Dyderski Stanisław, Grześkowiak Edmund, Szałek Edyta, Szkutnik Danuta, Dubai Vitali, Drobnik Leon
Department of Clinical Pharmacy and Biopharmacy, K. Marcinkowski University of Medical Sciences, Poznań, Poland.
Arzneimittelforschung. 2005;55(9):514-9. doi: 10.1055/s-0031-1296898.
The bioavailability of a new letrozole (CAS 112809-51-5) preparation was compared with the reference preparation of the drug in 25 healthy volunteers, aged between 18 and 33. A single dose of 2.5 mg was given orally in the fasted state, using a randomized two-way, cross-over protocol. A washout period of two weeks separated both treatment periods. Blood samples were obtained at regular time intervals, until 312 h after drug administration. After solid phase extraction (SPE) letrozole plasma levels were measured by high pressure liquid chromatography that was validated before the start of the study (UV detector, fluoroletrozole as an internal standard). The limit of quantification was 1.4 nmol/ml. The following pharmacokinetics parameters were calculated from letrozole plasma concentrations: AUC(0-infinity), AUC(0-t), Cmax, tmax, F(rel), MRT, t(1/2), k(el). The confidence intervals for the statistical calculations of AUC(0-infinity), Cmax, tmax were 95 % and AUC(0-t), MRT, t(1/2), k(el) were tested by means of the unpaired t-tests procedure and after logarithmic transformation for overall significant differences using analysis of variance--three-way ANOVA. The AUC(0-infinity) ratio test/reference and the 90 % confidence interval were 99.52 %, and 94.05-107.31%, respectively. The Cmax ratio test/reference and the 90 % confidence interval were 89.18 %, and 84.48-98.60%, respectively. AUC(0-infinity) and Cmax ratios (90 % CI) were within the 80-125 % interval required for bioequivalence as stipulated in the current international regulations of the European Agency for the Evalution of Medicinal Products and the Food and Drug Administration. Therefore it is concluded that the new letrozole preparation is therapeutically equivalent to the reference preparation for both the extent and the rate of absorption after single dose administration in healthy volunteers.
在25名年龄在18至33岁之间的健康志愿者中，将一种新型来曲唑（CAS 112809-51-5）制剂的生物利用度与该药物的参比制剂进行了比较。采用随机双向交叉试验方案，在禁食状态下口服单剂量2.5 mg。两个治疗周期之间间隔两周的洗脱期。在给药后312小时内定期采集血样。经固相萃取（SPE）后，采用研究开始前经验证的高压液相色谱法（紫外检测器，氟来曲唑作为内标）测定来曲唑血浆浓度。定量限为1.4 nmol/ml。根据来曲唑血浆浓度计算以下药代动力学参数：AUC(0-∞)、AUC(0-t)、Cmax、tmax、F(rel)、MRT、t(1/2)、k(el)。AUC(0-∞)、Cmax、tmax统计计算的置信区间为95%，AUC(0-t)、MRT、t(1/2)、k(el)采用不成对t检验程序进行检验，并在对数转换后使用方差分析——三因素方差分析检验总体显著性差异。AUC(0-∞)试验/参比制剂比值及90%置信区间分别为99.52%和94.05 - 107.31%。Cmax试验/参比制剂比值及90%置信区间分别为89.18%和84.48 - 98.60%。AUC(0-∞)和Cmax比值（90% CI）在欧洲药品评估局和美国食品药品监督管理局现行国际法规规定的生物等效性所需的80 - 125%区间内。因此得出结论，在健康志愿者单剂量给药后，新型来曲唑制剂在吸收程度和吸收速率方面与参比制剂具有治疗等效性。
