肾移植患者西罗莫司的群体药动学研究

目的:建立中国肾移植患者西罗莫司的群体药动学模型,为实施个体化用药提供理论支持。方法:选择47名肾移植术后采用西罗莫司+泼尼松+环孢素或他克莫司或霉酚酸酯(MMF)三联免疫抑制治疗的患者为研究对象,回顾性收集47名患者服药后的101个西罗莫司稳态血药浓度及相应的试验室检查数据,运用Winnonmix药动学软件,采用非线性混合效应模型(NONMEM)分析体重、年龄、性别、给药剂量、合并用药、肌酐清除率等对药动学参数的影响。最终模型的验证采用Jackknife法进行内部验证。结果:西罗莫司符合无滞后时间的一级消除动力学一室模型。固定效应结果量子,合用MMF和体重可影响药物清除率。最终模型公式为:CL/F(L·h-1)=11.01×0.14MMF+0.089×W。CL/F和Vd/F的群体典型值分别是11.01L·h-1和3616L,个体间变异分别为62.82%和85.07%。观测值和预测值间的残差(SD)和相关系数(r)分别是1.0ng·mL-1和0.94。结论:所建立的群体药动学模型能较好地估算服用西罗莫司的肾移植患者的个体及群体药动学参数,对指导临床个体化用药具有重要意义。     

群体药动学在免疫抑制剂合理用药中的应用

群体药动学(PPK)应用统计学原理,综合评价影响药动学个体间及个体内差异的各种因素,进一步利用Bayesian反馈,能够较为准确地预测患者个体药动学参数。PPK在免疫抑制剂环孢素、他克莫司、霉酚酸及西罗莫司的合理用药均有广泛应用。     

麦考酚酸制剂体内药动学参数、临床疗效及不良反应影响因素的研究进展

目的:了解麦考酚酸(MPA)制剂体内药动学参数、临床疗效及不良反应影响因素的研究进展,为临床合理用药提供循证依据。方法:查阅近年来国内外文献,从基因多态性、患者机体因素和药物因素等方面对MPA的体内药动学参数、临床疗效和不良反应的影响进行归纳和总结。结果与结论:吗替麦考酚酯(MMF)和麦考酚钠(EC-MPS)为MPA的2种常用制剂。MMF为器官和组织移植术后抗免疫排斥反应的一线用药,其体内药动学参数、临床疗效和不良反应发生率受基因多态性、患者机体因素(种族、血清白蛋白水平、术后时间和并发症等)和药物因素(联合用药、药物剂型和给药剂量)等影响。     

他克莫司的临床应用评价

目的:对他克莫司的药动学参数和不良反应等进行评价,为临床合理用药、个体化给药提供有益的信息和依据。方法:查阅他克莫司相关文献,对资料中的药物发生机制和常用药物进行分组,综合评价其临床应用。结果:他克莫司治疗窗窄、生物利用度低、个体差异大、联用时出现不良反应的几率较高。结论:临床上应高度重视他克莫司的合理使用,进行血液浓度监测应综合考虑联合用药等因素,实施个体化给药,保障用药安全。     

环孢素A药动学/药效学/不良反应的影响因素分析

目的：对影响环孢素A药动学、药效学、不良反应的药物因素及遗传因素进行分析。方法：主要查阅Pubmed、Embase及中国期刊全文数据库2010-2016年载录的相关文献,归纳总结出具体的影响因素。结果：药物因素（血药浓度、给药频率、合并用药等）及遗传因素（CYP3A和MDR1基因多态性等）对环孢素A药动学、药效学、不良反应均有影响。结论：基因多态性、合并用药为环孢素A药动学、药效学、不良反应的主要影响因素,临床上需结合患者实际情况进行监测以保证合理的个体化给药和用药安全。     

新型大环内酯类免疫抑制剂-西罗莫司

目的:综述新型大环内酯类免疫抑制剂西罗莫司的相关药学资料,为进一步了解西罗莫司提供参考.方法:通过查阅相关文献,并在此基础上对西罗莫司的化学结构、理化性质、免疫抑制作用机理、药代动力学、药效学、临床疗效、用法用量和血药浓度监测以及不良反应等方面进行综述.结论:西罗莫司为毒性较小的有潜力的新型强效免疫抑制剂,为移植者提供了一种新的治疗替代方法.     

西罗莫司治疗肾移植后排斥反应的疗效、不良反应与其血药浓度的相关性分析

目的:观察西罗莫司治疗肾移植后排斥反应时,其疗效、不良反应与血药浓度的相关性。方法:选择52名肾移植术后应用西罗莫司进行免疫抑制治疗的患者为研究对象,其中男性43人,女性9人。采用高效液相色谱(HPLC)法测定西罗莫司血药浓度,同时测定患者的肌酐清除率、肝功能指标、血常规等。结果:共收集西罗莫司血药浓度数据112份。西罗莫司的血药浓度与给药剂量/体重比呈正相关,与体重呈负相关,女性患者血药浓度明显高于男性患者(P<0.05),未发现西罗莫司血药浓度与年龄有明显相关性;西罗莫司的主要不良反应表现为肝功能损伤,将血药浓度分为<8ng·mL-1和>8ng·mL-1组,不同血药浓度组的肝功能差异有统计学意义(P<0.05);西罗莫司的临床疗效确切,将西罗莫司稳态谷浓度分成<4ng·mL-1、4～8ng·mL-1和>8ng·mL-1组,不同血药浓度组其肌酐清除率和肾功能恢复情况差异有统计学意义(P<0.05)。结论:西罗莫司副作用主要表现为肝功能异常,其血药浓度与临床疗效和不良反应均有相关性,西罗莫司稳态谷浓度宜控制在4～8ng·mL-1范围内。     

西罗莫司血药浓度监测的研究进展

目的:跟踪西罗莫司血药浓度监测的研究进展。方法:查阅近年来国内外相关文献,对西罗莫司的药动学和生理药动学模型(PBPK)的应用、西罗莫司血药浓度监测的样本和方法的研究进行归纳和总结。结果:PBPK预测性能良好,在临床剂量递增方案中能预测到±20%的浓度-时间曲线下面积值。选择干血斑样本进行检测,并进行预处理消除离子干扰,有利于提高检测结果的准确度。分析监测生物样本血药浓度的方法包括免疫法和色谱法,两种方法相关性已明确。结论:西罗莫司血药浓度监测的方法得到优化,精确度得到提高,可联合基因检测为患者制订给药方案,使患者得到更安全、合理的药物治疗。     

1例卡梅综合征患儿治疗的药学监护

目的:探讨临床药师在卡梅综合征患儿药物治疗中的作用。方法:临床药师参与1例卡梅综合征患儿的药物治疗实践,对化疗药物及免疫抑制剂进行药学监护,对西罗莫司进行血药浓度监测和剂量调整。结果:患儿病情稳定好转出院,未发生严重药物不良反应。结论:临床药师通过参与特殊病例的药物治疗,以个体化药学监护为切入点,保障患儿用药安全,发挥了临床药师作用。     

常用药动学公式的拓展及应用

目的:应用药动学理论指导临床合理用药。方法:对基本药动学公式进行拓展和转换,得到临床实用的新公式;创建实用药动学参数表,应用该表得到临床需要的药动学参数。结果:有了实用药动学参数表,随时可考察临床用药的合理性,结合血药浓度监测,可做到用药个体化。结论:实用药动学参数表可作为指导个体化用药的重要工具。     

Sirolimus-induced hyperlipidaemia in liver transplant recipients is not dose-dependent

BACKGROUND: Sirolimus is a potent immunosuppressive medication that acts by inhibiting T-cell proliferation. It has been used in kidney transplantation because of its lack of nephrotoxicity. It is now being investigated in liver transplantation, but there are concerns about safety and long-term side effects such as dyslipidaemia. Hypertriglyceridaemia is a common adverse event seen with sirolimus use, and often does not respond to dose reduction or anti-lipemic drugs. METHOD: We report six patients who have developed significant hyperlipidaemia while receiving sirolimus, in spite of therapeutic trough levels. CONCLUSION: All six patients showed either resolution or improvement in lipid levels with discontinuation of sirolimus.     

克罗恩病治疗中英夫利西单抗药物监测的临床意义

目的：英夫利西单抗（infliximab,IFX）是首个用于克罗恩病的生物制剂,疗效显著,但30%~60%的患者会出现药物失应答。治疗药物监测（therapeutic drug monitoring,TDM）的应用,可为指导临床用药提供依据,达到安全、合理、有效、经济的用药目的。方法：通过查阅近年来在克罗恩病治疗中IFX药物监测的研究及应用情况,就IFX的药动学特点、影响因素、谷浓度及抗IFX抗体（antibodies to infliximab,ATI）与疗效相关性等作一综述。结果：研究显示,IFX免疫原性、患者病理生理状态、遗传因素、联合用药等与IFX药动学有关,监测IFX谷浓度及ATI水平能预测临床应答、内镜下表现及不良反应。结论：进行TDM可优化IFX药物治疗方案,更好地控制疾病活动度,具有重要的临床指导意义。     

Combination treatment with sirolimus and ciclosporin in clinical renal transplantation: A comprehensive review

Sirolimus is a potent new immunosuppressive agent that has been shown to reduce the incidence of acute rejection episodes among renal transplant recipients as well as provide a unique approach to optimize treatment outcomes in difficult transplant situations. Owing to its properties as a critical-dose drug, therapeutic concentration monitoring of sirolimus readily compensates for intra- and interpatient variability and drug interactions with a variety of other agents such as ciclosporin. This review summarizes the results that demonstrate the efficacy of sirolimus in combination treatment with ciclosporin in human renal transplantation, as well as its potential in alternative therapeutic modalities in a broad range of transplant recipients. The clinical trials for SDZ-RAD, a macrocyclic lactone immunosuppressant structurally similar to sirolimus, also are reviewed herein. SDZ-RAD was developed in an attempt to improve the pharmacokinetic characteristics of sirolimus, particularly to increase the extent and reproducibility of its oral bioavailability and to reduce the extensive tissue distribution by virtue of its greater polarity. (c) 2001 Prous Science. All rights reserved.     

Benefit-risk assessment of sirolimus in renal transplantation.

Sirolimus (rapamycin) is a macrocyclic lactone isolated from a strain of Streptomyces hygroscopicus that inhibits the mammalian target of rapamycin (mTOR)-mediated signal-transduction pathways, resulting in the arrest of cell cycle of various cell types, including T- and B-lymphocytes. Sirolimus has been demonstrated to prolong graft survival in various animal models of transplantation, ranging from rodents to primates for both heterotopic, as well as orthotopic organ grafting, bone marrow transplantation and islet cell grafting. In human clinical renal transplantation, sirolimus in combination with ciclosporin (cyclosporine) efficiently reduces the incidence of acute allograft rejection. Because of the synergistic effect of sirolimus on ciclosporin-induced nephrotoxicity, a prolonged combination of the two drugs inevitably leads to progressive irreversible renal allograft damage. Early elimination of calcineurin inhibitor therapy or complete avoidance of the latter by using sirolimus therapy is the optimal strategy for this drug. Prospective randomised phase II and III clinical studies have confirmed this approach, at least for recipients with a low to moderate immunological risk. For patients with a high immunological risk or recipients exposed to delayed graft function, sirolimus might not constitute the best therapeutic choice--despite its ability to enable calcineurin inhibitor sparing in the latter situation--because of its anti-proliferative effects on recovering renal tubular cells. Whether lower doses of sirolimus or a combination with a reduced dose of tacrolimus would be advantageous in these high risk situations remains to be determined. Clinically relevant adverse effects of sirolimus that require a specific therapeutic response or can potentially influence short- and long-term patient morbidity and mortality as well as graft survival include hypercholesterolaemia, hypertriglyceridaemia, infectious and non-infectious pneumonia, anaemia, lymphocele formation and impaired wound healing. These drug-related adverse effects are important determinants in the choice of a tailor-made immunosuppressive drug regimen that complies with the individual patient risk profile. Equally important in the latter decision is the lack of severe intrinsic nephrotoxicity associated with sirolimus and its advantageous effects on arterial hypertension, post-transplantation diabetes mellitus and esthetic changes induced by calcineurin inhibitors. Mild and transient thrombocytopenia, leukopenia, gastrointestinal adverse effects and mucosal ulcerations are all minor complications of sirolimus therapy that have less impact on the decision for choosing this drug as the basis for tailor-made immunosuppressive therapy. It is clear that sirolimus has gained a proper place in the present-day immunosuppressive armament used in renal transplantation and will contribute to the development of a tailor-made immunosuppressive therapy aimed at fulfilling the requirements outlined by the individual patient profile.     

Sirolimus: the evidence for clinical pharmacokinetic monitoring

This review seeks to apply a decision-making algorithm to establish whether clinical pharmacokinetic monitoring (CPM) of sirolimus (rapamycin) in solid organ transplantation is indicated in specific patient populations. The need for CPM of sirolimus, although a regulatory requirement in Europe, has not yet been firmly established in North America and other parts of the world.Sirolimus has demonstrated immunosuppressive efficacy in renal, pancreatic islet cell, liver and heart transplant recipients. The pharmacological response of immunosuppressive therapy with sirolimus cannot be readily evaluated; however, a relationship between trough blood sirolimus concentrations, area under the plasma concentration-time curve (AUC) and the incidence of rejection has been proposed. Furthermore, sirolimus can be measured in whole blood by several assays--high-performance liquid chromatography with detection by tandem mass spectrometry, or with ultraviolet detection, radioreceptor assay or microparticle enzyme immunoassay.Both experimental animal and clinical data suggest that adverse events and their associated severity are correlated with blood concentrations. To prevent rejection and minimise toxicity, a therapeutic range of 4-12 microg/L (measured via chromatographic assays) is recommended when sirolimus is used in conjunction with ciclosporin. If ciclosporin therapy is discontinued, a target trough range of 12-20 microg/L is recommended. Sirolimus pharmacokinetics display large inter- and intrapatient variability, which may change in specific patient populations due to disease states or concurrent immunosuppressants or other interacting drugs. Due to the long half-life of sirolimus, dosage adjustments would ideally be based on trough levels obtained more than 5-7 days after initiation of therapy or dosage change. Once the initial dose titration is complete, monitoring sirolimus trough concentrations weekly for the first month and every 2 weeks for the second month appears to be appropriate. After the first 2 months of dose titration, routine CPM of sirolimus is not necessary in all patients, but may be warranted to achieve target concentrations in certain populations of patients, but the frequency of further monitoring remains to be determined and should be individualised.     

Sirolimus-associated proteinuria and renal dysfunction.

Sirolimus is a novel immunosuppressant with potent antiproliferative actions through its ability to inhibit the raptor-containing mammalian target of rapamycin protein kinase. Sirolimus represents a major therapeutic advance in the prevention of acute renal allograft rejection and chronic allograft nephropathy. Its role in the therapy of glomerulonephritis, autoimmunity, cystic renal diseases and renal cancer is under investigation. Because sirolimus does not share the vasomotor renal adverse effects exhibited by calcineurin inhibitors, it has been designated a 'non-nephrotoxic drug'. However, clinical reports suggest that, under some circumstances, sirolimus is associated with proteinuria and acute renal dysfunction. A common risk factor appears to be presence of pre-existing chronic renal damage. The mechanisms of sirolimus-associated proteinuria are multifactorial and may be due to an increase in glomerular capillary pressure following calcineurin inhibitor withdrawal. It has also been suggested that sirolimus directly causes increased glomerular permeability/injury, but evidence for this mechanism is currently inconclusive. The acute renal dysfunction associated with sirolimus (such as in delayed graft function) may be due to suppression of compensatory renal cell proliferation and survival/repair processes. Although these adverse effects occur in some patients, their occurrence could be minimised by knowledge of the molecular effects of sirolimus on the kidney, the use of sirolimus in appropriate patient populations, close monitoring of proteinuria and renal function, use of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers if proteinuria occurs and withdrawal if needed. Further long-term analysis of renal allograft studies using sirolimus as de novo immunosuppression along with clinical and laboratory studies will refine these issues in the future.     

肾移植术后患者全血西罗莫司浓度监测结果分析

目的:探讨肾移植术后患者全血西罗莫司浓度的治疗窗以及西罗莫司对血常规、肝肾功能、血脂和尿蛋白的影响。方法:采用微粒子发光免疫分析技术（MEIA）测全血西罗莫司谷浓度。对3年来294例次肾移植术后患者全血西罗莫司浓度,以及西罗莫司对血常规、肝肾功能、血脂和尿蛋白的影响进行分析。结果:294例次全血西罗莫司浓度中有206例次（70%）在3～8ng·ml^-1范围内。肾移植6个月后,全血西罗莫司浓度测定值随移植时间延长而降低。服用西罗莫司后的尿蛋白数值升高,与服用之前相比差异有统计学意义（P<0.05或0.01）。结论:全血西罗莫司谷浓度治疗窗:术后1～3个月为4～6ng·ml^-1,第4～6个月为3～6ng·ml^-1,>6个月为3～5ng·ml^-1。     

Pharmacological management of polycystic kidney disease

Introduction: Autosomal-dominant polycystic kidney disease (ADPKD) represents a therapeutic challenge as effective treatment to retard the growth of cysts in the kidneys and the liver has not been available despite decades of intense basic and clinical research.

Areas covered: Several clinical trials have been performed in recent years to study the effect of diverse drugs on the growth of renal and hepatic cysts, and on functional deterioration of the glomerular filtration rate. The drug classes that have been tested in randomized clinical trials include the mammalian target of rapamycin (mTOR) inhibitors, sirolimus and everolimus, the somatostatin analogues (octreotide, lanreotide, pasireotide), and most recently, the vasopressin V₂ receptor antagonist, tolvaptan. The results with the mTOR inhibitors were disappointing, but more encouraging with the somatostatin analogues and with tolvaptan. Additional drugs are being tested, which include among others, the SRC-ABL tyrosine kinase inhibitor, bosutinib, and the traditional Chinese herbal medication, triptolide. Additional therapeutic strategies to retard cyst growth aim at blood pressure control via inhibition of the renin–angiotensin system and the sympathetic nervous system.

Expert opinion: Given the accumulated knowledge, it is currently uncertain whether drugs will become available in the near future to significantly change the course of the relentlessly progressing polycystic kidney disease.     

Adoptive transfer of CD4+CD25+ regulatory cells combined with low-dose sirolimus and anti-thymocyte globulin delays acute rejection of renal allografts in Cynomolgus monkeys

Although donor alloantigen specific Treg cells play an important role in transplant tolerance, therapeutic applications are limited by their low frequency. In this study, isolated Tregs from Cynomolgus monkeys were efficiently expanded by a co-culture system, and maintained suppressive function on the proliferation of CD4(+) effector cells in vitro. Adoptive transfer of expanded donor alloantigen specific Tregs without any immunosuppressants could prolong survival of MHC-mismatched allografts in Cynomolgus monkeys. To reach the feasibility of clinical transplantation, our objectives focused on whether exposure of monkey Tregs to immunosuppressants could preserve suppressive function in vitro and in vivo. The results showed that low-dose sirolimus selectively expanded Tregs, increased the expression of CD25(bright) and Foxp3 markers, and suppressed TCR- or allo-antigens induced CD4(+) T cell proliferation in vitro. In vivo, after pre-treated with anti-thymocyte globulin (ATG) for consecutive 3days, a 14-day therapy of adoptive infusion of donor alloantigen-specific Tregs combined with low-dose sirolimus delayed acute rejection of renal allografts in Cynomolgus monkeys, showing an MST of 48.5days as compared with those of untreated and sirolimus-treated monkeys (7days and 22days). The frequencies of CD4(+)CD25(bright) T cells were significantly elevated in mesenteric lymph nodes vs. those in inguino lymph nodes and peripheral blood. In summary, expanded donor alloantigen specific Tregs exposed to sirolimus can preserve inhibition in vitro and in vivo. Tregs are more resistant to sirolimus than other T cells. Expanded donor alloantigen specific Tregs combined with sirolimus and ATG prolongs renal allograft survival in monkeys, suggesting that sirolimus might be one of the best synergists for Tregs therapy.