharmacology Portal.

    In common with other medicines, antiepileptic drugs are used not only as monotherapy, but also in combination with one another or with other medicines. However, when establishing reference ranges, potential pharmacodynamic interactions in polytherapy are disregarded. As in all pharmacotherapy, therefore, clinical assessment of the patient should guide the treatment.

    An overview of the former reference ranges and the new, updated national reference ranges is shown in Table 1 (11). The reference ranges apply to samples obtained just prior to the next regular dose and 12–24 hours after the previous dose. The recommendation is for most of the existing reference ranges to be retained, or adjusted only slightly. Total concentration is measured as standard, but free concentrations of drugs with a high degree of protein binding can also be measured for particular indications.

    Table 1

    Former reference ranges for antiepileptic drugs in Norway and the new, harmonised reference ranges (11)1. Changes are marked in italic bold text.

    Antiepileptic drug

    Brand name (example)

    Introduced

    Former reference range (µmol/l)

    New reference range (µmol/l)

    Brivaracetam2

    Briviact

    2016

    --

    --

    Eslicarbazepine

    Zebinix

    2010

    30-100; 50-140; 10-100; 45-140

    12–100

    Ethosuximide

    Suxinutin

    1955

    300-600

    280-700

    Felbamate

    Taloxa

    1993

    125-250

    125-250

    Phenobarbital

    Fenemal

    1912

    50-130

    50-130

    Phenytoin Free phenytoin

    Fenantoin

    1938

                40-80 ca. 10%

                40-80 ca.10%

    Gabapentin

    Neurontin

    1994

    20-120

    20-120

    Carbamazepine Free carbamazepine

    Tegretol

    1962

    15-45 24-33% (= 4-12.5 µmol/l)

    15-45 24-33% (= 4-12.5 µmol/l)

    Clobazam N-desmethylclobazam

    Frisium

    1984

                0.1-1 1-10

               0.1-1 1-10

    Clonazepam

    Rivotril

    1973

    60-220 nanomol/l

    40-120 nanomol/l

    Lacosamide

    Vimpat

    2009

    10-40

    10-40

    Lamotrigine

    Lamictal

    1992

    10-50; 10-60

    10-50

    Levetiracetam

    Keppra

    2000

    30-240

    30-240

    Oxcarbazepine3

    Trileptal

    1989

    45-140; 50-140

    12-140

    Perampanel2

    Fycompa

    2012

    --

    0.25-2.85

    Pregabalin

    Lyrica

    2004

    10-30

    10-35

    Rufinamide2

    Inovelon

    2007

    20-130

    12-130

    Stiripentol2

    Diacomit

    2008

    --

    15-95

    Sulthiame2

    Ospolot

    1960

    --

    5-35

    Topiramate

    Topimax

    1995

    15-60

    6-30

    Valproate Free valproate

    Orfiril

    1967

         250/300-600/700 ca. 10%

              300-700 ca. 10%

    Vigabatrin4

    Sabrilex

    1991

    --

    --

    Zonisamide

    Zonegran

    1990

    45-180

    45-180

    1 When establishing reference ranges, potential pharmacodynamic interactions in polytherapy are disregarded. As in all pharmacotherapy, therefore, clinical assessment of the patient must guide the treatment.

    2 Analysis is under development and will shortly be available at the National Centre for Epilepsy, Oslo University Hospital

    3 Reference range refers to the active metabolite licarbazepine (previously known as monohydroxy derivative, MHD)

    4 Vigabatrin is an irreversible enzyme inhibitor, and no direct association has been established between its serum concentration and clinical efficacy

    We hope that harmonisation of the reference ranges for antiepileptic drugs will contribute to better treatment for patients. Thorough documentation and research on new antiepileptic drugs in clinical practice will provide sorely needed knowledge on pharmacokinetic variability and its impact on clinical efficacy and tolerance, and lead to even better collaboration between laboratories (12, 13).

    All authors were part of the working group that prepared the report on the new reference ranges. All authors work in laboratory departments that perform therapeutic drug monitoring. None of the authors received direct personal financial gain from the current work.

    We wish to thank pharmacist Jan Borg Rasmussen, head of the clinical pharmacology laboratory at Filadelfia Epilepsy Hospital, Dianalund, Denmark, for discussions and helpful input.

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