title: Increasing plasma concentration tolerability study of flunarizine in comedicated epileptic patients.
abstract: 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.
authors.affiliation: Neurology Service, DVA West Los Angeles Medical Center, California.
authors.forename: D M
authors.initials: DM
authors.lastname: Treiman
authors.forename: G W
authors.initials: GW
authors.lastname: Pledger
authors.forename: C
authors.initials: C
authors.lastname: DeGiorgio
authors.forename: J Y
authors.initials: JY
authors.lastname: Tsay
authors.forename: J J
authors.initials: JJ
authors.lastname: Cereghino
mesh_terms: D000328:Adult; D000927:Anticonvulsants / Q000627:therapeutic use*; D002220:Carbamazepine / Q000627:therapeutic use; D004244:Dizziness / Q000139:chemically induced; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D004827:Epilepsy / Q000188:drug therapy*; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D005444:Flunarizine / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D006261:Headache / Q000139:chemically induced; D006760:Hospitalization; D006801:Humans; D008297:Male; D010672:Phenytoin / Q000627:therapeutic use; D010865:Pilot Projects; D012890:Sleep
chemical_list: D000927:Anticonvulsants; D002220:Carbamazepine; D010672:Phenytoin; D005444:Flunarizine