Flunarizine for treatment of partial seizures

Abstract

The National Institutes of Health sponsored a randomized, double-blind, multicenter, placebo-controlled trial of flunarizine (FNR) in epileptic patients receiving concomitant phenytoin (PHT) or carbamazepine (CBZ). Because of FNR's long half-life (up to 7 weeks), a parallel rather than crossover design was used. Each patient received an individualized loading dose and maintenance dosage targeted at a 60-ng/ml plasma FNR concentration. Of 93 patients randomized, 92 provided seizure data for the full 25-week treatment period; one placebo-treated patient dropped out for personal reasons. Fifty-four patients received CBZ only, nine received PHT only, and 30 received both CBZ and PHT. Eighty-seven patients had a history of complex partial seizures, and 60 had secondarily generalized seizures. Eight patients discontinued FNR prematurely, all because of adverse neurologic or psychiatric signs or symptoms; depression was the specific cause in three cases. Calculated maintenance dosages, based on single-dose pharmacokinetic profiles, ranged from 7 to 138 mg/day (mean, 40 mg/day). Plasma FNR concentrations generally exceeded the target, with the highest concentrations observed immediately after loading; excluding the first three treatment weeks and all concentrations after a FNR dosage change, the median plasma FNR concentration was 71.7 ng/ml. The percent reduction from baseline seizure rate was statistically greater (p = 0.002) in the FNR-treated group (mean, 24.4%) than in the placebo-treated group (mean, 5.7%).

A dynamic Mover–Stayer model for recurrent event processes subject to resolution

“…In health research, examples include exacerbations of symptoms in patients with respiratory disease (Grossman et al, 1998), seizures in individuals with epilepsy (Pledger et al, 1994), and recurrent episodes of bleeding in patients with thrombocytopenia (Heddle et al, 2003;Webert et al, 2006). There has been considerable statistical research in the last 20 years on methods for the analysis of recurrent event data.…”

A Limited Sampling Method for the Estimation of Flunarizine Area Under the Curve (Auc) and Maximum Plasma Concentration (Cmax)

“…The design and conduct of this concentration-controlled trial are described elsewhere. 11 The single-dose pharmacokinetic pro®le was conducted for the purpose of estimating pharmacokinetic parameters, such as clearance and volume of distribution. 2 It was considered important in the trial to accurately estimate the terminal elimination rate constant because of its eect on the extrapolation of the area under the concentration±curve.…”

“…Clinical trials of¯unarizine conducted in epileptic patients with existing antiepileptic drugs have produced con¯icing results. 3,11 Pharmacokinetic studies of¯unarizine indicate a long half-life of 22 days. 3 Considerably high interindividual variation in steady-state plasma concentrations of¯unarizine has been observed (from 20 ng mL 71 to more than 250 ng mL 71 ).…”

Rising dose study of safety and tolerance of flunarizine

“…These trials utilized crossover designs with fixed doses (Overweg et al 1984;Fr6scher et al 1988;Starrveld et al 1989; Keene et al 1989; Alving et al 1989; Battaglia et al 1991), which were unsuitable, as flunarizine exhibits high inter-individual variability in clearance and a long elimination half-life. A recent NIH study (Pledger et al 1994) circumvented these difficulties by using a parallel group design and by adjusting the dose in each patient to achieve a target level of 60 ng • ml-~ (Pledger and Treiman 1991). In patients receiving flunarizine the percent reduction from baseline seizure rate was modest (mean = 24%), but significantly greater than in the placebo-treated group (mean = 6%) (Pledger et al 1994).…”

“…A recent NIH study (Pledger et al 1994) circumvented these difficulties by using a parallel group design and by adjusting the dose in each patient to achieve a target level of 60 ng • ml-~ (Pledger and Treiman 1991). In patients receiving flunarizine the percent reduction from baseline seizure rate was modest (mean = 24%), but significantly greater than in the placebo-treated group (mean = 6%) (Pledger et al 1994). To avoid unblinding the study, the target flunarizine concentration had to be low enough to avoid an excessive incidence of adverse events.…”