Study On The Bioequivalence Of Itraconazole Capsules In Human Volunteers And Pharmacokinetic Study Of Combined Itraconazole And Terbinafine In Rat

Itraconazole is a triazole antifungal drug with a broad spectrum of activity against most human fungal pathogens. It can be used for both superficial part and deep part of fugal infection clinically. The pharmacokinetic study was conducted by measuring the itraconazole plasma concentration and calculating the pharmacokinetic parameters using the developed and validated bioanalytical method. The bioequivalence between the test and reference preparation was evaluated. The pharmacokinetic study of combined itraconazole and terbinafine in rats was also investigated in the present studies.A method was developed and successfully applied to determine itraconazole concentrations in human plasma with relatively high extraction efficiency and good separation selectivity. The method was used to evaluate the bioequivalence of itraconazole capsules in 20 healthy volunteers. A single oral dose of itraconazole capsules was given according to a randomized crossover design. The main pharmacokinetic parameters of the test preparation and the reference preparation were as follows:Tmax were 3.2±0.6 and 3.2±0.7 h, Cmax were 214.3±73.0 and 206.9±63.4 ng·mL-1, t1/2 were 22.5±11.1 and 21.1±7.9 h, AUC0-72 were 2459±1141 and 2404±900 ng·h·mL-1, AUC0-∞were 2882±1259 and 2781±939 ng·h·mL-1. The relative bioavailability of the test ITZ capsules was 101.6±24.4%. The result of statistical analysis showed that there was no significant difference between Tmax, Cmax, and AUC0-72 of the two products. The results of statistic analysis show that the reference preparation and the test preparation are bioequivalent.It has been investigated the HPLC method which was developed and validated for the simultaneous determination of the analytes for the pharmacokinetic study of combined itraconazole and terbinafine. The chromatographic separation was carried out by gradient elution with 0.5% formic acid and acetonitrile. The UV-detector program consisted of a 0-7 min sequence set at 230 nm for terbinafine,7.01-17.0 min sequence set at 261 nm for itraconazole and internal standard (diazepam, I.S.). The limit of quantification (LOQ) for itraconazole and terbinafine were both 50 ng·mL-1. The mean extraction recoveries were≥70.6% for itraconazole and≥77% for terbinafine from biological matrixes. Accuracy, expressed as the relative error, ranged from 1.4% to 2.9% for itraconazole and from-3.6% to 9.4% for terbinafine. The method was successfully applied to the estimation of itraconazole and terbinafine in rat plasma. No significant differences were observed for the major pharmacokinetic parameters such as Cmax, Tmax,t1/2 and AUC0-t of itraconazole. But there were significant differences of terbinafine.