Harmonised reference ranges for antiepileptic drugs

Arne Reimers, Jon Andsnes Berg, Margrete Larsen Burns, Cecilie Johannessen Landmark About the authors
Artikkel

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

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 (810).

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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