Clinical pharmacokinetics of new-generation antiepileptic drugs at the extremes of age

In recent years, several new-generation antiepileptic drugs (AEDs) have been introduced in clinical practice. These agents, which include felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, vigabatrin and zonisamide, are being increasingly used in the treatment of epilepsy at the extremes of age. For a rational prescribing of these drugs in specific age groups, major pharmacokinetic changes that occur during development and aging need to be taken into consideration. A review of available evidence indicates that the apparent oral clearance (CL/F) of new-generation AEDs in children is increased by 20-170% (depending on the type of drug and characteristics of the patients studied) compared with adults, with the highest CL/F values usually being observed in the youngest age groups. These findings do not necessarily apply to the first weeks of life, when drug eliminating capacity is still undergoing maturation, as in the case of lamotrigine for which preliminary data suggest that CL/F in neonates aged <2 months can be much lower than in infants aged 2-12 months. At the other extreme of age, in the elderly, CL/F is almost invariably reduced (on average by 10-50%) compared with values found in non-elderly adults. Age-related CL/F changes, together with the large interindividual pharmacokinetic variability, contribute to the need for individualised dosage requirements in these patients. Measurement of serum drug concentrations can be useful as an aid to dosage individualization in these age groups but interpretation of therapeutic drug monitoring data should also take into account the possibility of age-related changes in pharmacodynamic sensitivity and, for neonates and the elderly, alterations in drug binding to serum proteins.