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      Reference ranges for antiepileptic drugs revisited: a practical approach to establish national guidelines


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          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.


          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.


          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.


          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.

          Most cited references56

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          Establishing reference intervals for clinical laboratory test results: is there a better way?

          Reference intervals are essential for clinical laboratory test interpretation and patient care. Methods for estimating them are expensive, difficult to perform, often inaccurate, and nonreproducible. A computerized indirect Hoffmann method was studied for accuracy and reproducibility. The study used data collected retrospectively for 5 analytes without exclusions and filtering from a nationwide chain of clinical reference laboratories in the United States. The accuracy was assessed by the comparability of reference intervals as calculated by the new method with published peer-reviewed studies, and reproducibility was assessed by the comparability of 2 sets of reference intervals derived from 2 different data sets. There was no statistically significant difference between the calculated and published reference intervals or between the 2 sets of intervals that were derived from different data sets. A computerized Hoffmann method for indirect estimation of reference intervals using stored test results is proved to be accurate and reproducible.
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            The clinical pharmacology profile of the new antiepileptic drug perampanel: A novel noncompetitive AMPA receptor antagonist.

            The clinical pharmacology profile of a drug critically determines its therapeutics, and this review summarizes the characteristics associated with the antiepileptic drug (AED) perampanel. A PubMed literature search was performed for perampanel. Congress abstract data are included where necessary and Eisai Ltd provided access to unpublished data on file. After oral ingestion, perampanel is rapidly absorbed and peak plasma concentrations occur 0.5-2.5 h later; its bioavailability is ~100%. Although the rate of perampanel absorption is slowed by food co-ingestion, the extent absorbed remains unchanged; therefore, perampanel can be administered without regard to meal times. The pharmacokinetics of perampanel are linear and predictable over the clinically relevant dose range (2-12 mg); perampanel is 95% protein-bound to albumin and α1-acid glycoprotein. Perampanel is extensively metabolized (>90%) in the liver, primarily by cytochrome P450 (CYP) 3A4, to various pharmacologically inactive metabolites. In healthy volunteers, the apparent terminal half-life is ~105 h, whereas the calculated effective half-life is 48 h. These half-life values allow for once-daily dosing, which will aid patient compliance and in the event of a missed dose, will have minimal impact on seizure control. In healthy volunteers prescribed carbamazepine, half-life decreases to 25 h. Clearance values are not significantly different in adolescents (~13.0 ml/min) and the elderly (~10.5 ml/min) compared with adults (10.9 ml/min). Perampanel has minimal propensity to cause pharmacokinetic interactions. However, it is the target of such interactions and CYP3A4-inducing AEDs enhance its clearance; this can be used to advantage because dose titration can be faster and thus optimum therapeutic outcome can be achieved sooner. Perampanel 12 mg, but not 4 or 8 mg, enhances the metabolism of the progesterone component of the oral contraceptive pill, necessitating the need for an additional reliable contraceptive method. Overall, perampanel has a favorable clinical pharmacology profile, which should aid its clinical use.
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              Abuse Potential of Pregabalin: A Systematic Review.

              Several case reports and epidemiological studies have raised concern about the abuse potential of pregabalin, the use of which has increased substantially over the last decade. Pregabalin is, in some cases, used for recreational purposes and it has incurred attention among drug abusers for causing euphoric and dissociative effects when taken in doses exceeding normal therapeutic dosages or used by alternative routes of administration, such as nasal insufflation or venous injection. The magnitude of the abuse potential and the mechanism behind it are not fully known.

                Author and article information

                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                08 February 2018
                : 12
                : 271-280
                [1 ]Department of Clinical Pharmacology, St Olavs University Hospital, Trondheim, Norway
                [2 ]Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
                [3 ]Laboratory of Clinical Biochemistry, Section of Clinical Pharmacology, Haukeland University Hospital, Bergen, Norway
                [4 ]Department of Pharmacology, Section for Clinical Pharmacology, The National Center for Epilepsy, Oslo University Hospital, Oslo, Norway
                [5 ]Department of Neurology and Clinical Neurophysiology, St Olavs University Hospital, Trondheim, Norway
                [6 ]Department of Neuromedicine and Movement Science, Norwegian University of Science and Technology, Trondheim, Norway
                [7 ]The National Center for Epilepsy, Oslo University Hospital, Oslo, Norway
                [8 ]Programme for Pharmacy, Faculty of Health Sciences, Oslo Metropolitan University, Oslo, Norway
                Author notes
                Correspondence: Arne Reimers, Department of Clinical Pharmacology, St Olavs University Hospital, Pb 3250 Sluppen, 7006 Trondheim, Norway, Tel +47 7282 9109, Email arne.reimers@ 123456ntnu.no
                © 2018 Reimers et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Original Research

                Pharmacology & Pharmaceutical medicine
                antiepileptic drug,serum concentration,reference range,therapeutic drug monitoring


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