Serum protein binding of 25 antiepileptic drugs in a routine clinical setting: A comparison of free non–protein‐bound concentrations

• DOI: 10.1111/epi.13802
• Publication Date: 2017-05-25T16:56:46Z
• Authors: Philip N. Patsalos; Miguel Zugman; Charlotte Lake; Anthony James; Neville Ratnaraj; Josemir W. Sander
• Keywords: Adult; PHARMACOKINETICS; PLASMA-CONCENTRATIONS; Epilepsy treatment; Clinical Neurology; HEALTHY-SUBJECTS; Biological Availability; Therapeutic drug monitoring; METABOLISM; SALIVA; Gas Chromatography-Mass Spectrometry; Benzodiazepines; 03 medical and health sciences; 0302 clinical medicine; CARBAMAZEPINE; VALPROIC ACID; Humans; Retrospective Studies; Science & Technology; Epilepsy; EPILEPTIC PATIENTS; PHENYTOIN; OXCARBAZEPINE; 3. Good health; Free fraction; Carbamazepine; Blood-Brain Barrier; Anticonvulsants; Neurosciences & Neurology; New antiepileptic drugs; Life Sciences & Biomedicine; Ultracentrifugation; Protein Binding

SummaryObjectiveGiven that only the free non–protein‐bound concentration of an antiepileptic drug (AED) crosses the blood–brain barrier, entering the brain and producing an antiepileptic effect, knowledge and measurement of the free drug fraction is important. Such data are sparse, particularly for newer AEDs, and have arisen from the use of disparate methodologies and settings over the past six decades. We report on the protein binding of 25 AEDs that are available for clinical use, along with two pharmacologically active metabolites (carbamazepine‐epoxide and N‐desmethyl clobazam), using standardized methodology and under set conditions.MethodsThe protein binding of the various AEDs was undertaken in sera of 278 patients with epilepsy. Separation of the free non–protein‐bound component was achieved by using ultracentrifugation (Amicon Centrifree Micropartition System) under set conditions: 500 μl serum volume; centrifugation at 1,000 g for 15 min, and at 25°C. Free and total AED concentrations were measured by use of fully validated liquid chromatography/mass spectroscopy (LC/MS) techniques.ResultsGabapentin and pregabalin are non–protein‐bound, whereas highly bound AEDs (≥88%) include clobazam, clonazepam, perampanel, retigabine, stiripentol, tiagabine, and valproic acid as well as the N‐desmethyl‐clobazam (89%) metabolite. The minimally bound drugs (<22%) include ethosuximide (21.8%), lacosamide (14.0%), levetiracetam (3.4%), topiramate, (19.5%) and vigabatrin (17.1%). Ten of the 25 AEDs exhibit moderate protein binding (mean range 27.7–74.8%).SignificanceThese data provide a comprehensive comparison of serum protein binding of all available AEDs including the metabolites, carbamazepine‐epoxide and N‐desmethyl‐clobazam. Knowledge of the free fraction of these AEDs can be used to optimize epilepsy treatment.