他克莫司血药浓度监测在膜性肾病治疗中的意义

目的:探讨他克莫司血药浓度监测在膜性肾病治疗中的意义。方法:41例膜性肾病患者服用他克莫司达到稳态血药浓度后,用酶扩大免疫分析法测定他克莫司血药谷浓度,对患者进行随访,记录临床治疗效果,应用统计学软件SPSS 16.0分析他克莫司血药浓度与临床疗效的相关性。结果:完全缓解(CR)组的他克莫司平均血药浓度为(7.47±2.74)ng/ml,部分缓解(PR)组为(5.72±1.19)ng/ml,无缓解(NR)组为(3.30±1.08)ng/ml,总缓解率为75.61%。CR组血药浓度最高,其次为PR组,NR组明显低于前二者,三者两两比较差异有统计学意义(P<0.05)。结论:他克莫司治疗膜性肾病的临床疗效与血药浓度相关,监测全血他克莫司谷浓度在膜性肾病治疗中具有重要的临床指导意义。     

他克莫司联合糖皮质激素治疗难治性特发性膜性肾病的临床疗效评价

目的:评价他克莫司联合糖皮质激素治疗难治性特发性膜性肾病的临床疗效.方法:本研究所选对象为我院2012年3月～2015年7月收治的难治性特发性膜性肾病患者90例,均给予他克莫司联合糖皮质激素治疗.结果:进行为期1年的随访发现,全部患者中,71例完全缓解,19例部分缓解,临床缓解率为100.0％.结论:选择他克莫司联合糖皮质激素治疗难治性特发性膜性肾病具有比较显著的临床效果,具有临床应用价值.     

他克莫司治疗儿童肾小球疾病血药浓度监测及临床疗效评价

目的 通过研究儿童肾小球疾病治疗药物他克莫司血药浓度监测及用药情况,评价他克莫司治疗肾小球疾病的疗效及不良反应.方法 选取2019年4月至2021年4月服用他克莫司治疗肾小球疾病的患儿,记录他克莫司血药谷浓度,临床病理生理指标,观察不良反应,评估临床疗效等.结果 89例患儿监测他克莫司血药谷浓度201次,达标率为48....     

伏立康唑对儿童肾移植患者他克莫司血药浓度影响的案例分析

目的 ：探讨伏立康唑对儿童肾移植患者他克莫司血药浓度的影响。方法 ：1例儿童肾移植患者,长期口服他克莫司抗排异治疗后继发真菌感染,给予伏立康唑注射液治疗后导致他克莫司血药浓度升高,临床药师结合治疗药物监测结果对他克莫司剂量进行调整,使其血药浓度维持在目标浓度范围内。结果 ：治疗药物监测有助于儿童肾移植患者的临床预后。结论 ：长期服用他克莫司的儿童肾移植患者,合用伏立康唑治疗时,他克莫司的剂量应调整为原来的1/2,后续根据血药浓度调整给药剂量。     

胆汁淤积性肝病婴儿肝移植后他克莫司浓度影响的因素

目的 探讨胆汁淤积性肝病婴儿肝移植后他克莫司浓度影响因素,为个体化治疗提供依据。方法 回顾性分析2018年1月—2020年12月北京友谊医院肝移植中心的胆汁淤积性肝病婴儿(≤12个月)肝移植病例56例,收集使用伏立康唑前3 d内他克莫司的剂量及血药浓度、临床指标,使用伏立康唑后3,5,7 d他克莫司的剂量和血药浓度及伏立康唑的剂量和血药浓度,对他克莫司的血药浓度与性别、临床指标及合并伏立康唑进行相关性分析。结果 性别、血清白蛋白浓度与他克莫司的血药浓度有显著相关性(P<0.05);合并伏立康唑后,他克莫司的维持剂量显著降低(P<0.01),标准化血药浓度较合并前显著性升高(P<0.01),他克莫司浓度无显著变化(P>0.01);合并伏立康唑后他克莫司减量情况个体差异很大,且减量情况与伏立康唑浓度高低无显著相关性。结论 伏立康唑对他克莫司的影响存在显著的个体差异性,说明书中减量至原剂量1/3并不适用所有患者,两者联用后应密切监测他克莫司血药浓度,及时调整给药剂量使血药浓度达到有效范围。     

他克莫司给药后个体代谢差异与CYP3A基因型的相关性研究进展

他克莫司是近年来兴起的临床常用抗生素类免疫抑制剂,对于接受器官移植的患者具有明显的免疫抑制改善作用。他克莫司体内代谢个体差异较大,治疗窗和安全范围小,有研究表明可能由于编码细胞色素P450酶系基因的相关作用导致他克莫司药物代谢动力学个体间变异。本文通过总结最新研究内容,对影响他克莫司代谢的相关基因进行概述。     

他克莫司对特发性膜性肾病的疗效观察

目的：探究他克莫司对特发性膜性肾病的临床疗效。方法：选取本院收治的特发性膜性肾病患者42例作为研究对象,随机分为研究组和对照组,研究组给予他克莫司联合泼尼松龙治疗,对照组给予环孢素联合泼尼松龙治疗,观察两组临床治疗效果、不良反应及并发症。结果：研究组尿蛋白、血清白蛋白、内生肌酐清除率、血肌酐、甘油三酯及胆固醇指标均优于对照组,差异具有统计学意义（P＜0.05）,研究组总有效率为95.24%,对照组总有效率为85.71%,差异具有统计学意义（P＜0.05）。结论：他克莫司联合泼尼松龙治疗特发性膜性肾病临床疗效高,值得临床推广。     

他克莫司在特发性膜性肾病治疗中应用观察

目的探讨他克莫司在特发性膜性肾病治疗中应用的临床疗效观察。方法选择2008年3月-2010年3月收治的符合入选标准特发性膜性肾病患者48例,将其分为治疗组24例,对照组24例,治疗组采用他克莫司治疗,对照组采且环磷酰胺治疗,观察两组临床疗效。结果治疗组总有效率为75．00％,明显优于对照组的37．50％,差异有统计学意义（P〈0．05）。结论他克莫司在特发性膜性肾病治疗中是一种新型免疫抑制剂,是治疗表现为肾病综合征的特发性膜性肾病新的治疗并有效的药物。     

器官移植术后他克莫司与三唑类抗真菌药的相互作用及影响因素研究进展

他克莫司作为一线免疫抑制剂,广泛用于器官移植术后自身排斥反应的防治。因他克莫司有治疗窗狭窄、个体差异大等特点,且为CYP450酶的底物,所以与其他药物联用时易发生药物-药物相互作用。三唑类抗真菌药是CYP450酶的抑制剂,与他克莫司联用会导致他克莫司血药浓度升高且毒性增加,临床使用期间应定期监测他克莫司血药浓度,以保障用药的安全性和有效性。现就他克莫司与三唑类抗真菌药之间的潜在相互作用及影响因素进行综述,为器官移植患者个体化使用他克莫司提供参考。     

地尔硫■在器官移植和小儿肾病综合征患者中对他克莫司血药浓度的影响规律研究进展

他克莫司是钙调磷酸酶抑制剂型免疫抑制剂,在临床上有着广泛的应用,但它在体内血药浓度易受多种因素影响,部分患者常规剂量达不到有效治疗浓度。地尔硫■是非二氢吡啶类钙离子拮抗剂,通过抑制CYP3A代谢酶和P-糖蛋白活性,使他克莫司代谢和排出减少,从而导致血药浓度上升,临床常作为他克莫司保留剂以提高他克莫司治疗效果,减少患者药物治疗费用。该文综述了地尔硫■对他克莫司血药浓度的作用机制和在不同疾病状态下对患者血药浓度的影响规律,以期为临床使用地尔硫■作为他克莫司保留剂提供参考和借鉴。     

Clinical Evaluation of Modified Release and Immediate Release Tacrolimus Formulations

The science of drug delivery has evolved considerably and has led to the development of multiple sustained release formulations. Each of these formulations can present particular challenges in terms of clinical evaluation and necessitate careful study to identify their optimal use in practice. Tacrolimus is an immunosuppressive agent that is widely used in organ transplant recipients. However, it is poorly soluble, has an unpredictable pharmacokinetic profile subject to important genetic polymorphisms and drug-drug interactions, and has a narrow therapeutic index. For these reasons, it represents an agent that could benefit from modified release formulations to overcome these limitations. The objective of this review is to discuss the clinical evaluation of immediate and modified release tacrolimus formulations in renal transplant recipients. Clinical trials from early development of immediate release tacrolimus to formulation-specific post-marketing trials of modified release tacrolimus formulations are reviewed with an emphasis on key elements relating to trial design end endpoint assessment. Particular elements that can be addressed with formulation alterations, such as pharmacokinetics, pharmacogenomics, and toxicity and corresponding clinical evaluations are discussed. In addition, current knowledge gaps in the clinical evaluation of immediate and modified release tacrolimus formulations are discussed to highlight potential avenues for the future development of different tacrolimus formulations with outcomes relevant to the regulators, the transplant community, and to transplant recipients. This review shows that new formulations may alter tacrolimus bioavailability, alleviate certain adverse events while potentially enhancing patient convenience.     

临床药师参与1例自身免疫病合并抗结核治疗患者的药学实践

目的探讨在接受他克莫司治疗的自身免疫病患者合并抗结核(含利福平)治疗时,保证他克莫司有效全血浓度的方案。方法临床药师通过查阅文献,了解患者治疗方案中存在的药物相互作用,建议医生调整治疗方案,在临床实践中定期随访患者,考察调整后治疗方案的可行性和有效性。结果本案例中患者在将利福平换为利福喷丁后,他克莫司血药浓度短暂升高后再次降低,后期加用五酯胶囊服用10 d后,他克莫司的血药浓度提升到有效范围。结论自身免疫病患者应用包含利福平的抗结核方案时,为控制自身免疫病,可适度上调他克莫司的剂量,但考虑他克莫司治疗剂量范围窄,因此可换用肝药酶诱导作用弱于利福平的其他利福霉素类药物,或加用五酯胶囊来提高他克莫司血药浓度,保证抗结核治疗的同时兼顾免疫治疗的疗效。     

Cloned enzyme donor immunoassay tacrolimus assay compared with high-performance liquid chromatography-tandem mass spectrometry and microparticle enzyme immunoassay in liver and renal transplant recipients

The immunosuppressant drug tacrolimus has a narrow therapeutic index and is subject to a large variation in individual bioavailability and clearance. With its narrow therapeutic index, therapeutic drug monitoring is standard clinical practice in the management of transplant recipients. In this study, we report the evaluation of the cloned enzyme donor immunoassay (CEDIA) for the determination of whole-blood tacrolimus concentrations compared with high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) and microparticle enzyme immunoassay (MEIA) using samples obtained from liver (n = 100) and renal (n = 88) transplant recipients. Linear regression analysis showed a relationship of CEDIA = 1.24 HPLC-MS/MS -0.18 (r = 0.81). The mean bias (+/-SEM) for all patients when compared with HPLC-MS/MS was 22.2% (+/-2.1%). The precision of the CEDIA method for all samples showed a root mean square error of 3.1 microg/L. Liver transplant recipient samples showed a mean (+/-SEM) bias compared with HPLC-MS/MS of 12.5% (+/-1.6%). The precision of the CEDIA method for these samples showed a root mean square error of 1.5 microg/L. The data suggest that in the renal transplant group, the CEDIA and MEIA methods have a bias of 33.3% and 20.1%, respectively, compared with HPLC-MS/MS. The CEDIA tacrolimus immunoassay has been shown to be a rapid method for the determination of whole-blood tacrolimus concentrations and may be considered when HPLC-MS/MS is not available. When used in the clinical setting with other parameters, it would be a useful adjunct in the management of liver transplant recipients, but a significant bias in renal transplant patients needs to be further investigated.     

Rectal and sublingual administration of tacrolimus: a single-dose pharmacokinetic study in healthy volunteers

AimsThe immunosuppressant tacrolimus is usually administered orally. When this is not feasible, other routes of administration may be useful. Previous research suggested that tacrolimus may be applied sublingually or rectally. Pharmacokinetic data are sparse. The aim of this study was to investigate and compare the pharmacokinetics of these alternative formulations with orally administered tacrolimus.MethodsThree single, fixed-dose formulations of tacrolimus were administered in a random sequence in 18 healthy subjects, using a cross-over study design. For sublingual administration, 3 mg of powder obtained from oral capsules was applied under the tongue for a period of 15 min without swallowing, with mouth rinsing afterwards. For rectal administration, a suppository containing 15 mg of the oral powder was used. Oral administration consisted of 7 mg of instant-release tacrolimus capsules (Prograf). Main pharmacokinetic outcome parameters were compared by anova.ResultsSublingual administration showed no clinically significant exposure, contrary to rectal administration, where all subjects had clinically relevant exposure, with a lower relative bioavailability (78%), a lower maximal blood concentration and a later time of maximal blood concentration compared with oral administration.ConclusionsSublingual administration of a single dose of tacrolimus does not result in systemic exposure if care is taken not to swallow saliva and to rinse the oral cavity afterwards. Rectal administration of tacrolimus results in clinically relevant systemic exposure and might represent an alternative formulation in case oral administration is not feasible. When used as a topical agent, systemic side-effects should be considered.     

Pharmacokinetic considerations relating to tacrolimus dosing in the elderly

Relaxation of the upper age limits for solid organ transplantation coupled with improvements in post-transplant survival have resulted in greater numbers of elderly patients receiving immunosuppressant drugs such as tacrolimus. Tacrolimus is a potent agent with a narrow therapeutic window and large inter- and intraindividual pharmacokinetic variability. Numerous physiological changes occur with aging that could potentially affect the pharmacokinetics of tacrolimus and, hence, patient dosage requirements. Tacrolimus is primarily metabolised by cytochrome P450 (CYP) 3A enzymes in the gut wall and liver. It is also a substrate for P-glycoprotein, which counter-transports diffused tacrolimus out of intestinal cells and back into the gut lumen. Age-associated alterations in CYP 3A and P-glycoprotein expression and/or activity, along with liver mass and body composition changes, would be expected to affect the pharmacokinetics of tacrolimus in the elderly. However, interindividual variation in these processes may mask any changes caused by aging. More investigation is needed into the impact aging has on CYP and P-glycoprotein activity and expression. No single-dose, intense blood-sampling study has specifically compared the pharmacokinetics of tacrolimus across different patient age groups. However, five population pharmacokinetic studies, one in kidney, one in bone marrow and three in liver transplant recipients, have investigated age as a co-variate. None found a significant influence for age on tacrolimus bioavailability, volume of distribution or clearance. The number of elderly patients included in each study, however, was not documented and may have been only small. It is likely that inter- and intraindividual pharmacokinetic variability associated with tacrolimus increase in elderly populations. In addition to pharmacokinetic differences, donor organ viability, multiple co-morbidity, polypharmacy and immunological changes need to be considered when using tacrolimus in the elderly. Aging is associated with decreased immunoresponsiveness, a slower body repair process and increased drug adverse effects. Elderly liver and kidney transplant recipients are more likely to develop new-onset diabetes mellitus than younger patients. Elderly transplant recipients exhibit higher mortality from infectious and cardiovascular causes than younger patients but may be less likely to develop acute rejection. Elderly kidney recipients have a higher potential for chronic allograft nephropathy, and a single rejection episode can be more devastating. There is a paucity of information on optimal tacrolimus dosage and target trough concentration in the elderly. The therapeutic window for tacrolimus concentrations may be narrower. Further integrated pharmacokinetic-pharmacodynamic studies of tacrolimus are required. It would appear reasonable, based on current knowledge, to commence tacrolimus at similar doses as those used in younger patients. Maintenance dose requirements over the longer term may be lower in the elderly, but the increased variability in kinetics and the variety of factors that impact on dosage suggest that patient care needs to be based around more frequent monitoring in this age group.     

Metabolism of tacrolimus (FK506) and recent topics in clinical pharmacokinetics

Tacrolimus (FK506), an immunosuppressive drug, is co-medicated with multiple drugs under clinical conditions. Tacrolimus is highly lipophilic and is excreted from the body after receiving extensive metabolism. Due to its narrow therapeutic window following organ transplantation, tacrolimus requires therapeutic drug monitoring by an enzyme immunoassay using the monoclonal antibody raised against tacrolimus. Therefore, metabolism studies including drug-drug interaction and metabolite identification studies are essential for the efficient development and clinically optimal usage of this drug. Tacrolimus was metabolized by the cytochrome P450 (CYP) 3A subfamily. Metabolic drug-drug interaction studies were conducted to provide information regarding the optimal usage of tacrolimus, and its metabolism was inhibited by known CYP3A inhibitors such as ketoconazole, cyclosporine A, and nifedipine. Recent reports on clinical pharmacokinetics indicate that dose levels of tacrolimus need to be adjusted in transplant patients with CYP3A5 polymorphism.     

Validation of methods to study the distribution and protein binding of tacrolimus in human blood

INTRODUCTION: Tacrolimus is a macrolide immunosuppressant that has a narrow therapeutic index, displays considerable variability in response, and has the potential for serious drug interactions. Therapeutic drug monitoring and dose individualisation for tacrolimus is complicated but essential. Few studies have investigated the blood distribution and protein binding of tacrolimus and the results of these studies are conflicting. The aim of the present study is to establish and validate methods to investigate the distribution of tacrolimus in human blood. To conduct these studies at clinically relevant concentrations the use of 3H-dihydro-tacrolimus instead of tacrolimus was investigated. METHODS: The use of radiolabelled tacrolimus was validated by conducting studies with a mixture of both labelled and unlabelled drug where tacrolimus was analysed by LC-MS/MS. The in vitro distribution of tacrolimus and 3H-dihydro-tacrolimus was investigated in blood collected from healthy subjects using Ficoll-Paque reagent and density gradient ultracentrifugation, respectively. The unbound fraction of tacrolimus in plasma was studied using equilibrium dialysis conducted at 37 degrees C. RESULTS: In blood, tacrolimus was found to be mainly associated with erythrocytes (85.3+/-1.5%), followed by diluted plasma proteins (14.3+/-1.5%) and lymphocytes (0.46+/-0.10%). In plasma, tacrolimus was found to mainly be associated with the soluble protein fraction (61.2+/-2.5%), high-density lipoproteins (HDL, 28.1+/-5.4%), low-density lipoproteins (LDL, 7.8+/-1.6%), and very low-density lipoproteins (VLDL, 1.4+/-0.3%). The unbound fraction of tacrolimus was found to be only 1.2+/-0.12%. Statistical comparison indicated that there was no significant difference in the blood distribution and plasma protein binding of 3H-dihydro-tacrolimus when compared with tacrolimus. DISCUSSION: These results have important implications for therapeutic drug monitoring of tacrolimus and subsequent studies of tacrolimus distribution in transplant recipients.     

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。     

The rate of gastric emptying determines the timing but not the extent of oral tacrolimus absorption: simultaneous measurement of drug exposure and gastric emptying by carbon-14-octanoic acid breath test in stable renal allograft recipients.

Tacrolimus is characterized by a highly variable oral bioavailability and narrow therapeutic window. Tacrolimus absorption from the gastrointestinal tract is to a large extent determined by the genotypic, phenotypic, and functional expression of P-glycoprotein and CYP3A in the gut wall and liver. It is disputed whether the gastric emptying rate per se is important for determining oral bioavailability of tacrolimus and whether delayed gastric emptying is clinically relevant for therapeutic drug dosing. We conducted a pharmacokinetic study in 50 renal recipients, measuring simultaneously the rate of gastric emptying using a carbon-14-octanoic acid breath test and quantifying drug exposure by area under the concentration-time curve sampling. Gastric half emptying time (t1/2) significantly correlated with time to reach maximum blood tacrolimus (tmax) concentration (r2 = 0.30; p < 0.0001), whereas the gastric emptying coefficient, reflecting the overall gastric emptying rate, showed a weak inverse correlation with tmax (r2 = 0.14; p = 0.007). The time-dependent rate of gastric emptying strongly correlated with the simultaneously measured blood tacrolimus concentration over the first 4 h after oral drug administration (r2 = 0.96; p < 0.0001). Comparison between patients with and without delayed gastric emptying confirmed that maximum blood tacrolimus concentration was reached significantly more slowly in the former group (tmax, 2 +/- 1 h versus 1.48 +/- 0.68 h; p = 0.04), whereas the extent of tacrolimus absorption was not different. Despite a strong association between gastric emptying rate and the timing of tacrolimus absorption from the gut in stable recipients, gastric emptying rate does not affect the total extent of drug absorption and is not responsible for significant alterations in drug exposure, even in situations of delayed gastric emptying.     

Mechanisms of clinically relevant drug interactions associated with tacrolimus

The clinical management of tacrolimus, a macrolide used as immunosuppressant after transplantation, is complicated by its narrow therapeutic index in combination with inter- and intraindividually variable pharmacokinetics. As a substrate of cytochrome P450 (CYP) 3A enzymes and P-glycoprotein, tacrolimus interacts with several other drugs used in transplantation medicine, which also are known CYP3A and/or P-glycoprotein inhibitors and/or inducers. In clinical studies, CYP3A/P-glycoprotein inhibitors and inducers primarily affect oral bioavailability of tacrolimus rather than its clearance, indicating a key role of intestinal P-glycoprotein and CYP3A. There is an almost complete overlap between the reported clinical drug interactions of tacrolimus and those of cyclosporin. However, in comparison with cyclosporin, only few controlled drug interaction studies have been carried out, but tacrolimus drug interactions have been extensively studied in vitro. These results are inconsistent and are of poor predictive value for clinical drug interactions because of false negative results. P-glycoprotein regulates distribution of tacrolimus through the blood-brain barrier into the brain as well as distribution into lymphocytes. Interaction of other drugs with P-glycoprotein may change tacrolimus tissue distribution and modify its toxicity and immunosuppressive activity. There is evidence that ethnic and gender differences exist for tacrolimus drug interactions. Therapeutic drug monitoring to guide dosage adjustments of tacrolimus is an efficient tool to manage drug interactions. In the near future, progress can be expected from studies evaluating potential pharmacokinetic interactions caused by herbal preparations and food components, the exact biochemical mechanism underlying tacrolimus toxicity, and the potential of inhibition of CYP3A and P-glycoprotein to improve oral bioavailability and to decrease intraindividual variability of tacrolimus pharmacokinetics.