Kirchner Gabriele I, Meier-Wiedenbach Ivo, Manns Michael P
Department of Gastroenterology, Hepatology and Endocrinology, Zentrum Innere Medizin, Medizinische Hochschule Hannover, Hannover, Germany.
Clin Pharmacokinet. 2004;43(2):83-95. doi: 10.2165/00003088-200443020-00002.
Everolimus is an immunosuppressive macrolide bearing a stable 2-hydroxyethyl chain substitution at position 40 on the sirolimus (rapamycin) structure. Everolimus, which has greater polarity than sirolimus, was developed in an attempt to improve the pharmacokinetic characteristics of sirolimus, particularly to increase its oral bioavailability. Everolimus has a mechanism of action similar to that of sirolimus. It blocks growth-driven transduction signals in the T-cell response to alloantigen and thus acts at a later stage than the calcineurin inhibitors ciclosporin and tacrolimus. Everolimus and ciclosporin show synergism in immunosuppression both in vitro and in vivo and therefore the drugs are intended to be given in combination after solid organ transplantation. The synergistic effect allows a dosage reduction that decreases adverse effects. For the quantification of the pharmacokinetics of everolimus, nine different assays using high performance liquid chromatography coupled to an electrospray mass spectrometer, and one enzyme-linked immunosorbent assay, have been developed. Oral everolimus is absorbed rapidly, and reaches peak concentration after 1.3-1.8 hours. Steady state is reached within 7 days, and steady-state peak and trough concentrations, and area under the concentration-time curve (AUC), are proportional to dosage. In adults, everolimus pharmacokinetic characteristics do not differ according to age, weight or sex, but bodyweight-adjusted dosages are necessary in children. The interindividual pharmacokinetic variability of everolimus can be explained by different activities of the drug efflux pump P-glycoprotein and of metabolism by cytochrome P450 (CYP) 3A4, 3A5 and 2C8. The critical role of the CYP3A4 system for everolimus biotransformation leads to drug-drug interactions with other drugs metabolised by this cytochrome system. In patients with hepatic impairment, the apparent clearance of everolimus is significantly lower than in healthy volunteers, and therefore the dosage of everolimus should be reduced by half in these patients. The advantage of everolimus seems to be its lower nephrotoxicity in comparison with the standard immunosuppressants ciclosporin and tacrolimus. Observed adverse effects with everolimus include hypertriglyceridaemia, hypercholesterolaemia, opportunistic infections, thrombocytopenia and leucocytopenia. Because of the variable oral bioavailability and narrow therapeutic index of everolimus, blood concentration monitoring seems to be important. The excellent correlation between steady-state trough concentration and AUC makes the former a simple and reliable index for monitoring everolimus exposure. The target trough concentration of everolimus should range between 3 and 15 microg/L in combination therapy with ciclosporin (trough concentration 100-300 microg/L) and prednisone.
依维莫司是一种免疫抑制性大环内酯类药物，在西罗莫司（雷帕霉素）结构的40位带有稳定的2 - 羟乙基链取代基。依维莫司的极性比西罗莫司大，研发它是为了改善西罗莫司的药代动力学特性，尤其是提高其口服生物利用度。依维莫司的作用机制与西罗莫司相似。它阻断T细胞对同种异体抗原反应中生长驱动的转导信号，因此作用阶段比钙调神经磷酸酶抑制剂环孢素和他克莫司更靠后。依维莫司和环孢素在体外和体内的免疫抑制中均表现出协同作用，因此在实体器官移植后打算联合使用这两种药物。这种协同效应允许减少剂量，从而降低不良反应。为了定量分析依维莫司的药代动力学，已经开发了九种使用高效液相色谱与电喷雾质谱联用的不同检测方法，以及一种酶联免疫吸附测定法。口服依维莫司吸收迅速，在1.3 - 1.8小时后达到峰值浓度。7天内达到稳态，稳态峰浓度、谷浓度以及浓度 - 时间曲线下面积（AUC）与剂量成正比。在成年人中，依维莫司的药代动力学特性不因年龄、体重或性别而有所不同，但儿童需要根据体重调整剂量。依维莫司个体间药代动力学变异性可由药物外排泵P - 糖蛋白的不同活性以及细胞色素P450（CYP）3A4、3A5和2C8的代谢作用来解释。CYP3A4系统对依维莫司生物转化的关键作用导致其与其他由该细胞色素系统代谢的药物发生药物相互作用。在肝功能损害患者中，依维莫司的表观清除率明显低于健康志愿者，因此这些患者的依维莫司剂量应减半。与标准免疫抑制剂环孢素和他克莫司相比，依维莫司的优势似乎在于其肾毒性较低。依维莫司观察到的不良反应包括高甘油三酯血症、高胆固醇血症、机会性感染、血小板减少和白细胞减少。由于依维莫司口服生物利用度可变且治疗指数较窄，血药浓度监测似乎很重要。稳态谷浓度与AUC之间的良好相关性使得前者成为监测依维莫司暴露的简单可靠指标。在与环孢素（谷浓度100 - 300μg/L）和泼尼松联合治疗时，依维莫司的目标谷浓度应在3至15μg/L之间。
