Judit Bajnogel

Effect of tofisopam on the single-oral-dose pharmacokinetics and pharmacodynamics of the cyp3a4 probe drug alprazolam

Interaction between tacrolimus, a substrate of the cytochrome P450 3A4 enzyme (CYP3A4), and the 2,3benzodiazepine anxiolytic tofisopam has been reported in kidney transplant patients. Tofisopam increased the plasma concentration of tacrolimus, leading to aggravation of patients’ renal function. In vitro findings with human recombinant CYP3A4 have indicated that tofisopam inhibits the activity of the enzyme (IC50=0.8 μM), but its effect was an order of magnitude weaker than that of ketoconazole (IC50=0.03 μM) [1]. A pharmacokinetic/pharmacodynamic drug-drug interaction study was done to evaluate the effect of tofisopam on CYP3A4 activity, using alprazolam as a probe drug. Sixteen Caucasian healthy male volunteers were enrolled in this double-blind, randomised, two-way crossover study after each gave written informed consent. The study protocol was approved by the Hungarian Clinical Pharmacological Ethical Committee of the Scientific Health Council and the local ethics committee of the Drug Research Center, Balatonfüred. Subjects received 100 mg of tofisopam three times a day (the highest recommended dose in clinical practice) or matched placebo for 9 days in a random order. On day 7 of each treatment period, a single 0.5-mg dose of alprazolam was administered 1 h after the morning dose of tofisopam. Alprazolam plasma concentrations were measured for 72 h using a validated capillary gas chromatographic-mass spectrometric method. The internal standard was midazolam in the assay. The lower limit of quantification for alprazolam was 0.1 ng/ml. The interassay precision and accuracy were 8.6–10.6% and 1.3–4.3%, respectively. The pharmacokinetic parameters for alprazolam were determined by a standard noncompartmental method using Kinetica version 4.02 validated software (InnaPhase, Champs sur Marne, France). The effect of tofisopam on the pharmacokinetics of alprazolam was evaluated using an analysis of variance model appropriate for the underlying crossover design. The 90% confidence interval (CI) about the geometric mean ratio of the two treatments for maximum plasma concentration (Cmax), the area under the plasma concentration time curve from zero to infinity (AUC), the elimination half-life (t1/2), and the apparent oral clearance (CL/F) were calculated and expressed as a percentage of the reference (alprazolam with placebo) treatment. To assess the possible pharmacodynamic interaction between the two drugs, cognitive tests (immediate and delayed word recall, digit symbol substitution test) and subjective ratings of drug effects were performed. Fifteen subjects completed the study. One subject was withdrawn because of intercurrent disease after the first treatment period. There was a significant but slight 124% (90% CI 115– 135%) and 121% (90% CI 113–135) increase in the AUC and t1/2 of alprazolam, respectively, and an 81% (74–87%) decrease in the CL/F of alprazolam during concomitant administration with tofisopam compared with placebo. The Cmax of alprazolam was not affected by tofisopam (Table 1). No significant differences in the performance on the pharmacodynamic tests were observed. The results of the study indicate that tofisopam only modestly inhibits hepatic CYP3A4 activity. This effect does not sufficiently explain the mechanism of the pharmacokinetic interaction between tofisopam and tacrolimus. Several studies indicate that in addition to hepatic CYP3A4, tacrolimus is a substrate of the intestinal CYP3A4 and P-glycoprotein (PgP) drug transporter [2]. Interaction between the two drugs may occur at the S. Drabant (*) . M. Tóth . A. Bereczki . J. Bajnógel . J. Tömlö EGIS Pharmaceuticals Ltd., Keresztúri út 30-38, Budapest, Hungary, 1106 e-mail: clinpharm.rd@egis.hu Tel.: +36-1265-5774 Fax: +36-1265-5758