Suarez-Kurtz G, Bozza F A, Vicente F L, Ponte C G, Struchiner C J
Instituto Nacional de Câncer, Coordenação de Pesquisa, Programa de Farmacologia, Rio de Janeiro, Brazil.
Antimicrob Agents Chemother. 1999 Jan;43(1):134-40. doi: 10.1128/AAC.43.1.134.
The extensive interindividual variability in oral bioavailability of itraconazole prompted an assessment of the bioequivalence of two formulations marketed in Brazil, namely, Sporanox (reference) and Traconal (test). Eighteen healthy volunteers received single 200-mg oral doses of each formulation at 2-week intervals in a randomized, crossover protocol. The concentrations of itraconazole and hydroxy-itraconazole in plasma were measured by high-performance liquid chromatography, and the datum points (n = 396) were subsequently used to develop limited-sampling strategy models for estimation of the areas under the curve (AUCs) for both compounds. The 90% confidence intervals for individual percent ratios (test/reference formulations) of the maximum concentration of drug in serum, the AUC from 0 to 48 h and the AUC from time zero to infinity (AUC0-infinity) for itraconazole and hydoxy-itraconazole were below the range of 80 to 125%, suggesting that these formulations are not bioequivalent. Linear regression analysis of the AUC0-infinity against time and a "jackknife" validation procedure revealed that models based on three sampling times accurately predict (R2, >0.98; bias, <3%; precision, 3 to 7%) the AUC0-infinity for each of the four formulation-compound pairs tested. Increasing the number of sampling points to more than three adds little to the accuracy of the estimates of AUC0-infinity. The three-point models developed for the reference formulation were validated retrospectively and were found to predict within 2% the AUC0-infinity reported in previous studies performed under similar protocols. In conclusion, the data in this study indicate (i) that the tested formulations are not bioequivalent when single doses are compared and (ii) that limited-sampling strategy models based on three points predict accurately the AUC0-infinitys for itraconazole and hydroxy-itraconazole and could be a valuable tool in pharmacokinetic and bioequivalence studies of single oral doses of itraconazole.
伊曲康唑口服生物利用度存在广泛的个体间差异，这促使人们对在巴西销售的两种制剂进行生物等效性评估，即斯皮仁诺（参比制剂）和曲康唑（受试制剂）。18名健康志愿者按照随机交叉试验方案，每隔2周接受一次单剂量200mg的每种制剂口服给药。采用高效液相色谱法测定血浆中伊曲康唑和羟基伊曲康唑的浓度，随后利用这些数据点（n = 396）建立有限采样策略模型，以估算两种化合物的曲线下面积（AUC）。伊曲康唑和羟基伊曲康唑血清中药物最大浓度、0至48小时的AUC以及从零时间至无穷大的AUC（AUC0-无穷大）的个体百分率比（受试制剂/参比制剂）的90%置信区间低于80%至125%的范围，这表明这些制剂并非生物等效。对AUC0-无穷大与时间进行线性回归分析以及“留一法”验证程序表明，基于三个采样时间点建立的模型能够准确预测（R2>0.98；偏差<3%；精密度为3%至7%）所测试的四种制剂-化合物组合中每种的AUC0-无穷大。将采样点数增加到三个以上对AUC0-无穷大估计值的准确性提升不大。为参比制剂建立的三点模型经过回顾性验证，发现其预测值与先前在类似试验方案下进行的研究中报告的AUC0-无穷大相差在2%以内。总之，本研究数据表明：（i）单剂量比较时，受试制剂并非生物等效；（ii）基于三个时间点的有限采样策略模型能够准确预测伊曲康唑和羟基伊曲康唑的AUC0-无穷大，在单剂量口服伊曲康唑的药代动力学和生物等效性研究中可能是一种有价值的工具。
