Topiramate belongs to the second generation of antiepilep-

tic drugs (AEDs) and has been approved for treatment of adults and children with different kinds of epilepsy as mono or as adjunctive therapy. The exact mechanism of topiramate action is unknown; however, it is considered that antiepileptic effects are exerted by modulation of voltage-dependent sodium channels, enhancement of g-aminobutyrate (GABA)ergic inhibition on the GABAA receptor, inhibition of carbonic anhydrase isoenzymes, and possibly, through the activity at non-N-methyl-D-aspartate receptors. The effectiveness of topiramate in adults and children with partial onset and primary generalized seizures was established as initial monotherapy as well as adjunctive treatment. Following oral administration of topiramate, absorption is rapid and almost complete with bioavailability ranging from 81 to 95%. Peak plasma concentrations of the drug are reached within 1—4 h after administration. Food delays topiramate absorption by approximately 2 h, but the extent of absorption remains unaffected. Plasma protein-bound fraction of topiramate varies from 9 to 17%. In the dose range 100 to 1200 mg the mean apparent volume of distribution is between 0.6 and 1.0 l/kg. In women the volume of distribution is about 50% less than in men, which is attributed to a higher percentage of body fat in women. This difference is not considered to be clinically relevant. Over 80% of topiramate is eliminated via the kidneys, predominantly as unchanged drug. To date, six trace metabolites formed by glucuronidation, hydroxylation and hydrolysis have been identified in humans. In animal seizure models the metabolites have little or no anticonvulsant activity. At steadystate the renal clearance of topiramate is 1.02 l/h and its elimination half-life (t1/2) varies from 20 to 30 h. 1,4) Consequently, the steady-state is being reached in 4 to 8 d. Over the dose range 100—800 mg the relationship between topiramate dose and serum concentration is linear in both adults and children. With the commonly used dosage regimen, serum topiramate concentrations in the range between 16 and 60 mmol/l have been reported. A wide range of doses and serum concentrations have been associated with optimal clinical response. Topiramate serum concentration was found to correlate with the time to the first seizure, while in the majority of studies no clear relationship between average plasma concentration of topiramate and seizure reduction was found. Based on these findings, clinical response, rather than blood concentrations is used to guide topiramate dosage adjustments. Topiramate pharmacokinetic data mostly come from single dose studies with frequent blood sampling in healthy volunteers as well as from studies with sparse sampling in epileptic patients. However, both types of studies provide little information on interand intraindividual variability in pharmacokinetics of topiramate. So far there is no published study with a population pharmacokinetic model of topiramate. Pharmacokinetic variability can be addressed using a nonlinear mixed effects modelling approach. A population pharmacokinetic model is a prerequisite for optimal therapeutic drug monitoring and individual dose adjustments as it allows estimation of an individual patient’s pharmacokinetic parameters based on sparse concentration measurements, and 1176 Vol. 33, No. 7 Regular Article