Change of the blood concentration of tacrolimus after the switch from fluconazole to voriconazole in patients receiving allogeneic hematopoietic stem cell transplantation

The purpose of this study was to assess the impact by switching co-administered triazole antifungal agent from fluconazole (FCZ) to voriconazole (VCZ) on the blood concentration of tacrolimus (FK506) in patients receiving allogeneic hematopoietic stem cell transplantation. We performed a retrospective study presented as case reports. The blood concentration of FK506 was increased after the switch from FCZ to VCZ, resulting in increase of the concentration/dose (C/D) ratio of FK506. Thus, the mean C/D ratios of FK506 with oral administration was surprisingly increased over 4.5-fold after the switch. Therefore, it was necessary to reduce the FK506 dose when co-administered FCZ is switched to VCZ. We should be careful when interpreting the results of these case reports; however, in some patients, it is recommended that the dose of FK506 be reduced to one-fifth after the switch.     

异基因造血干细胞移植患者全血中环孢素A浓度的监测分析

目的对我院2000~2003年间所进行的异基因造血干细胞移植(allo-HSCT)患者全血中环孢素A(CsA)浓度的监测结果加以分析,以便探讨其临床有效性和安全性,为更好地开展CsA浓度监测和科研工作提供参考。方法采用反相高效液相色谱法(RP-HPLC)测定12例allo-HSCT患者全血中CsA浓度。结果全血中CsA线性范围为25~1600μg.L-1,最低检测浓度为10μg.L-1,回收率为90.14%,日内和日间变异均小于9.0%。监测allo-HSCT患者CsA血药浓度共107例次:达有效血药浓度(100~400μg.L-1)74例次(69.2%);低于100μg.L-1为19例次(17.7%);高于400μg.L-1为14例次(13.1%)。12例患者CsA平均血药浓度为218.61±110.04μg.L-1,每位患者的血药浓度波动较大,且个体差异也较大。结论CsA血药浓度受多种因素的影响,对allo-HSCT患者进行CsA浓度监测具有重要的临床意义。     

异基因造血干细胞移植患者体内环孢素A和伏立康唑的相互作用

目的 分析异基因造血干细胞移植（Allo-HSCT）患者,静脉滴注伏立康唑（VRZ）与环孢素A（CsA）后的药物相互作用（DDI）,为临床精准药物治疗提供依据。方法 进行一项患者自身对照研究,根据纳入排除标准,收集2019年1月—12月在某院进行Allo-HSCT的患者,采用LC-MS/MS法测定术前CsA给药后3～5 d的血药浓度2次,测定术后VRZ给药5～7 d后,CsA和VRZ同一时间的血药浓度2次,分别求其给药前后CsA、VRZ血药浓度的平均值。使用SPSS 20.0对VRZ给药前后CsA标准化血药浓度（C/D）的差异及VRZ血药浓度对CsA的C/D变化进行统计分析。结果 共纳入Allo-HSCT患者15例,用Wilcoxon符号秩和检验比较给药VRZ前后,CsA的C/D中位数变化,有显著性差异（P<0.001）。对VRZ血药浓度与CsA的C/D比值增幅进行Spearman相关性分析,两者无显著相关性（ρ=?0.273,P=0.32）。结论 CsA与VRZ之间存在明显的药物相互作用（DDI）,VRZ使CsA血药浓度显著升高,但VRZ与CsA之间的DDI程度大小与VRZ血药浓度无关,可能与患者个体差异有关。     

异基因造血干细胞移植术后患者静脉用环孢素A群体药动学研究

目的：研究并建立环孢素A（cyclosporine,CsA）静脉持续滴注方式在中国异基因造血干细胞移植术后患者中的群体药动学模型,为临床制定个体化给药方案提供依据。方法：回顾性统计了62例行异基因造血干细胞移植术的患者CsA静脉持续滴注期间的血药浓度监测结果共571例次,同时收集患者的人口学资料、临床指标及合并用药等,运用非线性混合效应模型程序建立群体药动学模型。结果：红细胞压积、术后时间以及唑类抗真菌药物的使用是影响清除率的主要协变量。最终模型为CL=θ₁·θ₂^（POD/15）·θ₃^{（HCT/0.26）}·θ₄^ⅠNHⅠ,V=θ₅。CsA清除率（CL）和分布容积（V）的群体典型值分别为28.4 L·h^-1,586.7 L,个体间变异分别为15.8%,52.3%,个体内变异系数为16.2%。Bootstrap法验证模型有效稳定,外部验证结果模型预测值与观察值有较好的相关性。贝叶斯反馈法计算患者CsA的AUC_0-24值为5.17±1.19（2.58~9.94）g·L^-1·h。结论：本研究建立的群体药动学模型可用于异基因造血干细胞移植术后患者CsA的血药浓度预测及个体参数的估算,为个体化治疗提供有效依据。     

泊沙康唑对异基因造血干细胞移植受者环孢素血药浓度的影响

目的:探讨异基因造血干细胞移植(allo-HSCT)受者体内泊沙康唑对环孢素血药浓度的影响.方法:纳入27例allo-HSCT受者,采用环孢素免疫抑制治疗且血药浓度位于治疗窗(150～300 μg·L-1)内,之后合用泊沙康唑预防真菌感染.收集受者合用泊沙康唑前与合用1～10 d内的环孢素谷浓度(C0)、浓度剂量比(C...     

Preventive effects of newquinolones for endogenous infection in patients receiving allogeneic hematopoietic stem cell transplantation--comparison between bone marrow transplantation, peripheral blood stem cell transplantation, and cord blood transplantation

We performed a retrospective study to examine the preventive effects of newquinolones for endogenous infection in patients receiving various allogeneic hematopoietic stem cell transplantation including bone marrow transplantation (BMT), peripheral blood stem cell transplantation (PBSCT), and cord blood transplantation (CBT). Forty-nine patients were enrolled. Ciprofloxacin or norfloxacin was orally administered for intestinal sterilization from day -14 until engraftment. As a result, the period from transplantation until engraftment was significantly longer in CBT group than in BMT group. The febrile index (the ratio of the febrile (> or =38.0 degrees C) period during neutropenia (< or =500 cells/mm(3)) and C-reactive protein (CRP)-positive index (the ratio of CRP-positive (> or =2.0 mg/dl) period during neutropenia) were comparable among the three groups. In addition, no gram-negative bacteria in stool was isolated in the three groups; that is, an endogenous infection of gram-negative bacteria, a potential pathogen, was well controlled by newquinolones. We should be careful when interpreting the results of this small study; however, newquinolones are clinically effective for endogenous infection of gram-negative bacteria in patients receiving not only BMT, but also PBSCT and CBT.     

553例次异基因造血干细胞移植受者全血环孢素浓度监测结果分析

目的：分析异基因造血干细胞移植（ allogeneic hematopoietic stem cell transplantation , allo-HSCT ）患者全血中环孢素A （CsA）浓度变化的可能影响因素,探讨治疗药物监测对于确保患者合理用药的临床意义。方法采用荧光偏振免疫（FPIA）法测定患者全血CsA浓度,收集79例allo-HSCT患者使用CsA后的临床资料,统计分析CsA血药浓度和临床表现、生化指标之间的关系。结果79例患者553次CsA血药浓度测定结果平均为（307．51±169．11）μg·L^-1,其中血药浓度在150～600μg· L^-1范围内者447例次（80．8％）、低于150μg· L^-1者67例次（12．1％）,高于600μg· L^-1者39例次（7．0％）。初步相关分析结果表明CsA血药浓度与间接胆红素、血清镁有较强的相关性,与其他生化指标的相关性不明显。结论 CsA血药浓度受多种因素的影响,对allo-HSCT患者进行CsA浓度监测具有重要的临床意义。     

Achievement of target cyclosporine concentrations as a predictor of severe acute graft versus host disease in children undergoing hematopoietic stem cell transplantation and receiving cyclosporine and methotrexate prophylaxis

This study evaluates our institution's target trough cyclosporine (CSA) concentrations as predictors of severe acute graft versus host disease (aGvHD) in children receiving either matched related or unrelated hematopoietic stem cell transplantation (HSCT). The outcomes of 87 consecutive children who underwent allogeneic HSCT and received CSA and methotrexate as prophylaxis against aGvHD between October 1, 1999 and September 30, 2002 were retrospectively evaluated. The proportion of time that each patient maintained a whole blood CSA concentration within or above the initial target range (105-155 ng/mL or 155-210 ng/mL) was calculated for each of the following time periods: in each week after HSCT from day 0 to +28; in the week preceding engraftment; and in the week preceding the onset of aGvHD. Patients were prospectively evaluated twice weekly for the presence and severity of aGvHD by senior attending physicians. The relationship between potential predictors and the development of severe aGvHD was examined using univariate logistic regression. The main variables of interest were the proportion of time that therapeutic or supratherapeutic CSA concentrations were maintained; median CSA concentrations; the number of methotrexate doses received; and the use of folinic acid rescue. Mean follow-up time was 3.0+/-1.9 years among children who survived beyond day +100. Three variables were significantly associated with the development of severe aGvHD on univariate analysis: initial CSA target concentration [odds ratio (OR), 0.24; P=0.03], proportion of time the target CSA concentration was achieved during the second week after transplant (OR, 0.16; P=0.02), and proportion of time the target CSA concentration was achieved during the week before engraftment (OR, 0.22; P=0.0489). Multivariable analysis demonstrated an inverse relationship between the median CSA concentration during the week before engraftment and the development of severe aGvHD (OR, 0.99; P=0.045). These results suggest that achievement of our CSA target concentrations is important to aGvHD outcomes.     

Drug–drug interactions in patients receiving hematopoietic stem cell transplantation

Introduction: Recipients of hematopoietic stem cell transplantation (HSCT) are exposed to numerous drugs in both pre- and post-transplantation period, which creates an opportunity for drug–drug interactions (DDIs); if clinically relevant DDIs happen, the risk of adverse treatment outcomes is increased.

Areas covered: This review is focused on DDIs in recipients of HSCT that were observed and published as clinical trials, case series or case reports. Relevant publications were found by the systematic search of the following online databases: MEDLINE, SCOPUS, EBSCO, and SCINDEX.

Expert opinion: The most important DDIs involve cytostatic or immunosuppressant drug on one side, and antimicrobial drugs on the other. The majority of clinically relevant interactions have pharmacokinetic character, involving drug metabolizing enzymes in the liver. Antifungal azoles inhibit metabolism of many cytostatic and immunosuppressant drugs at cytochromes and increase their plasma concentrations. Macrolide antibiotics and fluoroqunolones should be avoided in HSCT recipients, as they have much larger potential for DDIs than other antibiotic groups. HSCT recipients increasingly receive new immunomodulating drugs, and further observational studies are needed to reveal unsuspected DDIs with clinical relevance.     

异基因造血干细胞移植受者CYP3A4及CYP3A5基因多态性对他克莫司血药浓度及疗效的影响

目的 研究P4503A4*18B(CYP3A4*18B)及3A5*3(CYP3A5*3)突变频率,探讨基因多态性与异基因造血干细胞移植受者他克莫司(Tac)血药浓度的关系.方法 采用原位杂交荧光染色脱氧核糖核酸测序技术检测CYP3A4、CYP3A5基因型,酶联免疫吸附技术测定受者Tac浓度.比较术后7、15、30 d不同基因型受者间Tac浓度/剂量(C0/D)的差异.结果 16例中,CYP3A4*18B、CYP3A5*3突变等位基因发生的频率分别是25％和75％.CYP3A5纯合突变型受者中,CYP3A4野生纯合型者的浓度剂量比高于CYP3A4突变型.结论 异基因造血干细胞移植受者CYP3A4*18B和CYP3A5*3基因多态性对TAC药代动力学的影响显著,可以考虑应用临床.     

Forecasting of blood tacrolimus concentrations based on the Bayesian method in adult patients receiving living-donor liver transplantation

OBJECTIVE: To evaluate Bayesian prediction of blood tacrolimus concentrations in adult patients receiving living-donor liver transplantation (LDLT) using previously obtained population pharmacokinetic parameters. PATIENTS AND METHODS: Data were retrospectively collected from 47 adult patients receiving LDLT who were not included in the estimation of population pharmacokinetic parameters. Blood tacrolimus concentrations were predicted without or with the empirical Bayesian method using sparse samples obtained in the previous week. Predictive performance of the concentrations was evaluated by the mean prediction error (ME), mean absolute prediction error (MAE) and root mean square error (RMSE) as well as the percentage of successful predictions (percentage of absolute prediction error less than 3 microg/L, %PRED3). RESULTS: Concentrations predicted by the population mean pharmacokinetic parameter values coincided well with observed concentrations during the period of tacrolimus infusion immediately after the operation. For concentrations during subsequent oral therapy with tacrolimus, predictability by the population mean pharmacokinetic parameter values alone was not satisfactory. Bayesian forecasting using one or two blood concentrations obtained in the previous week significantly decreased (p<0.05) MAE and RMSE compared with predictions based on the population mean pharmacokinetic parameters on postoperative days 21 and 28, but not on day 14. During postoperative days 15-21, %PRED3 was increased to 68.6% or 71.2% with the Bayesian method using one or two blood concentrations, respectively, from 44.9% with the population mean pharmacokinetic parameter values. CONCLUSION: The present study demonstrated the applicability of the Bayesian method with use of one or two samples for prediction of blood tacrolimus concentrations in adult patients receiving LDLT.     

Effect of FOXP3 polymorphism on the clinical outcomes after allogeneic hematopoietic stem cell transplantation in pediatric acute leukemia patients

Forkhead BOX P3 (FOXP3) polymorphisms have recently been investigated as candidate risk factors in several tumors and autoimmune diseases. This study aims to evaluate the potential influence of FOXP3 rs3761548 polymorphism in the donor on the outcome of allogeneic hematopoietic stem cell transplantation (allo-HSCT). A total of 171 patients were enrolled for this study and genotyped using direct sequencing. Patients with rs3761548 CC genotype had higher incidence of hepatic veno-occlusive disease (HVOD) and cytomegalovirus (CMV) infection than that of the individuals with AA or AC genotype (P = 0.011, P = 0.023). Treatment-related mortality (TRM) rate of patients with AA or AC genotype was lower than that of the patients with CC genotype (P = 0.044) resulting in a difference in overall survival (OS). However, there was no difference in graft-versus-host disease (GVHD) relapse or blood stream infection (BSI), depending on the genotype at rs3761548 locus. In multivariate analysis, CC genotype showed as a risk factor in the development of HVOD and CMV infection, with low OS. In conclusion, this is the first report on FOXP3 rs3761548 SNP in allo-HSCT and we suggest that this SNP be considered a candidate marker for predicting the development of HVOD and CMV infection after allo-HSCT.     

异基因外周血干细胞移植治疗白血病并发症分析及防治

目的探讨不含全身照射（TBI）预处理方案异基因外周血干细胞移植（allo-PBSCT）治疗40例白血病并发症的发生情况及其防治。方法分析我院2001年1月～2008年10月allo-PBSCT治疗的40例患者临床资料。40例的供者均为HLA-Ⅰ/Ⅱ抗原完全相合的同胞,采用不含TBI改良Bu/Cy及减低剂量Bu＋Arac＋CTX＋氟达拉滨（Flu）预处理方案。氨磷汀预防口腔黏膜炎,前列腺素E1预防肝静脉闭塞病（HVOD）;40例均在预处理及移植后造血恢复期应用更昔洛韦预防巨细胞病毒（CMV）感染,采用环胞菌素A和短程MTX进行GVHD的预防。结果40例患者中出现Ⅰ度口腔黏膜炎23例（57.6%）,Ⅱ度口腔黏膜炎4例（10%）。Ⅳ度口腔黏膜炎2例（0.5%）;40例患者中均未发生急性GVHD及急性CMV感染;19例（47.5%）出现慢性GVHD,出血性膀胱炎（HC）发生率0.5%,间质性肺炎（IP）发生率0.25%;40例均未出现肝静脉闭塞病（HVOD）;40例移植患者中5例（12.5%）死于慢性GVHD移植相关并发症。结论预处理及移植后造血恢复期应用更昔洛韦预防CMV感染治疗,可能会减少移植患者CMV感染;使用细胞保护剂氨磷汀可能会减少或减轻移植患者口腔黏膜炎发生;慢性GVHD已日益成为影响异基因外周血干细胞移植后期生命及生活质量的重要因素。     

Mycophenolate mofetil pharmacokinetics in transplant patients receiving cyclosporine or tacrolimus in combination therapy

Mycophenolate mofetil is a highly effective immunosuppressant drug used in the prophylaxis of organ rejection in combination with cyclosporine or tacrolimus and corticosteroids. The present study is a retrospective data analysis of the routinely estimated mycophenolic acid plasma trough levels in 60 transplant patients (kidney, n = 49; lung, n = 11) receiving mycophenolate mofetil in combination with prednisone and cyclosporine (n = 45) or tacrolimus (n = 15). Coadministration of cyclosporine instead of tacrolimus resulted in a significant increase of median (range) of the ratio of dose-to-concentration 0.92 (0.11-8.33) (n=167) versus 0.38 (0.11-14.28) (n = 66); P < 0.0001. No correlation was seen between mycophenolate mofetil dose and mycophenolic acid trough concentrations. The dose-to-concentration in cyclosporine-treated patients increased significantly (P<0.0001) as the cyclosporine level increased, suggesting a possible interaction between mycophenolate mofetil and cyclosporine. No correlation was seen between dose-to-concentration and tacrolimus blood levels (P x 0.215). Further studies are necessary to investigate this issue.     

异基因造血干细胞移植后红系恢复影响因素分析

目的探讨异基因造血干细胞移植后影响红系恢复时间的因素。方法回顾分析53例异基因造血干细胞移植患者的移植方式、人血细胞抗原（HLA）相合与否、ABO血型相合与否及亲缘关系的有无对红系恢复时间的影响。结果影响红系恢复时间的因素主要为ABO血型主要不合及受、供者的亲缘关系。结论ABO血型主要不合和非亲缘骨髓移植的患者红系恢复较慢。     

异基因造血干细胞移植治疗慢性粒细胞白血病的疗效

目的 观察异基因造血干细胞移植(allo-HSCT)治疗慢性粒细胞白血病(CML)的疗效.方法 回顾性分析allo-HSCT 40例CML患者的临床资料.结果 40例患者随访13-106个月,31例存活(77.5％).移植前疾病状态和移植后是否合并巨细胞病毒感染可显著影响患者生存期;是否合并慢性移植物抗宿主病(GVHD)可影响患者生存质量.结论 allo-HSCT可使部分CML患者获得长期无病存活.慢性期移植及控制移植后的感染是提高生存的关键;预防并控制慢性GVHD可显著改善生存质量.     

Single-dose cyclosporine pharmacokinetics in various biological fluids of patients receiving allogeneic marrow transplantation

The clinical usefulness of cyclosporine is hampered by dose-limiting toxicities to the kidney that are not predicted by drug levels in serum or whole blood. Because of its lipophilic nature, circulating plasma lipoproteins may play a role in drug disposition. This study characterized the pharmacokinetic parameters of a single 2-mg/kg i.v. infusion of cyclosporine in the whole blood, plasma, high-density (HDL), low-density (LDL), and very low-density (VLDL) lipoprotein fractions of nine patients before bone marrow transplantation. The dose- and protein-corrected area under the concentration-time curve in whole blood; plasma; and HDL, LDL, and VLDL compartments were 44.6 +/- 11.3, 19.2 +/- 2.4; 33.6 +/- 12.3, 49.0 +/- 19.9, and 17.5 +/- 9.0 ng h/ml, respectively. The mean half-life of the drug from the VLDL fraction was significantly less than from the other biologic fluids. The systemic clearance rate of cyclosporine was greater in the total plasma or VLDL fractions compared with whole blood and the HDL and LDL fractions. The HDL-cyclosporine clearance inversely correlated with the serum creatinine (r = -0.71; p less than 0.05) and total bilirubin levels (r = -0.76; p less than 0.05). The plasma half-life and volume of distribution directly correlated with fasting HDL cholesterol levels (r = 0.94 and 0.99; p less than 0.01). Correlations between pharmacokinetic parameters and lipid fractions suggest a role of lipids in the distribution of cyclosporine. These data may be useful in the development of guidelines for therapeutic drug monitoring of cyclosporine in the transplantation population.     

ABO血型不合对异基因外周血干细胞移植造血重建的影响

目的探讨ABO血型不合对HLA相合的异基因外周血干细胞移植(allogeneic peripheral bloodstem cell transplantation,Allo-PBSCT)的影响。方法回顾分析6例ABO血型主要不合,9例次要不合的HLA相合的Allo-PBSCT术后受者造血重建情况,选用同期ABO相合的Allo-PBSCT受者作对比。结果15例ABO血型不合的Allo-PBSCT受者植入骨髓后均未发生急性溶血,有2例发生迟发性溶血。ABO血型不合对Allo-PBSCT骨髓植活、血小板恢复、粒系重建均无影响。在ABO血型主要不合组,红系恢复时间明显延迟。结论ABO血型不合并不是Allo-PBSCT的障碍,仅在ABO血型主要不合时,出现红系恢复时间延迟。