Increasing plasma concentration tolerability study of flunarizine in comedicated epileptic patients

Twelve patients with intractable partial seizures [4 receiving carbamazepine (CBZ), 4 phenytoin (PHT), and 4 both] entered a study of the tolerability of flunarizine (FNR) at specified plasma concentrations. After an 8-week baseline period, a single-dose pharmacokinetic study was performed for each patient to calculate a loading dose and maintenance dosage necessary to achieve a target plasma FNR concentration of 30 ng/ml. The first 8 patients received the loading dose (as divided doses) during a 1-week hospitalization and the maintenance dosage for the ensuing 8 weeks. These patients proceeded to treatment periods with target concentrations of 60 and then 120 ng/ml, using doses based on an assumed linear relation between dose and plasma concentration. The last 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 exceeded the 120-ng/ml target level and continued to increase with time, often necessitating a dosage reduction owing to intolerability. Calculated doses for a given target concentration varied by a factor of 12. The most frequently reported adverse experiences were sedation and increased fatigue; reports of dizziness, headache, and lethargy were also common. Based on this study, a target concentration of at least 60 but < 120 ng/ml is recommended for a controlled clinical trial of the antiepileptic efficacy of FNR.