Tacrolimus Blood Concentrations Research Articles

Intravenous Administration of Tacrolimus Stabilizes Control of Blood Concentration Regardless of CYP3A5 Polymorphism in Living Donor Liver Transplantation: Comparison of Intravenous Infusion and Oral Administration in Early Postoperative Period

BackgroundWe compared achievement rate of sufficient tacrolimus blood concentration in the early postoperative period and incidence of acute cellular rejection within 1 month after living donor liver transplantation (LDLT) between tacrolimus intravenous (IV) and oral administration groups. MethodsFrom October 2005 to November 2016, 61 LDLT patients administered tacrolimus, who could be genotyped for CYP3A5*3 and *1, were chosen from the electronic record database. The patients were then divided into the 2 groups (an IV group [n = 38] and an oral group [n = 23]). We defined patients with 1*1 or *1*3 as expressors and those with *3*3 as nonexpressors. Sufficient trough level tacrolimus blood concentration on postoperative day (POD) 3 was defined as 10–20 ng/mL. ResultsComparable concentrations were seen between the 2 groups, with mean blood concentration 13.7 ± 8.5 ng/mL in the oral group and 15.2 ± 4.3 ng/mL in the IV group. Achievement rate of sufficient tacrolimus concentration on POD 3 was significantly higher in the IV group than in oral group: 97% (37 of 38) vs 65% (15 of 23), respectively (P = .001). When we focused on achievement rate in the oral group according to CYP3A5 polymorphism, the frequency of expressors (17%) was significantly lower than that of nonexpressors (82%) (P = .016). However, in the IV group this negative influence was totally eliminated, resulting in high achievement rates regardless of CYP3A5 polymorphism. In terms of incidence of acute cellular rejection, there was no significant difference between the 2 groups (IV 32% vs oral 17%, P = .250). ConclusionIV administration of tacrolimus allowed us to obtain more stable control of blood concentration regardless of CYP3A5 genotype.

Tacrolimus interaction with oral oestrogen in kidney transplant recipients: A case-control study.

Oestrogens could inhibit the metabolism of drugs, such as calcineurin inhibitors, that are substrates for cytochrome P-450 microsomal enzymes. This study assessed the potential tacrolimus interaction with oral conjugated oestrogen in kidney transplant recipients who received conjugated oestrogen as prophylaxis against bleeding, before kidney biopsy. In this case-control study, 13 kidney transplant recipients who received oral conjugated oestrogen as prophylaxis against uraemic bleeding before allograft biopsy were considered as cases. Thirteen matched kidney transplant recipients with similar immunosuppressive regimen served as controls. In this study, comparisons were made between the groups regarding daily dose, blood trough concentrations and calculated concentration corrected for dose of tacrolimus at three time points of the study. All patients in the case group received conjugated oestrogen at a dose of 3.75mg/day for 4.78±0.83days. Without any change in tacrolimus dose, the blood concentration of tacrolimus increased during concomitant administration of conjugated oestrogen (from 8.10±2.85 to 12.35±4.62ng/mL; P=.11) and decreased after cessation of conjugated oestrogen (6.07±2.18ng/mL; P=.015). The calculated concentration corrected for dose of tacrolimus increased from 127.04±79.23 to 211.40±146.38 ngmLmgkg/d after conjugated oestrogen administration (P=.036). Thereafter, it decreased to 108.55±78.61 ngmLmgkg/d after cessation of oestrogen (P=.003). Only one patient experienced nausea while taking oestrogen without any change in her liver enzymes. Concomitant administration of oral oestrogen increased tacrolimus blood concentration. Hence, it is necessary to monitor tacrolimus blood levels during concomitant oestrogen therapy and for several days after oestrogen withdrawal.

Higher tacrolimus blood concentration is related to increased risk of post-transplantation diabetes mellitus after living donor liver transplantation

Background/AimsTo investigate the association between tacrolimus (TAC) blood concentration and the risk of post-transplantation diabetes mellitus (PTDM) development after living donor liver transplantation (LDLT). MethodsThis study reviewed the clinical data of 158 adult LDLT recipients. A cut-off of mean trough concentration of TAC (cTAC) value at the sixth month postoperatively was identified using a receptor operating characteristic curve. Other clinical complications rates were compared between different cTAC groups. ResultsThirty-four (21.5%) recipients developed PTDM during follow-up period. Recipients with PTDM suffered lower 1-, 5- and 10-year overall survival rates (85.2%, 64.9%, and 55.6% vs 92.4%, 81.4%, and 79.1%, p < 0.05) and allograft survival rates (87.9%, 76.9%, and 65.9% vs 94.1%, 88.5%, and 86.0%, p < 0.05) than those without PTDM. The best cut-off value of mean cTAC was 5.9 ng/mL. Recipients with higher cTAC (>5.9 ng/mL) were more likely to develop hyperlipidemia (39.6% vs 21.9%, p < 0.05), cardio-cerebral events (7.5% vs1.0%, p < 0.05), and infections (37.7% vs19.0%, p < 0.05) than recipients exposed to low cTAC (≤5.9 ng/mL). However, the two groups showed no difference in the incidence of acute and chronic rejection. ConclusionHigher mean cTAC at the sixth month postoperatively is related to increased risk of PTDM in LDLT recipients.

Tacrolimus Dose Optimization Strategy for Refractory Ulcerative Colitis Based on the Cytochrome P450 3A5 Polymorphism Prediction Using Trough Concentration after 24 Hours

Background: In the tacrolimus treatment for refractory ulcerative colitis (UC), dose adjustment is necessary because the required doses to keep appropriate drug concentrations are significantly different among individuals. Cytochrome P450 (CYP) 3A5 polymorphism affects tacrolimus blood concentrations. However, it is difficult to obtain genetic information in real clinical practice. In the present study, we investigated possible factors that may predict CYP3A5 polymorphism and proposed a dose optimization strategy based on the obtained predicting factors. Summary: We retrospectively analyzed 41 patients who underwent remission induction therapy with tacrolimus for UC in our hospital. First, we performed a correlation analysis of CYP3A5 polymorphism and pharmacokinetics. In the CYP3A5 non-expressers, the dose of tacrolimus (mg/kg) was lower and dose-adjusted trough levels (ng/mL per mg/kg) were higher compared with those in expressers. Next, we investigated factors that could predict CYP3A5 polymorphism. Trough concentration 24 h following tacrolimus administration was extracted as a significant factor. When the trough cutoff value at 24 h was set to 2.6 ng/mL, sensitivity and specificity for estimation of CYP3A5 polymorphism were 63 and 96% respectively. Therefore, when the trough concentration 24 h after administration is ≤2.6 ng/mL, the patient can be estimated as a CYP3A5 expresser and an increase in dose should be proposed. Key Message: The trough concentration 24 h after the first tacrolimus administration appears to be a useful predictor of ­CYP3A5 polymorphism. Performing dose optimization strategy based on the prediction of CYP3A5 polymorphism can lead to earlier and safer remission induction.

Tacrolimus Concentration in Saliva of Kidney Transplant Recipients: Factors Influencing the Relationship with Whole Blood Concentrations.

The objective of this study was to examine the association between tacrolimus concentration in oral fluids and in whole blood and to investigate the various factors that influence this relationship. Forty-six adult kidney transplant recipients were included in the study. Study A (ten patients) included the collection of several paired oral fluid samples by passive drool over a 12-h post-dose period. Study B (36 patients) included the collection of oral fluids pre-dose and at 2h after the tacrolimus dose under three conditions: un-stimulated, after stimulation with a tart candy, and after mouth rinsing. The tacrolimus concentration in oral fluids was measured by a specially developed sensitive and specific liquid chromatography mass spectrometry method. A salivary transferrin concentration of >1mg/dL was used as a cut-off value for oral fluid blood contamination. Rinsing the oral cavity before sampling proved to provide the most suitable sampling strategy giving a correlation coefficient value of 0.71 (p=0.001) between the tacrolimus concentration in oral fluids and the tacrolimus concentration in whole blood at trough. Mean and 95% confidence interval of tacrolimus concentration in oral fluids at the pre-dose concentration for samples collected after mouth rinsing was 584 (436, 782) pg/mL. The ratio of the tacrolimus concentration in oral fluids to the tacrolimus concentration in whole blood (*100) was 11% (95% confidence interval 9-13) for all sampling times. Oral fluid pH or weight of a saliva sample did not influence the tacrolimus concentration in oral fluids. Tacrolimus distribution into oral fluids exhibited a delay with a pronounced counter-clockwise hysteresis with respect to the time after dose. A multivariate analysis of variance revealed that the tacrolimus concentration in oral fluids is related to the tacrolimus concentration in whole blood and tacrolimus plasma-binding proteins including albumin and cholesterol. An optimal sampling strategy for the determination of the tacrolimus concentration in oral fluids was established. Measuring the tacrolimus concentration in oral fluids appears to be a feasible and non-invasive method for predicting the concentration of tacrolimus in whole blood.

Graft-versus-host Disease–free, Relapse-free Survival After HLA-identical Sibling Peripheral Blood Stem Cell Transplantation With Tacrolimus-based Graft-versus-host Disease Prophylaxis in Japanese Patients

The ideal post-allogeneic hematopoietic cell transplantation recovery is not just the cure of hematologic malignancies but also freedom from ongoing morbidity. Recent studies have revealed that HLA-identical sibling peripheral blood stem cell transplantation (PBSCT) had been providing impaired graft-versus-host disease (GVHD)–free relapse-free survival (GRFS) due to a higher risk of GVHD. Study on GVHD prophylaxis bears clinical reliance when focused on Japanese population because risk of GVHD differs among races. We identified 15 consecutive Japanese patients who received tacrolimus-based GVHD prophylaxis after myeloablative HLA-identical sibling PBSCT. No episode of grade ≥ II acute GVHD and only one episode of grade III toxicity were documented, with the control of mean weekly blood tacrolimus concentrations during the first 4 weeks at 13 to 17 ng/mL. An estimated 46.7% (95% CI: 21.4% to 71.9%) of the patients enjoyed their GRFS at 3 years after transplantation, and failure in the treatment of chronic GVHD was not reported during the median follow-up period of 1059 days (range, 784 to 1778 days) after the development of chronic GVHD. The results suggest that the application of tacrolimus with the optimization of its blood concentrations may effectively prevent ongoing morbidities after HLA-identical sibling PBSCT.

Association of Whole Blood Tacrolimus Concentrations with Kidney Injury in Heart Transplantation Patients.

Background and ObjectivesAcute kidney injury (AKI) is frequently observed after heart transplantation and is associated with morbidity and mortality. However, many confounding factors also contribute to the development of AKI in heart transplants. We hypothesized that supratherapeutic whole-blood tacrolimus trough concentrations are associated with AKI.MethodsIn a retrospective observational cohort from April 2005 to December 2012, all adult heart transplantation patients were included. AKI was assessed in the first 2 weeks after transplantation as classified by the Kidney Disease Improving Global Outcomes Network (KDIGO). Whole-blood tacrolimus trough concentrations were determined from day 1 to day 14 and at 1, 3, 6 and 12 months post-transplantation. The therapeutic range was 9 to 15 ng/ml in the first 2 months and tapered to 5–8 ng/ml thereafter. The relationship between supratherapeutic tacrolimus trough concentrations and AKI was evaluated. The impact of various potentially confounding factors on tacrolimus concentrations and AKI was considered.ResultsWe included 110 patients. AKI occurred in 57% of patients in the first week. Recovery from AKI was seen in 24%. The occurrence of chronic kidney disease (CKD) was 19% at 1 year. Whole-blood tacrolimus trough concentrations were often supratherapeutic and, despite correction for confounding factors, independently associated with AKI (OR 1.66; 95% CI 1.20–2.31).ConclusionsSupratherapeutic whole-blood tacrolimus trough concentrations are independently associated with the development of AKI in adult heart transplantation patients. More stringent dosing of tacrolimus early after transplantation may be critical in preserving the kidney function.Electronic supplementary materialThe online version of this article (10.1007/s13318-017-0453-7) contains supplementary material, which is available to authorized users.

Pharmacokinetic Interaction Between Tacrolimus and Fentanyl in Patients Receiving Allogeneic Hematopoietic Stem Cell Transplantation.

BACKGROUND Tacrolimus and fentanyl are well-known cytochrome P450 (CYP) 3A4 substrates with a narrow therapeutic range. However, the pharmacokinetic interaction between tacrolimus and fentanyl is unclear. The aim of this study was to determine whether drug interaction exists between tacrolimus and fentanyl. MATERIAL AND METHODS A retrospective study was performed in 6 patients who had received allogeneic hematopoietic stem cell transplantation between April 2010 and March 2015. The patients received continuous intravenous infusion of fentanyl with concomitant use of tacrolimus, and the blood concentrations of tacrolimus were evaluated using fluorescence polarization immunoassay. RESULTS The clearance (CL) of tacrolimus decreased significantly from 1.28 to 0.68 mL/min/kg with concomitant use of fentanyl. The CL changed with time and dose of fentanyl administration. In addition, the CL of tacrolimus was reverted by stopping fentanyl infusion. Horn's drug interaction probability scale indicated a probable category or possible category, suggesting a drug interaction between tacrolimus and fentanyl. No patient showed a difference in hepatic or renal function before and after fentanyl administration. No additional administration of other CYP3A4 inhibitors was observed, suggesting that the drug interaction was mediated by CYP3A4. CONCLUSIONS The influence of fentanyl on the pharmacokinetics of tacrolimus was demonstrated to be of clinical importance. It is proposed that the dose of tacrolimus be reduced by 40% when used in combination with fentanyl.

Letter to the Editor: Mobile Technology Can Improve Adherence and Lessen Tacrolimus Variability in Patients Receiving Kidney Transplants.

Medication adherence is of paramount importance in transplant recipients. Studies have demonstrated that variability in tacrolimus blood concentrations is associated with de novo formation of donor-specific antibodies and an increased incidence of rejection following renal transplantation.[1][1]-[3

Association Between Tacrolimus Pharmacokinetics and Cytochrome P450 3A5 and Multidrug Resistance Protein 1 Exon 21 Polymorphisms

BackgroundIndividual differences in the pharmacokinetics (PK) of tacrolimus (TAC), an immunosuppressive drug, are reportedly associated with single-nucleotide polymorphisms (SNPs) of cytochrome P450 (CYP) 3A5 and multidrug resistance protein 1 (MDR1). We determined the effect of SNPs in CYP3A5 and MDR1 exons 21 and 26 on TAC PK parameters. MethodsThirty-eight Japanese patients who underwent renal transplantation were genotyped for CYP3A5 and exons 21 and 26 of MDR1 with the use of polymerase chain reaction–restriction fragment length polymorphism analysis. TAC concentrations were determined 3 weeks after renal transplantation and PK parameters calculated. ResultsThe area under the blood concentration–time curve (AUC) in CYP3A5 expressers was significantly higher than that in CYP3A5 nonexpressers (CYP3A5*3/*3). Patients with the MDR1 exon 21 A allele (G2677A) showed higher dose-adjusted AUC (AUC/D) and lower doses of TAC than those who did not possess that allele. Furthermore, patients with both CYP3A5*3/*3 and MDR1 G2677A showed significantly lower TAC doses and higher dose-adjusted trough levels (C/D) and AUC/D than those without those genotypes. There was no significant association between MDR1 exon 26 polymorphism and the PK of TAC. ConclusionsPatients with both CYP3A5*3/*3 and MDR1 G2677A had higher blood TAC concentrations than those without those genotypes. Japanese patients should be carefully monitored for consideration of lower TAC doses, because 24% of Japanese patients have double mutations.

Correlation of blood concentration of tacrolimus with serum cystatin C in renal transplant recipients and effect of tacrolimus on glucose and lipid metabolism

To investigate the correlation between blood concentrations of tacrolimus (FK506) and cystatin C (Cys C) and the effect of FK506 on glycolipid metabolism in renal transplant recipients. A total of 325 patients receiving renal transplantation between August, 2014 and September, 2015 in Nanfang Hospital were divided into 4 groups according to the postoperative time (1 month group, 1-3 months group, 4-6 months group, and 7-12 months group). FK506 blood trough concentration was measured at the time of postoperative follow-up, and creatinine (Scr) and Cys C levels were also detected. Results Plasma FK506 concentration decreased with age in the recipients and showed a positive correlation with Cys C (r=0.985, P=0.015) but no obvious correlation with Scr (r=0.259, P=0.741). FK506 had no effect on blood glucose (5.53-5.59 mmol<L) or blood lipids (TG 1.47-1.55 mmol<L, TC 5.04-5.17 mmol<L, LDL-C 3.00-3.07 mmol<L, and VLDL 0.73-0.76 mmol<L) in patients 1-6 months after renal transplantation. FK506 does not affect the level of glycolipid metabolism in patients after renal transplantation. Cys C is positively related to blood concentration of FK506 in the renal transplantation recipients. The rational use of FK506 can improve the effectiveness and safety of the treatment in the recipients.

Effective Treatment With Daclatasvir and Asunaprevir in Kidney Transplant Patients Infected With Hepatitis C Virus: A Report of Two Cases

BackgroundHepatitis C virus (HCV) infection is known to affect long-term patient and graft survivals after kidney transplantation (KT). Recently, combination therapy with the use of 2 oral direct-acting antivirals, daclatasvir (DCV) and asunaprevir (ASV) reportedly showed a high rate of HCV eradication. We report the safety and efficacy of DCV and ASV therapy in 2 KT patients. MethodsThe safety and viral responses were investigated in a prospective study of KT patients infected with HCV genotype 1. Two patients received 60 mg DCV once daily plus 100 mg ASV twice daily for 24 weeks. ResultsA 69-year-old woman and a 57-year-old man underwent DCV and ASV therapy for 24 weeks. In both cases, the HCV genotype was 1b. Case 1 had undergone KT twice and had received treatment with pegylated interferon and ribavirin. She received DCV and ASV therapy 12 years after the 2nd KT, and had undetectable virus after only 6 weeks of treatment and at 24 weeks after the end of treatment (SVR24). The post-transplantation immunosuppressive therapy at that time comprised tacrolimus, mycophenolate mofetil, and prednisolone. The other case, after failure of interferon treatment, received DCV and ASV therapy 27 years after his KT and achieved SVR24. His immunosuppressive regimen at that time was mizoribine and prednisolone. DCV and ASV therapy did not affect renal graft function or tacrolimus blood concentrations. ConclusionsDCV and ASV therapy had high antiviral effect and a low rate of adverse events in KT patients.

Tacrolimus Trough Concentrations Increase in Intestinal Transplant Recipients During Episodes of Acute Cellular Rejection

Background: Intestinal transplantation (Itx) is a therapeutic option for patients with short gut syndrome and other end stage gastrointestinal disease states. Acute cellular rejection (ACR) is common within the first year of intestinal transplant (67%). During ACR, T cell infiltration, increased local pro-inflammatory cytokines, including IL-1beta, IL-2, IL-6, and TNF-alpha, and down regulation of the expression of messenger RNAs of CYP3A and Multi drug resistance 1 (MDR1) gene will occur. This is anticipated to inhibit CYP3A-mediated gut metabolism and transporter-mediated efflux of drugs via p-glycoprotein (P-gp). Pro-inflammatory release also damages the mucosal barrier, which increases intestinal permeability. However, it is not known how these physiological changes during ACR affect the pharmacokinetic parameters of absorption and bioavailability in enteral medications. The purpose of this study was to evaluate the impact of acute cellular rejection (ACR) on dose-normalized tacrolimus blood concentrations in intestinal transplant recipients. Method: A retrospective, single-center, cohort study of adult intestinal transplant recipients experiencing acute cellular rejection from February 1998 to July 2013 was conducted. Primary outcome was change in dose-normalized tacrolimus concentrations. Secondary outcomes included differences in percent change of dose-normalized tacrolimus by rejection grade, treatment agent, time post-transplantation, and rejection episode. Serum creatinine and blood urea nitrogen levels were assessed for nephrotoxicity. Results: One hundred thirteen intestinal transplant recipients experienced 284 ACR episodes. Median dose-normalized concentrations were higher during ACR compared to before or after ACR (8.7 ng/mL/mg vs 3.1 ng/mL/mg, respectively p < 0.001). Increases in absolute TAC levels were associated with increases in SCr (p = 0.004), BUN (p < 0.001), and potassium (p < 0.001) during ACR. These observations demonstrate increased systemic concentrations and toxicities with tacrolimus in ITx transplant patients during ACR. Conclusions: Systemic availability of tacrolimus is increased during acute rejection of SBTx. Higher exposure to other enteral medications are expected during ACR in SBTx patients.

Dimensionタクロリムス試薬（TAC）の改善点および新たな注意点―低濃度域における精密性とEDTAの影響―

Dimensionタクロリムス試薬（TAC）の改善点および新たな注意点―低濃度域における精密性とEDTAの影響―

Sex Differences in the Blood Concentration of Tacrolimus in Systemic Lupus Erythematosus and Rheumatoid Arthritis Patients with CYP3A5*3/*3

The purpose of this study was to describe the impact of sex and cytochrome P450 3A5 (CYP3A5) variant on the blood concentration of tacrolimus in patients with systemic lupus erythematosus or rheumatoid arthritis. The blood concentration of tacrolimus (ng/mL) divided by the daily dose of tacrolimus (mg/day) and the patient’s weight (kg) (C/D) was obtained from 55 patients. The C/D value was analysed according to genetic variation in CYP3A5 or ATP binding cassette subfamily B member 1 (ABCB1), sex, and age. The C/D value in the CYP3A5*3/*3 group was significantly higher than in the CYP3A5*1/*1 and *1/*3 groups (p < 0.05, effect size: d = 1.40). In the CYP3A5*3/*3 group, the concentration of tacrolimus was significantly higher in men than in women (p < 0.05, effect size: d = 1.78). Furthermore, in the CYP3A5*3/*3 group, the concentration of tacrolimus was significantly higher in women aged over 50 years than in women aged under 50 years (p < 0.05, effect size: d = 1.18). In contrast, ABCB1 genetic variations did not show any significant effect on the C/D value. Since the blood concentration of tacrolimus in patients with CYP3A5*3/*3 varies depending on sex and age, these factors should be considered when studying the difference of sex in CYP3A.

High tacrolimus blood concentrations early after lung transplantation and the risk of kidney injury

PurposeLung transplant recipients often develop acute kidney injury (AKI) evolving into chronic kidney disease (CKD). The immunosuppressant tacrolimus might be associated with the emergence of AKI. We analyzed the development and recovery of kidney injury after lung transplantation and related AKI to whole-blood tacrolimus trough concentrations and other factors causing kidney injury.MethodsWe retrospectively studied kidney injury in 186 lung-transplantation patients at the UMC Utrecht between 2001 and 2011. Kidney function and whole-blood tacrolimus trough concentrations were determined from day 1 to 14 and at 1, 3, 6, and 12 months postoperative. Systemic inflammatory response syndrome (SIRS), septic shock, and nephrotoxic medications were evaluated as covariates for AKI. We analyzed liver injury and drug-drug interactions.ResultsAKI was present in 85 (46%) patients. Tacrolimus concentrations were supra-therapeutic in 135 of 186 patients (73%). AKI in the first week after transplantation was related to supra-therapeutic tacrolimus concentrations (OR 1.55; 95% CI 1.06–2.27), ≥3 other nephrotoxic drugs (OR 1.96; 95% CI 1.02–3.77), infection (OR 2.48; 95% CI 1.31–4.70), and cystic fibrosis (OR 2.17; 95% CI 1.16–4.06). Recovery rate of AKI was lower than expected (19%), and the cumulative incidence of severe CKD at 1 year was 15%.ConclusionsAfter lung transplantation, AKI is common and often evolves into severe CKD, which is a known cause of morbidity and mortality. Supra-therapeutic whole-blood tacrolimus trough concentrations are related to the early onset of AKI. Conscientious targeting tacrolimus blood concentrations might be vital in the early phase after lung transplantation.What is known about this subject?• Lung transplant recipients often develop acute kidney injury evolving into chronic kidney disease increasing both morbidity and mortality.• To date, the pathophysiology of kidney injury after lung transplantation has not been fully elucidated.• The immunosuppressant tacrolimus is difficult to dose, especially in the unstable clinical setting, and is nephrotoxic.What this study adds:• For the first time, supra-therapeutic whole-blood tacrolimus trough concentrations are related to the emergence of acute kidney injury in the first days after lung transplantation.• Supra-therapeutic whole-blood tacrolimus trough concentrations often occur early after lung transplantation.• AKI after lung transplantation shows low recovery rates.

Effectiveness of Measuring Genetic Polymorphisms in Metabolizing Enzymes of Tacrolimus within One Medical Facility.

Because genetic polymorphisms cause diverse activity in drug metabolizing enzymes, drug concentrations in the blood may be variable among patients. We analyzed the genotypes of CYP3A5 and MDR1, and investigated their relationship with whole blood drug concentrations. Eight patients were administered an oral dose of tacrolimus for one week or longer prior to enrollment in this study. Whole blood concentrations for tacrolimus were measured 12 hours post oral administration, on the same day as genotyping, within our hospital using a fully automated gene analyzer. The procedures became so rapid that collection of blood samples could be completed within the same day (approximately one hour). The genotype frequency of CYP3A5 was *3/*3 in five patients, *1/*3 in two patients, and *1/*1 in one patient. All five patients with *3/*3 showed favorable increases in tacrolimus blood concentrations. In the two patients with *1/*3, an increase in tacrolimus blood concentration was not readily achieved in one patient, but increased favorably in the other patient. In the patient with *1/*1, tacrolimus was not detectable in the patient's blood. A favorable treatment effect was obtained by changing tacrolimus to cyclosporine. It is notable that genotypes in patients where tacrolimus was not detected in the blood were wild types: 2677G/G and 3435C/C in MDR1. The measurement of genetic polymorphisms in metabolizing enzymes of tacrolimus, within one medical facility, is applicable for the selection of immunosuppressants and individual dosing for the treatment of autoimmune disease.

五酯胶囊对肾移植术后早期他克莫司药代动力学和肝肾功能的影响

目的：五味子，木兰科的多年生草本植物北五味子属的成熟果实，其在许多国家广泛用作滋补类营养品和恢复性加强肝脏及其他器官的功能。五酯胶囊，一种五味子醇提制剂，是一个著名的中药，在中国广泛使用。五酯胶囊及其活性成分木酚素/木脂素显著保护肝损伤，在中国通常与TAC联合应用来防止药物引起的肝炎。本研究旨在探讨五酯胶囊对肾移植术后早期他克莫司血药浓度和肝肾功能的影响。方法：回顾性研究113名肾移植受者，未用五酯胶囊者55人，匹配年龄和性别后应用五酯胶囊者58人，所有患者接受Tac + MMF + Pred三联免疫抑制治疗。检测3天、7天和30天时Tac的血药浓度的变化，使用微粒酶免疫测定(MEIA)法。与此同时，测试所有患者的肝脏、肾脏功能。肝功能、肾功能、全血他克莫司浓度进行了两组之间的分析比较。结果：我们发现五酯胶囊可以显著提高3天、7天和30天时TAC血药浓度。3天、7天和30天时，五酯胶囊组全血Tac浓度平均增加了40.1%、23.3%、15.0%。更重要的是，直接胆红素也显著降低。两组之间其他的肝肾功能指标没有显著的差异(P > 0.05)。结论：五酯胶囊可以显著提高肾移植受者的Tac血药浓度，且具有保护肝脏的作用，没有明显的不良反应。 Objective: Fructus Schisandrae, the ripe fruits of perennial plant of Schisandra chinensis (Turcz.) Baill, perennial herb of family Magnoliaceae, is widely used as a restorative, tonic nutrition to enhance the function of liver and other organs in many countries. Wuzhi capsule, an ethanol extract preparation of Fructus Schisandrae, is a well-known herbal medicine widely used in China. Wuzhi capsule and its active lignans significantly protect liver injury, and are often prescribed with TAC to prevent drug-induced hepatitis in China. This study aimed to investigate the effects of Wuzhi capsule on blood concentration of tacrolimus and liver function, renal function after renal transplantation. Methods: One hundred and thirteen renal transplant recipients were randomly assigned to two groups, i.e., 58 in the WC group and 55 in the control group. All patients received Tac + MMF + Pred triple immunosuppressive therapy. One month was taken as one therapeutic course. Changes of the blood concentration of Tac were detected 3, 7, 30 d after medication in the two groups using microparticle enzyme immune assay (MEIA). Meanwhile, the liver and kidney functions were tested. Liver function, renal function, and whole-blood concentrations of tacrolimus were analyzed to compare between the two groups. Results: We found that WZ capsule could significantly increase TAC blood concentration at 3, 7, 30 d. At 3, 7, 30 d after the application of WC capsule, the blood Tac concentration increased 40.1%, 23.3%, 15.0% averagely. More importantly, serum DBIL was also remarkably reduced. There was no significant difference in the liver and renal functions between the two groups (P > 0.05). Conclusion: WC capsule could significantly increase the blood Tac concentration of renal transplant recipients with liver protection, and has no obvious adverse reaction.

Early Post-Transplantation Tacrolimus Levels Correlate with Acute Graft-Versus-Host Disease in Allogeneic Hematopoietic Stem Cell Transplantation from Related and Unrelated Donors

Introduction: Acute graft-versus-host disease (aGVHD) is a leading cause of transplant related mortality following allogeneic hematopoietic stem cell transplantation (HCT). The most widely used aGVHD prophylaxis regimen is a combination of a calcineurin inhibitor and a short course of methotrexate. Results of studies on the optimal blood levels of the calcineurin inhibitor tacrolimus to prevent aGVHD are mixed, with some showing no correlation and others indicating that trough levels between 7-15 ng/mL required to adequately prevent aGVHD. Currently, the established target trough level for this agent is 10 to 20 ng/mL. We retrospectively evaluated the relationship between tacrolimus blood concentration and the incidence of grade II-IV aGVHD in a large cohort of adult patients following allogeneic HCT from either an HLA-matched related or matched unrelated donors.Methods: We evaluated all related/unrelated allografts between January 2004 and December 2012 at the Cardinal Bernardin Cancer Center at Loyola University. Inclusion criteria included age 18 years or older, first allogeneic HCT for a hematological malignancy, and use of tacrolimus and short term methotrexate for aGVHD prophylaxis. Donors included human leukocyte antigen (HLA) identical sibling (Allo-Sib) or unrelated donors (MUD) either fully matched or 1 antigen mismatched (10%). Both myeloablative and non-myeloablative conditioning regimens were included. Disease risk was defined by the ASBMT classification and Co-Morbidity Index by Sorror et al (HCT-CI). Infusional tacrolimus was initiated on day -2 of HCT at dose of 0.03 mg/kg/d and AM trough blood concentrations measured every other day during the entire hospital stay with the goal of maintaining a level of 10-15 ng/ml and then twice weekly after discharge. Dose adjustments or withholds were based primary on serum creatinine and trough levels per a set protocol that withholds for levels greater than 20 ng/ml or creatinine greater than 2.0 mg/dl. Acute GVHD was graded based on the International Bone Marrow Transplant Registry System. Univariate and multivariate analyses exploring all risk factors for aGVHD were performed.Results: A total of 428 patients met the inclusion criteria. Median age was 48.5 years with a male predominance (60.6%). HCT-CI was evenly distributed with 121 (28.2%) low risk, 151 (35.3%) intermediate risk, and 156 (36.4%) high risk. Per ASBMT disease risk classification, more patients had high disease risk (n=211, 49.3%); 64 (15%) with intermediate risk, and 153 (35.7%) with low risk. Acute GVHD II-IV developed in 186 (43%) patients in this largely myeloablative patient population (89%), with donor source split nearly evenly between MUD (45%) and Allo-sib (55%). An extensive univariate analysis for the factors associated with the development of aGVHD was developed (Table 1). The strongest predictor of aGVHD was a level of tacrolimus < 5 ng/ml in weeks 3 and 4 after transplant: of those with no aGVHD only 16.9% had a level < 5 ng/ml during these weeks vs 27.4% with aGVHD (p = .009). Other tacrolimus trough cut points, i.e. 10 ng/ml, 2.5 ng/ml and the mean (13.4 ng/ml in each group) were not associated with a higher rate of aGVHD. In the univariate analysis, AML and allo-sib grafts were noted to be associated with lower risk of aGVHD. In multivariate analysis (Table 2), tacrolimus levels less than 5 ng/ml in weeks 3 or 4 was found to be the most statistically significant factor in predicting aGVHD incidence (Odds ratio 82 95% CI 1.13-2.94; p = .01); other significant factors include HCT-CI (p = .02) and graft source (p = .04).Conclusion: In one of the largest retrospective studies examining the correlation of early tacrolimus blood concentrations and acute GHVD incidence, we show that trough tacrolimus levels less than 5 ng/ml in weeks 3-4 following Allo-Sib or MUD HCT is a strong predictor for an increased risk of aGVHD. We affirm that higher HCT-CI and donor source are risk factors for aGVHD after allografts. This not only helps define more accurately the lower limits of acceptable tacrolimus levels, but appears to emphasize the importance for close monitoring and dose adjustment of these levels at a time when patients are typically discharged to the outpatient setting. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Effects of Miconazole Oral Gel on Blood Concentrations of Tacrolimus and Cyclosporine: A Retrospective Observational Study.

Although azole antifungal agents have been shown to affect the pharmacokinetics of calcineurin inhibitors such as tacrolimus (TAC) and cyclosporine (CyA) by inhibiting drug metabolism, there are few clinical reports on drug interactions between miconazole (MCZ) oral gel and calcineurin inhibitors. In this study, the effects of MCZ oral gel on the blood concentrations of TAC and CyA were investigated. In this retrospective study, 18 patients concomitantly administered MCZ oral gel and TAC (9 for dermatomyositis, 3 for myasthenia gravis, 2 for systemic lupus erythematosus, 2 for rheumatoid arthritis, 1 for polymyositis, 1 for prevention of graft-versus-host disease after bone marrow transplantation), and 15 patients concomitantly administered MCZ oral gel and CyA (11 for interstitial pneumonia, 2 for pemphigus, 1 for eosinophilic granulomatosis with polyangiitis, 1 for systemic lupus erythematosus) were evaluated. The dose-adjusted blood concentrations of TAC or CyA were compared before and after the initiation of MCZ oral gel. The trough blood concentration/dose (C/D) ratios of TAC and CyA increased significantly with the administration of MCZ oral gel. The median C/D ratios of TAC and CyA increased by 108% (range: -44% to 216%) and 44% (range: -34% to 195%), respectively. These results suggest that MCZ oral gel affects the pharmacokinetics of TAC and CyA. Detailed monitoring of the blood concentrations of these drugs, followed by dose adjustments, is needed for each patient because of the difficulties associated with accurately predicting the degree of the effects of MCZ oral gel.