INCREASING PLASMA-CONCENTRATION TOLERABILITY STUDY OF FLUNARIZINE IN COMEDICATED EPILEPTIC PATIENTS

Twelve patients with intractable partial seizures [4 receiving carbama zepine (CBZ), 4 phenytoin (PHT), and 4 both] entered a study of the to lerability of flunarizine (FNR) at specified plasma concentrations. Af ter an 8-week baseline period, a single-dose pharmacokinetic study was performed for each patient to calculate a loading dose and maintenanc e dosage necessary to achieve a target plasma FNR concentration of 30 ng/ml. The first 8 patients received the loading dose (as divided dose s) during a 1-week hospitalization and the maintenance dosage for the ensuing 8 weeks. These patients proceeded to treatment periods with ta rget concentrations of 60 and then 120 ng/ml, using doses based on an assumed linear relation between dose and plasma concentration. The las t 4 patients were studied only at the 120-ng/ml target level. Results indicated that this procedure successfully approximated target levels of 30 and 60 ng/ml, but observed concentrations in the last period exc eeded the 120-ng/ml target level and continued to increase with time, often necessitating a dosage reduction owing to intolerability. Calcul ated doses for a given target concentration varied by a factor of 12. The most frequently reported adverse experiences were sedation and inc reased fatigue; reports of dizziness, headache, and lethargy were also common. Based on this study, a target concentration of at least 60 bu t <120 ng/ml is recommended for a controlled clinical trial of the ant iepileptic efficacy of FNR.