Abstract
In the past twenty years, 14 new antiepileptic drugs have been approved for use in the United States and/or Europe. These drugs are eslicarbazepine acetate, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, rufinamide, stiripentol, tiagabine, topiramate, vigabatrin and zonisamide. In general, the clinical utility of therapeutic drug monitoring has not been established in clinical trials for these new anticonvulsants, and clear guidelines for drug monitoring have yet to be defined. The antiepileptic drugs with the strongest justifications for drug monitoring are lamotrigine, oxcarbazepine, stiripentol, and zonisamide. Stiripentol and tiagabine are strongly protein bound and are candidates for free drug monitoring. Therapeutic drug monitoring has lower utility for gabapentin, pregabalin, and vigabatrin. Measurement of salivary drug concentrations has potential utility for therapeutic drug monitoring of lamotrigine, levetiracetam, and topiramate. Therapeutic drug monitoring of the new antiepileptic drugs will be discussed in managing patients with epilepsy.
Highlights
Background on Therapeutic Drug Monitoring ofAntiepileptic MedicationsDrugs used to prevent and treat seizures have been among the most common medications for which therapeutic drug monitoring (TDM) is performed [1,2]
References for drugs whose half-lives are altered in patients receiving liver enzyme inducers: felbamate [36], lamotrigine [37], oxcarbazepine [38], rufinamide [39], tiagabine [40], topiramate [41] and zonisamide [15]. b Half-life increases to 30–90 h during concomitant therapy with valproic acid. c All parameters refer to the active metabolite 10hydroxycarbazepine. d Monitoring of free drug may be useful for these drugs. e Drug shows zeroorder elimination kinetics. f References for reference ranges: felbamate [42, 43], gabapentin [44], lacosamide [45], lamotrigine [46], levetiracetam [47], oxcarbazepine (10-hydroxycarbazepine metabolite) [48], pregabalin [2], stiripentol [49], tiagabine [50], topiramate [51], vigabatrin [23], zonisamide [52]
Multiple analytical methodologies have been reported for the measurement of gabapentin in plasma/serum including HPLC [68,69], HPLC-tandem mass spectrometry (LC/MS/MS) [70], gas chromatography/mass spectrometry (GC/MS) [71] and GC/MS/MS [72]
Summary
Drugs used to prevent and treat seizures (antiepileptic drugs, AEDs) have been among the most common medications for which therapeutic drug monitoring (TDM) is performed [1,2]. TDM has been applied mainly to the 'older' or first-generation AEDs that have been on the market in the United States and Europe for several decades, namely carbamazepine, phenobarbital, phenytoin, Pharmaceuticals 2010, 3 primidone, and valproic acid. Factors that can negatively affect the correlation between clinical effect and serum/plasma concentration include tolerance to the drug, irreversibility of drug action and active metabolites. TDM of newer AEDs in saliva has not yet been widely applied [5], but has been studied for six drugs: gabapentin [6], lamotrigine [7], levetiracetam [8], oxcarbazepine A study has demonstrated that salivary samples for monitoring AEDs can be collected by the patient and mailed to a clinical laboratory without significant degradation of sample [12]
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