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Clinical Pharmacokinetics of New-Generation Antiepileptic Drugs at the Extremes of Age: An Update

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Abstract

Epilepsies occur across the entire age range, and their incidence peaks in the first years of life and in the elderly. Therefore, antiepileptic drugs (AEDs) are commonly used at the extremes of age. Rational prescribing in these age groups requires not only an understanding of the drugs’ pharmacodynamic properties, but also careful consideration of potential age-related changes in their pharmacokinetic profile. The present article, which updates a review published in 2006 in this journal, focuses on recent findings on the pharmacokinetics of new-generation AEDs in neonates, infants, children, and the elderly. Significant new information on the pharmacokinetics of new AEDs in the perinatal period has been acquired, particularly for lamotrigine and levetiracetam. As a result of slow maturation of the enzymes involved in glucuronide conjugation, lamotrigine elimination occurs at a particularly slow rate in neonates, and becomes gradually more efficient during the first months of life. In the case of levetiracetam, elimination occurs primarily by renal excretion and is also slow at birth, but drug clearance increases rapidly thereafter and can even double within 1 week. In general, infants older than 2–3 months and children show higher drug clearance (normalized for body weight) than adults. This pattern was confirmed in recent studies that investigated the pediatric pharmacokinetics of several new AEDs, including levetiracetam, rufinamide, stiripentol, and eslicarbazepine acetate. At the other extreme of age, in the elderly, drug clearance is generally reduced compared with younger adults because of less efficient drug-metabolizing activity, decreased renal function, or both. This general pattern, described previously for several AEDs, was confirmed in recent studies on the effect of old age on the clearance of felbamate, levetiracetam, pregabalin, lacosamide, and retigabine. For those drugs which are predominantly eliminated by renal excretion, aging-related pharmacokinetic changes could be predicted by measuring creatinine clearance (CLCR). Overall, most recent findings confirm that age is a major factor influencing the pharmacokinetic profile of AEDs. However, pharmacokinetic variability at any age can be considerable, and the importance of other factors should not be disregarded. These include genetic factors, co-morbidities, and drug interactions, particularly those caused by concomitantly administered AEDs which induce or inhibit drug-metabolizing enzymes.

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Acknowledgments

Domenico Italiano has no conflicts of interest to report. Emilio Perucca received research grants from the European Union, the Italian Medicines Agency, the Italian Ministry of Health, and the Italian Ministry for Education, University and Research. He also received speaker’s or consultancy fees and/or research grants from Bial, Eisai, GSK, Lundbeck, Medichem, Pfizer, Sun Pharma, Supernus, UCB Pharma, Upsher-Smith, and Vertex. No funding has been received by the authors for this work.

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  1. Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy

    Domenico Italiano

  2. Division of Clinical and Experimental Pharmacology, Department of Internal Medicine and Therapeutics, University of Pavia and National Institute of Neurology IRCCS C Mondino Foundation, Via Ferrata 9, 27100, Pavia, Italy

    Emilio Perucca

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  1. Domenico Italiano
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  2. Emilio Perucca
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Correspondence to Emilio Perucca.

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Italiano, D., Perucca, E. Clinical Pharmacokinetics of New-Generation Antiepileptic Drugs at the Extremes of Age: An Update. Clin Pharmacokinet 52, 627–645 (2013). https://doi.org/10.1007/s40262-013-0067-4

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  • DOI: https://doi.org/10.1007/s40262-013-0067-4

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