Kovarik J M, Mueller E A, van Bree J B, Tetzloff W, Kutz K
Department of Human Pharmacology, Drug Safety Assessment, Sandoz Pharma, Ltd., Basle, Switzerland.
J Pharm Sci. 1994 Mar;83(3):444-6. doi: 10.1002/jps.2600830336.
The inter- and intraindividual variability of cyclosporine pharmacokinetics from a microemulsion formulation were compared with the currently marketed formulation in a sequential bioreplication study. Twenty-four healthy male volunteers were randomized to receive each formulation on two separate occasions; the reference treatment was a single oral dose of 300 mg of Sandimmune and the test treatment was a single oral dose of 180 mg of Sandimmune Neoral, both given as soft gelatin capsules. Serial venous blood samples were obtained over a period of 48 h after each administration, and cyclosporine concentrations were measured in whole blood by a specific monoclonal RIA method. Between- and within-subject variabilities were quantified from the appropriate sums of squares from analysis of variance and statistically compared between formulations. Both inter- and intraindividual variation for the peak concentration, time to reach the peak, area under the curve, and terminal half-life of the test formulation were significantly reduced (p < 0.05) with two exceptions. For area under the curve between subjects (p < 0.2) and peak concentration within subjects (p < 0.1), trends toward reduced variability for the test formulation were evident. These results were further reflected in the inter- and intraindividual coefficients of variation of the pharmacokinetic parameters that ranged from 3 to 22% for the test formulation compared with 19 to 41% for the reference formulation. In comparison with the currently marketed formulation, reduced variability in the pharmacokinetics of cyclosporine following oral administration of Sandimmune Neoral provides a more predictable and consistent concentration-time profile.
在一项序贯生物复制研究中，将微乳剂剂型环孢素的个体间和个体内药代动力学变异性与当前市售剂型进行了比较。24名健康男性志愿者被随机分为两组，在两个不同的时间分别接受每种剂型；对照治疗为单次口服300mg山地明，试验治疗为单次口服180mg新山地明，均制成软胶囊给药。每次给药后48小时内采集系列静脉血样，采用特异性单克隆放射免疫分析法测定全血中环孢素浓度。根据方差分析中适当的平方和对受试者间和受试者内变异性进行量化，并对不同剂型进行统计学比较。试验剂型的峰浓度、达峰时间、曲线下面积和终末半衰期的个体间和个体内变异均显著降低（p<0.05），但有两个例外。受试者间曲线下面积（p<0.2）和受试者内峰浓度（p<0.1），试验剂型变异性降低的趋势明显。这些结果进一步反映在药代动力学参数的个体间和个体内变异系数上，试验剂型为3%至22%，而对照剂型为19%至4%。与当前市售剂型相比，口服新山地明后环孢素药代动力学变异性降低，提供了更可预测和一致的浓度-时间曲线。
