Carbamazepine in comparative trials: pharmacokinetic characteristics too often forgotten

To compare the use of carbamazepine (CBZ) in comparative monotherapy trials with its use in practice.

CBZ is often the drug of first choice for partial onset seizures and is frequently used as the reference drug in comparative trials with newly developed antiepileptic compounds. There are several issues related to CBZ that may have an impact on the final outcome of these trials. CBZ has nonlinear time-dependent kinetics due to autoinduction, and this may cause adverse reactions on starting treatment; somnolence and rash usually occur in the first weeks and may be related to the dose and titration schedule. Total daily dose or the serum levels of the drug do not correlate with therapeutic efficacy.

Review of the current literature on the pharmacokinetics properties of CBZ and of comparative trials of new antiepileptic drugs that used CBZ as the reference drug.

The use of CBZ differed in comparative clinical trials and in clinical practice, with slower and lower titration rates used in the latter. This may be disadvantageous for CBZ because its pharmacokinetics peculiarities are ignored. If CBZ is to be used in these trials, titration rates and dosages should resemble those used in clinical practice because this is likely to improve efficacy and tolerability. Otherwise, the results of these trials may support regulatory applications but have little relevance to clinical practice. We suggest an initial CBZ dose of 100 mg/d and a slow titration schedule with dose incremental steps of 100 mg/d every week up to 600 mg/d. Blood levels should determine the initial target dose, but after this has been achieved titration should be based on seizure control and tolerability rather than by blood levels.