Tsai Jui-Chen, Cheng Ching-Ling, Tsai Yi-Fang, Sheu Hamm-Ming, Chou Chen-Hsi
Institute of Clinical Pharmacy, College of Medicine, National Cheng Kung University, Tainan, 1 University Road, Tainan, Taiwan 70101.
J Pharm Sci. 2004 Jan;93(1):207-17. doi: 10.1002/jps.10536.
The United States Food and Drug Administration recommends pilot dose duration-response and pivotal bioequivalence studies to be conducted using reflectance colorimetry for assessment of the in vivo bioequivalence of topical dermatologic corticosteroids. The major objectives of the present studies were to examine the applicability of the standardized pharmacodynamic modeling-based methodology to super-potent clobetasol 17-propionate (CP) in the Chinese population and to evaluate the bioequivalence of two generic ointments and four generic creams containing 0.05% (w/w) CP with respect to Dermovate formulations using such methodology. In the pilot dose duration-response study, although the E(max) model (where E(max) is the maximum fitted value of AUEC, which is the area under the baseline-corrected, untreated control-site-corrected a* scale data from 0 to 24 h after drug removal) did not provide acceptable model fits, E(max) parameter estimates of -38.97 +/- 3.62 and -41.89 +/- 11.28 a*-scale. h, and ED(50) (dose duration required to achieve 50% of the fitted E(max) value) estimates of 0.40 +/- 0.37 and 0.42 +/- 0.16 h were obtained for Dermovate ointment and cream, respectively, by population analyses. The estimates for the two formulations were not statistically different, so in vivo bioequivalence studies were conducted at an ED(50)dose duration of approximately 0.5 h for both Dermovate formulations. The results demonstrated that one generic ointment was bioequivalent to Dermovate, whereas the other was not. None of the generic creams were shown to be bioequivalent to Dermovate cream. The in vivo bioequivalence data from the vasoconstriction assay were linearly correlated with stratum corneum uptake of the drug at the same dose duration until the maximal vasoconstriction response was achieved. The studies illustrated the applicability of the standardized pharmacodynamic modeling-based methodology in detecting the product differences between a variety of generic 0.05% CP formulations and reference Dermovate formulations in Chinese skin.
美国食品药品监督管理局建议进行预试验剂量持续时间-反应和关键生物等效性研究，使用反射比色法评估局部皮质类固醇的体内生物等效性。本研究的主要目的是检验基于标准化药效学建模方法在中国人群中对超强效丙酸氯倍他索（CP）的适用性，并使用该方法评估两种含0.05%（w/w）CP的仿制软膏和四种仿制乳膏相对于得肤宝制剂的生物等效性。在预试验剂量持续时间-反应研究中，尽管E(max)模型（其中E(max)是AUEC的最大拟合值，AUEC是药物去除后0至24小时基线校正、未处理对照部位校正的a标度数据的曲线下面积）未提供可接受的模型拟合，但通过群体分析分别得出得肤宝软膏和乳膏的E(max)参数估计值为-38.97±3.62和-41.89±11.28 a标度·小时，以及ED(50)（达到拟合E(max)值的50%所需的剂量持续时间）估计值为0.40±0.37和0.42±0.16小时。两种制剂的估计值无统计学差异，因此对两种得肤宝制剂均在约0.5小时的ED(50)剂量持续时间下进行了体内生物等效性研究。结果表明，一种仿制软膏与得肤宝生物等效，而另一种则不然。没有一种仿制乳膏显示与得肤宝乳膏生物等效。血管收缩试验的体内生物等效性数据在相同剂量持续时间下与药物的角质层摄取呈线性相关，直至达到最大血管收缩反应。这些研究说明了基于标准化药效学建模方法在检测中国皮肤中各种0.05%CP仿制制剂与参比得肤宝制剂之间的产品差异方面的适用性。
