Budde Klemens, Neumayer Hans-Hellmut, Lehne Gustav, Winkler Michael, Hauser Ingeborg Anni, Lison Arno, Fritsche Lutz, Soulillou Jean-Paul, Fauchald Per, Dantal Jaques
Department of Nephrology, Charité University Hospital, Schumannstrasse 20-21, D-10117 Berlin, Germany.
Nephrol Dial Transplant. 2004 Oct;19(10):2606-14. doi: 10.1093/ndt/gfh322. Epub 2004 Aug 17.
Current immunosuppressant regimens need to be improved to prevent acute and chronic graft rejection. The novel macrocyclic immunosuppressant everolimus (Certican, RAD) is currently in clinical development to address this issue.
The primary objective of this multicentre, randomized, double-blind, placebo-controlled, dose-escalating phase 1 study was to evaluate the safety and tolerability of everolimus at four dose levels (0.75, 2.5, 5 and 10 mg/day) in maintenance renal transplant patients receiving cyclosporin and steroids. The secondary objective was to assess the pharmacokinetic profile of two different formulations (capsule and tablet) of everolimus.
Fifty-four subjects were randomized for 4 weeks treatment with everolimus (n = 44) or placebo (n = 10). Dose levels of everolimus between 0.75 and 5 mg daily were well tolerated, permitting dose escalation to the highest everolimus dose of 10 mg daily. At this dose, everolimus was associated with a higher incidence and severity of adverse events, most notably thrombocytopenia. Pharmacodynamic assessment showed a relationship between drug exposure and thrombocytopenia. Notable reversible elevations of cholesterol were also observed at the 10 mg/day dose. Other changes in laboratory evaluations, including triglycerides, were minor, reversible and did not appear to be dose dependent. The bioavailability of the tablet formulation was 2.6-fold higher compared with the capsule, with evidence for dose proportionality over the dose range tested. Within-subject pharmacokinetic variability was low (coefficient of variation: 10-19%); however, between-subject variability ranged from 34 to 60% for AUC and C(max).
These results indicate that up to 5 mg/day everolimus results in a dose-proportional exposure, and is adequately well tolerated in renal transplant recipients receiving cyclosporin and steroids.
当前的免疫抑制方案需要改进，以预防急性和慢性移植排斥反应。新型大环免疫抑制剂依维莫司（Certican，RAD）目前正处于临床开发阶段，以解决这一问题。
这项多中心、随机、双盲、安慰剂对照、剂量递增的1期研究的主要目的是评估依维莫司在四个剂量水平（0.75、2.5、5和10毫克/天）对接受环孢素和类固醇治疗的维持性肾移植患者的安全性和耐受性。次要目的是评估依维莫司两种不同剂型（胶囊和片剂）的药代动力学特征。
54名受试者被随机分为接受依维莫司（n = 44）或安慰剂（n = 10）治疗4周。每日0.75至5毫克剂量水平的依维莫司耐受性良好，允许将剂量递增至每日最高依维莫司剂量10毫克。在此剂量下，依维莫司与不良事件的发生率和严重程度较高相关，最显著的是血小板减少症。药效学评估显示药物暴露与血小板减少症之间存在关联。在10毫克/天剂量下还观察到胆固醇明显可逆性升高。实验室评估中的其他变化，包括甘油三酯，较小且可逆，似乎与剂量无关。片剂剂型的生物利用度比胶囊高2.6倍，在所测试的剂量范围内有剂量比例关系的证据。受试者内药代动力学变异性较低（变异系数：10 - 19%）；然而，受试者间AUC和C(max)的变异性范围为34%至60%。
这些结果表明，每日高达5毫克的依维莫司可导致剂量比例性暴露，并且在接受环孢素和类固醇治疗的肾移植受者中耐受性良好。
