Adjustment of carbamazepine dose to offset the effects of the interaction with remacemide hydrochloride in a double-blind, multicentre, add-on drug trial (CR2237) in refractory epilepsy

Purpose: The efficacy of remacemide hydrochloride (REM) as an antiepileptic drug (AED) was tested in a double-blind, add-on trial in patients with ref ractory epilepsy. Concurrent drugs included carbamazepine (CBZ). The interf ering effects of the pharmacokinetic interaction between REM and CBZ were o ffset by the monitoring of plasma CBZ concentration and the appropriate red uction of CBZ dose by an unblinded observer. Methods: Patients taking CBZ entered a 4-week run-in period to stabilise th eir dosage regimen to Tegretol tablets and blinded capsules containing Tegr etol tablets. They then entered an 8-week baseline period during which vari ation of plasma CBZ concentration was used to derive an individual Shewart Control Chart for each patient. These charts were used to define the thresh old for CBZ dose reduction after the addition of trial drug. Where necessar y the unblinded observer adjusted that portion of the daily dose of CBZ con cealed in the opaque capsules, thereby maintaining the blind for the invest igator and the patient. Results: CBZ dosage reductions ranging from 14 to 50% were required by 63% of patients who received REM. Substantial increases in plasma CBZ concentra tion, which would have confounded the results of the trial, were thus avoid ed. The small increases in CBZ concentration that occurred in spite of this procedure were of similar magnitude in responders (patients who experience d greater than or equal to 50% reduction in seizure frequency during treatm ent) and nonresponders, and in bath groups the mean increase was <1 mg/L. Conclusions: The method is offered as a model solution for problems caused by pharmacokinetic interactions in add-on trials.