Mueller E A, Kovarik J M, van Bree J B, Lison A E, Kutz K
Department of Human Pharmacology, Sandoz Pharma, Ltd., Basel, Switzerland.
Transplantation. 1994 Apr 27;57(8):1178-82. doi: 10.1097/00007890-199404270-00007.
The steady-state pharmacokinetics and tolerability of a microemulsion formulation of cyclosporine (Sandimmune Neoral) were compared with Sandimmune in 18 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 Sandimmune. Two approaches were assessed for changing patients over from Sandimmune to Sandimmune Neoral. In period II (2 weeks), doses were converted based on the area under the curve ratio derived from a relative bioavailability study comparing the two formulations in healthy volunteers. In period III (2 weeks), doses were titrated to provide comparable steady-state trough concentrations as at study entry. Sandimmune 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. Dose conversion in period II based on the AUC ratio derived from healthy volunteers was inadequate for achieving comparable cyclosporine exposure as assessed by steady-state AUC and troughs. The concentration-controlled approach (period III) indicated that maintaining the same cyclosporine dose when changing between formulations yields comparable steady-state trough concentrations. Concomitant with this conversion, steady-state peak concentration and AUC increased on average by 39% and 15%, respectively, due to absorption-related differences between the formulations. These increases were not associated with adverse events or changes in blood pressure or clinical laboratory parameters. Furthermore, they were not detrimental to the transplanted kidney as monitored by ultrasound examination. The pharmacokinetic profiles from Sandimmune Neoral exhibited less variability and yielded a stronger correlation between trough concentration and systemic exposure (AUC) compared with Sandimmune.
在18名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），患者以稳定的、个体化的山地明每日两次给药方案进入研究。评估了两种将患者从山地明转换为新山地明的方法。在阶段II（2周），根据健康志愿者中比较两种制剂的相对生物利用度研究得出的曲线下面积比来转换剂量。在阶段III（2周），滴定剂量以提供与研究开始时相当的稳态谷浓度。在阶段IV（2周）重新使用山地明。每周门诊时评估安全性和耐受性，并在每个研究阶段结束时表征全血中环孢素的稳态药代动力学。根据健康志愿者得出的AUC比在阶段II进行的剂量转换，对于通过稳态AUC和谷浓度评估实现相当的环孢素暴露而言是不足的。浓度控制方法（阶段III）表明，在制剂之间转换时维持相同的环孢素剂量会产生相当的稳态谷浓度。与此转换同时，由于制剂之间与吸收相关的差异，稳态峰浓度和AUC平均分别增加了39%和15%。这些增加与不良事件、血压变化或临床实验室参数无关。此外，通过超声检查监测，它们对移植肾无害。与山地明相比，新山地明的药代动力学特征变异性较小，谷浓度与全身暴露（AUC）之间的相关性更强。
