Kovarik J M, Mueller E A, van Bree J B, Flückiger S S, Lange H, Schmidt B, Boesken W H, Lison A E, Kutz K
Sandoz Pharma, Ltd., Basle, Switzerland.
Transplantation. 1994 Sep 27;58(6):658-63.
The steady-state pharmacokinetics and tolerability of a microemulsion formulation of cyclosporine (Sandimmune Neoral) were compared with the commercial formulation (Sandimmune) in 55 clinically stable renal allograft recipients. In study period I (2 weeks' duration), patients entered the study on a stable, individualized twice-daily dosage regimen of the commercial formulation. In period II (2 weeks), they were changed over to the microemulsion formulation at the same dose as at study entry. In period III (2 weeks), dose titration was subsequently allowed if necessary to provide comparable steady-state trough concentrations as at study entry. The commercial formulation was reinstituted during period IV (2 weeks). Safety and tolerability were assessed at weekly clinic visits, and the steady-state pharmacokinetics of cyclosporine in whole blood were characterized at the end of each study period. A milligram-to-milligram dose conversion was adequate when making the initial change between formulations in order to maintain steady-state trough concentrations in the target therapeutic range. Concomitant with this conversion, the steady-state peak concentration and area under the curve increased on average by 59% and 30%, respectively, due to absorption-related differences between the formulations. These increases were not associated with an increase in adverse experiences or changes in blood pressure or clinical laboratory parameters over the first four weeks after the change-over. Trough concentrations were more stable and were more strongly correlated with systemic exposure (area under the curve) during treatment with the microemulsion formulation. Intraindividual coefficients of variation in steady-state peak concentration, time to attain the peak, area under the curve, and percent peak-trough fluctuation ranged from 18% to 74% from the commercial formulation. Variability from the microemulsion formulation was significantly less, ranging from 10% to 22%.
在55例临床稳定的肾移植受者中，比较了环孢素微乳剂（新山地明）与市售制剂（山地明）的稳态药代动力学和耐受性。在研究阶段I（为期2周），患者以市售制剂稳定的个体化每日两次给药方案进入研究。在阶段II（2周），他们以与研究开始时相同的剂量换用微乳剂。在阶段III（2周），如有必要随后进行剂量滴定，以提供与研究开始时相当的稳态谷浓度。在阶段IV（2周）重新使用市售制剂。每周门诊就诊时评估安全性和耐受性，并在每个研究阶段结束时对全血中环孢素的稳态药代动力学进行表征。在制剂之间进行初始转换时，毫克对毫克的剂量转换足以维持目标治疗范围内的稳态谷浓度。伴随这种转换，由于制剂之间吸收相关的差异，稳态峰浓度和曲线下面积平均分别增加了59%和30%。这些增加与转换后前四周内不良事件的增加、血压或临床实验室参数的变化无关。在使用微乳剂治疗期间，谷浓度更稳定，并且与全身暴露（曲线下面积）的相关性更强。市售制剂稳态峰浓度、达峰时间、曲线下面积和峰谷波动百分比的个体内变异系数范围为18%至74%。微乳剂的变异性明显较小，范围为10%至22%。
