Limited-sampling strategy models for itraconazole and hydroxy-itraconazolebased on data from a bioequivalence study

The extensive interindividual variability in oral bioavailability of itraco nazole prompted an assessment of the bioequivalence of two formulations mar keted in Brazil, namely, Sporanox (reference) and Traconal (test). Eighteen healthy volunteers received single 200-mg oral doses of each formulation a t 2-week intervals in a randomized, crossover protocol. The concentrations of itraconazole and hydroxy-itraconazole in plasma were measured by high-pe rformance liquid chromatography, and the datum points (n = 396) were subseq uently used to develop limited-sampling strategy models for estimation of t he areas under the curve (AUCs) for both compounds. The 90% confidence inte rvals for individual percent ratios (test/reference formulations) of the ma ximum concentration of drug in serum, the AUC from 0 to 48 h and the AUC fr om time zero to infinity (AUC(0-infinity)) for itraconazole and hydoro-itra conazole were below the range of 80 to 125%, suggesting that these formulat ions are not bioequivalent. Linear regression analysis of the AUC(0-infinit y) against time and a "jackknife'' validation procedure revealed that model s based on three sampling times accurately predict (R-2, > 0.98; bias, <3%; precision, 3 to 7%) the AUC(0-infinity) for each of the four formulation-c ompound pairs tested. Increasing the number of sampling points to more than three adds little to the accuracy of the estimates of AUC(0-infinity). The three-point models developed for the reference formulation were validated retrospectively and were found to predict within 2% the AUC(0-infinity) rep orted in previous studies performed under similar protocols, In conclusion, the data in this study indicate (i) that the tested formulations are not b ioequivalent when single doses are compared and (ii) that limited-sampling strategy models based on three points predict accurately the AUC(0-infinity )s for itraconazole and hydroxy-itraconazole and could be a valuable tool i n pharmacokinetic and bioequivalence studies of single oral doses of itraco nazole.