ABSTRACT
OBJECTIVES: To assess the bioequivalence of two Tizanidine 4 mg tablet formulations (Tizanidine® of the Pharma International company, as test product, and Sirdalud® of Novartis as a reference product), and to investigate possible effects of smoking on pharmacokinetics of tizanidine. METHODS: A single-blind, randomized, single dose, two treatment, two-period, two-sequence, crossover bioequivalence study with 1 week washout period in 36 healthy volunteers. The drug was administered with 240 ml of water after 10-hour overnight fasting. After dosing, serial blood samples were collected for a period of 14 hours. Plasma harvested from blood was analyzed for tizanidine by a newly developed method using HPLC coupled with an MS/MS detector. The limit of quantitation of tizanidine was 0.080 ng/ml. Matrix-based calibration curves were linear over the range 0.080 - 8.00 ng/ml for tizanidine. The between- day coefficient of variation for quality control samples was less than 10%. RESULTS: The average bioavailability measures and pharmacokinetic parameters of the two tizanidine tablets were as follows: peak plasma concentration, Cmax, was 1.21 ± 0.84 ng/ml and 1.28 ± 1.11 ng/ml for Tizanidine PIC® and Sirdalud®, respectively. The time to peak plasma concentrations tmax were 0.83 ± 0.43 and 1.01 ± 0.5 hours, while the plasma half-life (t1/2) values were 1.20 ± 0.84 and 1.29 ± 0.57 hours. The area under the plasma concentration-time profiles AUC0âlast were 2.53 ± 2.10 ng×h/ml and 2.46 ± 2.23 ng×h/ ml, whereas the AUC0â∞were 2.81 ± 2.27 ng×h/ml and 2.75 ± 2.37 ng×h/ml for Tizanidine PIC® and Sirdalud®, respectively. The mean residence time (MRT) values were 2.16 ± 0.693 hours and 2.33 ± 0.65 hours. The 90% confidence intervals for test/reference ratio of Cmax, AUC0âlast and AUC0â∞ were found within the acceptable limits of 0.00 -125.00%, consequently no significant difference was found between the test and reference. CONCLUSION: Based on the pharmacokinetic and statistical results, it was concluded that; Tizanidine PIC® 4 mg tablets is bioequivalent to Sirdalud® 4 mg tablets of Novartis and smoking decreases Cmax and AUC of tizanidine.
