Optimization of cyclosporine therapy in renal transplantation by a pharmacokinetic strategy.
Optimization of cyclosporine therapy in renal transplantation by a pharmacokinetic strategy.
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通过药代动力学策略优化肾移植中的环孢素治疗。
DOI：
10.1097/00007890-198811000-00002
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发表时间：
1988
期刊：
影响因子：
6.2
通讯作者：
Grevel,J
中科院分区：
文献类型：
--
作者：
Kahan,BD;Grevel,J
虽然环孢素（CsA）由于有效的选择性抑制T细胞而非非特异性免疫功能而显示出高的免疫抑制功效，但药物的多效性毒性导致治疗指数低。因此，对于一个给定的个体，最多只有一个狭窄的剂量范围产生免疫抑制，而不会被毒性所掩盖。由于药物药代动力学和药效学存在显著的个体间和个体内变异性，因此选择适当的CsA剂量以达到这种状态是复杂的（1）。即使仅考虑肾移植受者，药物吸收、分布容积和代谢的药代动力学变化（通过清除率估计）也很大，因此基于人群中位数的策略对大部分患者无效。因此，有必要设计一个CsA策略，调整治疗，以弥补个体间的差异。这种策略的实施不仅使药物治疗变得简单，而且还揭示了CsA代谢产物谱和给定量CsA药效学效应的个体间差异的临床影响，反映了对免疫系统的治疗作用和对靶器官的毒性作用。因此，通过补偿药代动力学变化来实现均匀药物水平的给药策略对于最终解剖合理的CsA方案至关重要。
Although cyclosporine (CsA) displays high immunosuppressive efficacy due to potent selective inhibition of T cell, but not nonspecific, immune functions, the pleiotropic toxicities of the drug result in a low therapeutic index. Thus for a given individual there is at best only a narrow dosage range producing immunosuppression not beclouded by toxicity. Selection of the appropriate CsA dose to achieve this state is complicated by marked inter-and intraindividual variability in drug pharmacokinetics and pharmacodynamics (1). Even considering renal transplant recipients solely, pharmacokinetic variations in drug absorption, volume of distribution, and metabolism as estimated by clearance rates are so great that strategies based on median population values are not useful for a great proportion of patients. Thus it is necessary to devise a CsA strategy that tailors therapy to compensate for interindividual variations. Implementation of such a strategy not only standardizes drug therapy, but also reveals the clinical impact of interindividual differences in the profile of CsA metabolites and in pharmacodynamic effects of a given quantity of CsA, reflecting both the therapeutic actions on the immune system and toxic effects on target organs. Thus a dosing strategy that achieves uniform drug levels by compensating for pharmacokinetic variation is essential for the eventual dissection of a rational CsA regimen.