Tacrolimus Blood Concentrations Research Articles

Association between salivary microbiota and tacrolimus pharmacokinetic variability in kidney transplant

Kidney transplantation (KT) serves as a highly effective treatment for end-stage renal disease (ESRD). Nonetheless, the administration of tacrolimus, a commonly used immunosuppressant in KT, faces challenges due to the lack of dependable biomarkers for its efficacy and the considerable variability in tacrolimus pharmacokinetics (TacIPV). In this study, 183 saliva samples from 48 KT recipients under tacrolimus therapy, alongside 9 healthy control samples, were subjected to 16S rRNA sequencing. The analysis revealed significant differences in the composition of salivary microbiota among KT recipients, patients with ESRD, and healthy controls. Moreover, trough blood concentrations (C0) of tacrolimus were associated with alterations in microbiota composition. Notably, Capnocytophage consistently exhibited a negative correlation in both group-level and individual trends. Furthermore, distinct taxa were identified that effectively distinguished recipients with varying TacIPV, as demonstrated by a cross-validation random forest model (mean AUC = 0.7560), with Anaerolinea emerging as a prominent contributor to the classifier. These findings suggest that salivary microbiota is closely linked to tacrolimus C0 levels and could aid clinicians in differentiating KT recipients based on TacIPV.

Guiding the starting dose of the once-daily formulation of tacrolimus in "de novo" adult renal transplant patients: a population approach.

The once-daily extended-release tacrolimus formulation (ER-Tac) has demonstrated similar efficacy and safety to the twice-daily immediate-release formulation (IR-Tac), but few population-based pharmacokinetic models have been developed in de novo kidney transplant patients to optimize doses. Therefore, this study aimed i) at developing a population pharmacokinetic model for ER-Tac in de novo adult kidney transplant patients ii) and identifying genetic factors and time-varying covariates predictive of pharmacokinetic variability to guide tacrolimus dosage during the early post-transplant period. A total of 1,067 blood tacrolimus concentrations from 138 kidney transplant patients were analyzed. A total of 29 out of 138 patients were intensively sampled for 24h on the day 5 post-transplantation; meanwhile, for the remaining patients, concentrations were collected on days 5, 10, and 15 after transplantation. Tacrolimus daily doses and genetic and demographic characteristics were retrieved from the medical files. Biochemistry time-varying covariates were obtained on different days over the pharmacokinetic (PK) study. A simultaneous PK analysis of all concentrations was carried out using the non-linear mixed-effects approach with NONMEM 7.5. A two-compartment model with linear elimination and delayed absorption best described the tacrolimus pharmacokinetics. Between-patient variability was associated with oral blood clearance (CL/F) and the central compartment distribution volume (Vc/F). Tacrolimus concentrations standardized to a hematocrit value of 45% significantly improved the model (p < 0.001). This method outperformed the standard covariate modeling of the hematocrit-blood clearance relationship. The effect of the CYP3A5 genotype was statistically (p < 0.001) and clinically significant on CL/F. The CL/F of patients who were CYP3A5*1 carriers was 51% higher than that of CYP3A5*1 non-carriers. Age also influenced CL/F variability (p < 0.001). Specifically, CL/F declined by 0.0562 units per each increased year from the value estimated in patients who were 60years and younger. The 36% between-patient variability in CL/F was explained by CYP3A5 genotype, age, and hematocrit. Hematocrit standardization to 45% explained the variability of tacrolimus whole-blood concentrations, and this was of utmost importance in order to better interpret whole-blood tacrolimus concentrations during therapeutic drug monitoring. The dose requirements of CYP3A5*/1 carriers in patients aged 60years or younger would be highest, while CYP3A5*/1 non-carriers older than 60years would require the lowest doses.

Association of Therapeutic Monitoring of Tacrolimus with Laboratory Markers of Kidney Function in Receptors of Kidney Allograft

Introduction: Kidney transplantation is the most commonly performed type of transplant in Brazil. Tacrolimus is one of the primary drugs used in post-transplant immunosuppressive therapy, and one of its main adverse effects is nephrotoxicity. Laboratory tests to assess renal function are of great importance in monitoring post-kidney transplant patients, helping to diagnose events indicative of graft dysfunction. Objective: !e present study aimed to evaluate the association between laboratory changes in renal function and blood levels of tacrolimus in post-kidney transplant patients. Methods: Observational, analytical and cross-sectional study. !e results of blood levels of tacrolimus and measurements of urea, creatinine and estimated Glomerular Filtration Rate (eGFR) were analyzed, as well as the sociodemographic data of kidney transplant recipients followed at a university hospital who underwent laboratory tests between months from January 2021 to July 2022 in a period close to 1 year after the transplant. !e variables analyzed in the research were collected from the patient's medical records and subsequently analyzed; the statistical analyses considered p &lt; 0.05. !e project was approved by the Ethics Committee of the Walter Cantídio University Hospital under opinion number 5,436,434 and CAAE number 57396622.1.0000.5045. Results: !e sample was mainly composed of males, mixed race, with an average age of 51.5 years (SD ± 12.5) and from cities in the interior of Ceará. Regarding the percentage of patients with laboratory changes, 50.62% (n = 45) showed changes in tacrolimus blood levels. 56.79% (n = 46) had changes in serum creatinine levels, 49.38% (n = 40) had changes in serum urea levels, and 59.26% (n = 48) had altered eGFR. !e correlation analyses suggested a low signi#cance between variations of the variables studied. Conclusion: !e results indicate no relationship between variations in tacrolimus blood concentrations and the appearance of changes in the results of classic renal biomarkers at the end of the #rst year post-transplant. However, it is necessary to carry out new studies to understand better the impact of changes in blood levels of tacrolimus on the renal function of renal allograft recipients.

P.040: Association CYP3A5 gene polymorphisms with tacrolimus blood concentration in heart transplant recipients.

P.040: Association CYP3A5 gene polymorphisms with tacrolimus blood concentration in heart transplant recipients.

Population pharmacokinetics study of tacrolimus in liver transplant recipients: a comparison between patients with or without liver cancer before surgery.

The main challenge for immunosuppressive therapy using tacrolimus in liver transplantation is the considerable variability in its oral bioavailability and the narrow treatment range. Many population pharmacokinetic (PopPK) models have been established to precisely estimate the PK variability of tacrolimus in liver transplant recipients. However, it remains unclear whether there is a significant difference in the PK behavior of tacrolimus between patients with or without liver cancer before surgery. Therefore, we aimed to compare the differences of PK parameters and simulate exposures of tacrolimus between populations preoperatively diagnosed with liver cancer or not by PopPK modeling. In total, 802 blood concentrations of tacrolimus from 196 patients (118 liver cancer and 78 non-liver-cancer samples) were included in this study. Demographic data and clinical parameters were integrated to perform a PopPK analysis using the nonlinear mixed-effects modeling approach. Potential covariates were evaluated by using a stepwise method. Goodness-of-fit plot and bootstrap were performed to assess the model stability and predictive performance. Simulations were introduced to optimize dosing regimens of both the liver cancer and non-liver-cancer groups according to the guidance. The PK of tacrolimus was best described by a one-compartment model with first-order absorption and linear elimination, with weight and direct bilirubin as the significant covariates. In the process of constructing the basic model, we tried to separately estimate the PK parameters in liver cancer and non-liver-cancer populations. The results showed that the PK parameters in the two populations were similar, and the individual variation in Ka in non-liver-cancer subjects was large. Hence, the final model did not distinguish between the two populations. Moreover, a minor increase of less than 10% was observed in the simulated exposure in the patients preoperatively diagnosed with liver cancer compared with that in non-liver-cancer groups. The established PopPK model was capable of optimizing tacrolimus dosing in whole populations who underwent liver transplantation. Although a minimal difference was found in tacrolimus exposure between the liver cancer and non-liver-cancer groups, more research is warranted to explore the differences between the two populations in the future, given the potential limitations of this study.

Prediction of the Intra-T Lymphocyte Tacrolimus Concentration after Kidney Transplantation with Population Pharmacokinetic Modeling.

The intracellular tacrolimus concentration in CD3+ T lymphocytes is proposed to be a better representative of the active component of tacrolimus than the whole blood concentration. However, intracellular measurements are complicated. Therefore, the aim of this study was to describe the relationship between intracellular and whole blood tacrolimus concentrations in a population pharmacokinetic model. Twenty-eight de novo kidney transplant recipients, treated with a once-daily oral extended-release tacrolimus formulation, were followed during the first-month post-transplantation. Additional whole blood and intracellular tacrolimus concentrations were measured at day 6 ± 1 (pre-dose, 4 and 8 hours post-dose) and day 14 ± 3 (pre-dose) post-transplantation. Pharmacokinetic analysis was performed using nonlinear mixed effects modeling software (NONMEM). The ratio between intracellular (n = 109) and whole blood (n = 248) concentrations was best described by a two-compartment whole blood model with an additional intracellular compartment without mass transfer from the central compartment. The ratio remained stable over time. Prednisolone dose influenced the absorption rate of tacrolimus, while hemoglobin, CYP3A4*22 allele carrier, and CYP3A5 expresser status were associated with the oral clearance of tacrolimus (P-value < 0.001). Furthermore, the intracellular tacrolimus concentrations were correlated with the intracellular production of interleukin-2 (P-value 0.015). The intracellular tacrolimus concentration can be predicted from a measured whole blood concentration using this model, without the need for repeated intracellular measurements. This knowledge is particularly important when the intracellular concentration is ready to be implemented into clinical practice, to overcome the complexities of cell isolation and analytical methods.

Model-Informed Dosing Optimization of Tacrolimus for Concomitant Administration with Itraconazole to Japanese Lung Transplant Recipients.

Tacrolimus is an immunosuppressant administered to patients undergoing lung transplantation. Itraconazole is often concomitantly used with tacrolimus to prevent fungal infections and increase tacrolimus concentration. However, the pharmacokinetics of tacrolimus in Japanese lung transplant recipients and the effect of itraconazole on its pharmacokinetics have not been adequately evaluated. Population pharmacokinetic analysis was conducted to develop an optimal dose adjustment method for use upon itraconazole initiation in Japanese lung transplant recipients. This study comprised Japanese lung transplant recipients whose blood tacrolimus and itraconazole concentrations were measured between January 2017 and December 2019. A nonlinear mixed-effects modeling program was used to explore the covariates of tacrolimus pharmacokinetics and effects of concomitant itraconazole use. Using the model, the optimal initial tacrolimus dose was calculated and a dose adjustment method comprising concomitant itraconazole use was developed. A total of 1693 tacrolimus trough blood concentrations and 85 itraconazole trough plasma concentrations were obtained from 43 patients. Postoperative day, albumin level, and administration route were extracted as covariates for tacrolimus pharmacokinetics. The drug-drug interaction between tacrolimus and itraconazole could be predicted more accurately by considering the concentration-dependent inhibition of itraconazole. The optimal initial tacrolimus dose was 2.0 mg twice daily for tube and 1.5 mg twice daily for oral administration. To maintain the target concentration, the tacrolimus dose was reduced by 60% upon itraconazole initiation. This study is the first to use population pharmacokinetic analysis to assess the interaction between tacrolimus and itraconazole in patients who underwent lung transplantation. These results provide useful insights for optimizing the initial tacrolimus dose for concomitant itraconazole use.

Effect of CYP3A5 Gene Polymorphisms on Tacrolimus Blood Concentrations and Adverse Events in Allogeneic Hematopoietic Stem Cell Transplant Patients

BackgroundTacrolimus is the core basic immunosuppressant after transplantation. Cytochrome P450 3A5 (CYP3A5) is the main enzyme involved in tacrolimus metabolism, and rs776746A>G is the most frequently studied polymorphism in the CYP3A5 gene. The aim of this study was to investigate the effect of CYP3A5 gene polymorphisms on tacrolimus blood concentrations and acute graft versus host disease (GVHD) in patients with allogeneic hematopoietic stem cell transplantation (allo-HSCT). MethodsThis study included adult patients who received allo-HSCT at the First Affiliated Hospital of Wannan Medical College from January 2021 to June 2022, and received postoperative treatment with tacrolimus. Tacrolimus blood levels were obtained by fully automatic chemiluminescence immunoassay analyzer. Polymerase chain reaction/restriction fragment length polymorphism was used to genotype for CYP3A5*3 allelic variants. ResultsIn a total of 50 transplant patients, 30 patients were detected with CYP3A5*3/*3 genotype, 15 patients with CYP3A5*1/*3 genotype, and 5 patients with CYP3A5*1/*1 genotype. The initial tacrolimus blood concentrations in allo-HSCT patients with CYP3A5*1/*1, *1/*3, and *3/*3 genes were 7.75, 8.61, and 10.19 ng/mL, respectively; The initial blood concentration/dose (C/D) ratios were 4.08, 4.42 and 5.66 ng/(mL·mg), respectively. The C/D ratios of allo-HSCT patients carrying CYP3A5*1/*1, *1/*3, and *3/*3 genes were 4.35 and 4.71 and 5.58, 4.19, 4.56 and 5.71 ng/(mL·mg) in the second and 3rd weeks after operation. These results showed that the blood concentration and C/D ratio of tacrolimus in patients with CYP3A5*3/*3 genotype were significantly higher than those in patients with CYP3A5*1/*3 or CYP3A5*1/*1 genotype. Moreover, the incidence of acute GVHD after allo-HSCT in patients with CYP3A5*1/*1 genotype was significantly higher than that in patients with CYP3A5*1/*3 or CYP3A5*3/*3 genotype. ConclusionsMost patients carry the mutant allele CYP3A5*3. CYP3A5 gene polymorphisms affect tacrolimus blood concentrations and acute GVHD after allo-HSCT.

Factors associated with changes in tacrolimus blood concentration after food initiation in patients with ulcerative colitis.

The therapeutic effect of tacrolimus against ulcerative colitis (UC) is correlated with its trough blood concentration. Conventionally, oral tacrolimus for the treatment of UC is initiated under fasting conditions; once the symptoms improve, food intake is resumed. Tacrolimus blood concentration decreases with food intake compared with that under fasting conditions. The aim of this study was to explore the characteristics of patients with UC whose tacrolimus blood concentrations tended to decrease after food initiation. Medical data of 13 patients with UC and treated with tacrolimus were retrospectively obtained. The participant characteristics associated with the changes in tacrolimus blood concentrations after food initiation were analyzed using regression analysis based on the rate of decrease in the concentration/dose (C/D) ratio after food initiation. Single regression analysis showed that the number of days required from tacrolimus initiation to food resumption (P = 0.0071) and individual differences in the increase in tacrolimus blood concentration after administration (P = 0.0247) were significantly associated with the rate of decrease in the C/D ratio after food initiation. Furthermore, multiple regression analysis showed a significant effect of the number of days to food resumption (P = 0.0004) and individual differences in the increase in tacrolimus blood concentration after administration (P = 0.0012). The results suggest that the degree of change in blood tacrolimus concentration after food initiation may be related to the severity of the symptoms and pathology of UC. Early identification of participant characteristics may help control tacrolimus blood concentration fluctuations after food initiation.

Meta-analysis of the effects of CYP3A5*3 gene polymorphisms on tacrolimus blood concentration and effectiveness in Chinese patients with membranous nephropathy.

The study aimed to systematically evaluate the relationship between CYP3A5*3 gene polymorphisms and the blood concentration and effectiveness of tacrolimus (TAC) in patients with membranous nephropathy (MN). PubMed, Cochrane Library, Embase, Web of Science, China Biomedical, China National Knowledge Infrastructure, Wanfang, Vipshop, ReadShow, Clinical Trials Registry, and other databases were searched. Studies on the relationship between CYP3A5*3 gene polymorphism and TAC blood concentration in MN patients were collected, and meta-analysis was performed using Stata 16 software. A total of eight publications were included in the study, including 498MN patients. CYP3A5*3 gene polymorphisms are associated with tacrolimus blood levels in patients with MN. The results of the relationship between CYP3A5*3 genotype polymorphisms and tacrolimus blood trough concentrations of the AA + AG genotype were lower than those of the GG genotype at ≤1month [WMD = -2.08, 95% CI (-2.57, -1.59), p < 0.001] and 1-6months [WMD = -0.63, 95% CI (-0.98, -0.27), p < 0.001]; however, they were not statistically significant at ≥6months (p = 0.211). Furthermore, the subgroup analysis revealed that the dose-adjusted concentration of tacrolimus (C0/D) of the AA + AG genotype was lower than that of the GG genotype at ≤1month [SMD = -1.93, 95% CI (-2.79, -1.08), p < 0.001], 1-6months [SMD = -2.25, 95% CI (-2.71, -1.79), p < 0.001], and ≥6months [SMD = -2.36, 95% CI (-2.86, -1.86), p < 0.001]. In addition, there was no statistically significant difference in effectiveness between the two groups at 3, 6, and 12months of TAC administration (p > 0.05). Serum TAC concentrations in MN patients were correlated with CYP3A5*3 genotype polymorphisms. Detection of the CYP3A5*3 genotype before the administration of TAC may provide some clinical value for optimizing the treatment of MN patients. https://inplasy.com/, identifier [INPLASY202430083].

Influence of Genetic Polymorphisms in CYP3A5, CYP3A4, and MDR1 on Tacrolimus Metabolism after kidney transplantation

Kidney transplantation stands as the ultimate recourse for restoring vital organ functions, particularly in cases of end-stage kidney disease where alternative treatments, such as dialysis, prove less effective. With over 102,000 kidney transplants conducted globally in 2022, the demand for organ transplantation is ever-increasing, fueled by a rising incidence of end-stage renal disease attributed to causes like diabetes and hypertension.&lt;br /&gt; Despite significant advancements in kidney transplantation, immunosuppressive therapy remains crucial to preventing graft rejection. Tacrolimus (TAC), a calcineurin inhibitor, plays a pivotal role in this regard. Discovered in 1984, TAC inhibits T-lymphocyte activation, preventing acute rejection by disrupting the transcription of crucial genes involved in early T-cell activation. However, the use of TAC is not without challenges. The drug exhibits serious side effects, a narrow therapeutic index, and unpredictable pharmacokinetics. Therapeutic drug monitoring (TDM) becomes imperative in daily practice to maintain TAC blood concentrations within the therapeutic range. This literature review delves into the genetic aspects influencing TAC metabolism, focusing on key polymorphisms in CYP3A5, CYP3A4, and ABCB1 genes. Genetic variations in CYP3A5, a major enzyme in TAC metabolism, impact enzyme activity, necessitating personalized dosing strategies. CYP3A4 polymorphisms, especially CYP3A4*22, demonstrate associations with altered TAC clearance and dose requirements. The ABCB1 gene, encoding P-glycoprotein, another player in TAC pharmacokinetics, also exhibits polymorphisms influencing drug absorption and distribution. The ABCB1 3435C&amp;gt;T variant, in particular, shows potential implications on Tacrolimus bioavailability. Understanding these genetic variations aids in the development of personalized dosing regimens. Studies suggest that tailoring TAC doses based on CYP3A5 genotypes significantly improves the proportion of patients achieving therapeutic concentrations. Additionally, incorporating genetic information, particularly CYP3A4*22, into dosing strategies enhances the precision of TAC therapy, reducing the risk of adverse effects.

Tacrolimus Monitoring in Liver Transplant Recipients, Posttransplant Cholestasis: A Comparative Between 2 Commercial Immunoassays and a Liquid Chromatography-Tandem Mass Spectrometry Method.

Cholestasis commonly occurs after orthotopic liver transplantation. It can be extrahepatic because of mechanical obstruction or intrahepatic because of various causes. During cholestasis episodes, blood concentrations of tacrolimus (TAC) metabolites may increase, potentially affecting TAC concentrations measured by immunoassays. This study aimed to simultaneously evaluate the analytical performance of 2 TAC immunoassays, a quantitative microsphere system (QMS) immunoassay, and chemiluminescence microparticle immunoassay, using liquid chromatography-tandem mass spectrometry (LC-MS/MS) as a reference method in liver transplant recipients. This single-center study included 265 patients who underwent orthotopic liver transplantation. In total, 942 blood samples were collected. TAC trough concentrations were measured using LC-MS/MS and 2 immunoassays in parallel. The plasma concentrations of conjugated bilirubin were measured in all samples. The results were analyzed using Bland-Altman plots and Passing-Bablok regressions. The Bland-Altman plot analysis showed that the TAC QMS immunoassay has a significant bias (+37%) compared with LC-MS/MS, and this bias was higher in patients with cholestasis with hyperbilirubinemia (≤+70% in patients with conjugated bilirubin >150 µmol/L). In comparison, the chemiluminescence microparticle immunoassay showed acceptable analytical performance in patients with hyperbilirubinemia (bias <10%). In agreement with previous findings, the TAC QMS immunoassay showed a positive bias compared with LC-MS/MS. This bias is remarkably high in patients with cholestasis and hyperbilirubinemia, suggesting the cross-reactivity of TAC metabolites with the monoclonal antibody used in the QMS immunoassay.

The efficacy and safety of tacrolimus in treating refractory IgA vasculitis nephritis: a single-center retrospective study on 16 cases.

This study aimed to observe the efficacy and safety of tacrolimus in the treatment of refractory immunoglobulin A vasculitis nephritis (IgAVN). Sixteen patients with IgAVN who had been previously treated with cyclophosphamide shock therapy at least five times, some of whom had also received mycophenolate but still had persistent proteinuria, were enrolled. The clinical and pathological data were collected and analysed. The average (mean±standard deviation) age at the initial assessment for the group of 16 patients was 10±2.7years. Finally, at the end of their respective follow-up time point, 6 of the 16 patients achieved complete remission (37.5%), 5 achieved partial remission (31.2%), and 5 had no remission (31.2%). A significant difference was found in the median proteinuria before and after a 6-month course of tacrolimus treatment [19.2 (11.2, 31.9) vs 7.8 (4.3, 13.9) mg/kg/day] (P<.05). During the first 6months of tacrolimus treatment, all patients' estimated glomerular filtration rate levels remained normal. The mean tacrolimus blood concentration was 6.0±2.6ng/mL. The median prednisone dosage was decreased from 10mg/day to 5mg/day, and prednisone was eventually stopped in three individuals. No drug-related adverse effects were observed during treatment. Tacrolimus has demonstrated efficacy in increasing remission rates, significantly lowering urinary protein levels, and reducing steroid use in children with refractory IgAVN. Further research is required to investigate its optimal blood concentrations, long-term effects and renoprotective properties.

Effect of Voriconazole on Tacrolimus Blood Concentration in Renal Transplant Recipients after Voriconazole Discontinuation

Effect of Voriconazole on Tacrolimus Blood Concentration in Renal Transplant Recipients after Voriconazole Discontinuation

Interaction between tacrolimus and calcium channel blockers based on CYP3A5 genotype in Chinese renal transplant recipients.

To investigate the effect of calcium channel blockers (CCBs) on tacrolimus blood concentrations in renal transplant recipients with different CYP3A5 genotypes. This retrospective cohort study included renal transplant recipients receiving tacrolimus-based immunosuppressive therapy with or without CCBs in combination. Patients were divided into combination and control groups based on whether or not they were combined with CCBs, and then further analyzed according to the type of CCBs (nifedipine/amlodipine/felodipine). Propensity score matching was conducted for the combination and the control groups using SPSS 22.0 software to reduce the impact of confounding factors. The effect of different CCBs on tacrolimus blood concentrations was evaluated, and subgroup analysis was performed according to the patients' CYP3A5 genotypes to explore the role of CYP3A5 genotypes in drug-drug interactions between tacrolimus and CCBs. A total of 164 patients combined with CCBs were included in the combination groups. After propensity score matching, 83 patients with nifedipine were matched 1:1 with the control group, 63 patients with felodipine were matched 1:2 with 126 controls, and 18 patients with amlodipine were matched 1:3 with 54 controls. Compared with the controls, the three CCBs increased the dose-adjusted trough concentration (C0/D) levels of tacrolimus by 41.61%-45.57% (P < 0.001). For both CYP3A5 expressers (CYP3A5*1*1 or CYP3A5*1*3) and non-expressers (CYP3A5*3*3), there were significant differences in tacrolimus C0/D between patients using felodipine/nifedipine and those without CCBs (P < 0.001). However, among CYP3A5 non-expressers, C0/D values of tacrolimus were significantly higher in patients combined with amlodipine compared to the controls (P = 0.001), while for CYP3A5 expressers, the difference in tacrolimus C0/D values between patients with amlodipine and without was not statistically significant (P = 0.065). CCBs (felodipine/nifedipine/amlodipine) can affect tacrolimus blood concentration levels by inhibiting its metabolism. The CYP3A5 genotype may play a role in the drug interaction between tacrolimus and amlodipine. Therefore, genetic testing for tacrolimus and therapeutic drug monitoring are needed when renal transplant recipients are concurrently using CCBs.

Drug-drug interaction between tacrolimus and caspofungin in Chinese kidney transplant patients with different CYP3A5 genotypes.

The effect of drug-drug interaction between tacrolimus and caspofungin on the pharmacokinetics of tacrolimus in different CYP3A5 genotypes has not been reported in previous studies. To investigate the effect of caspofungin on the blood concentration and dose of tacrolimus under different CYP3A5 genotypes. We conducted a retrospective cohort study in The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital from January 2015 to December 2022. All kidney transplant patients were divided into the combination or non-combination group based on whether tacrolimus was combined with caspofungin or not. Patients were subdivided into CYP3A5 expressers (CYP3A5*1/*1 or CYP3A5*1/*3) and CYP3A5 non-expressers (CYP3A5*3/*3). Data from the combination and the non-combination groups were matched with propensity scores to reduce confounding by SPSS 22.0. A total of 200 kidney transplant patients receiving tacrolimus combined with caspofungin or not were enrolled in this study. Statistical analysis was conducted on the dose-corrected trough concentrations (C0/D) and dose requirements (D) of tacrolimus using independent sample two-sided t-test and nonparametric tests to investigate the impact on patients with different. In this study, the C0/D values of tacrolimus were not significantly different between the combination and non-combination groups (p = 0.054). For CYP3A5 expressers, there was no significant difference in tacrolimus C0/D or D values between the combination and non-combination groups (p = 0.359; p = 0.851). In CYP3A5 nonexpressers, the C0/D values of tacrolimus were significantly lower in the combination than in the non-combination groups (p = 0.039), and the required daily dose of tacrolimus was increased by 11.11% in the combination group. Co-administration of caspofungin reduced tacrolimus blood levels and elevated the required daily dose of tacrolimus. In CYP3A5 non-expressers, co-administration of caspofungin had a significant effect on tacrolimus C0/D values. An approximate 10% increase in the weight-adjusted daily dose of tacrolimus in CYP3A5 non-expressers is recommended to ensure the safety of tacrolimus administration.

Elevation of tacrolimus concentration after administration of methotrexate for treatment of graft-versus-host disease in pediatric patients received allogeneic hematopoietic stem cell transplantation

BackgroundMethotrexate (MTX) is used to treat graft-versus-host disease (GVHD) following allogeneic hematopoietic stem cell transplantation (allo-HSCT). Recently, a case was encountered in which the blood concentration of tacrolimus (TCR) at steady state increased after intravenous MTX administration for GVHD treatment (therapeutic IV-MTX administration). Therefore, this study aimed to investigate the effect of therapeutic IV-MTX administration on the pharmacokinetics of TCR.MethodsThis single-center, retrospective, observational study included patients who underwent allo-HSCT and received therapeutic IV-MTX administration during immunosuppressive therapy with continuous intravenous infusion (CIV) of TCR from April 2004 to December 2021. Here, each therapeutic IV-MTX administration was defined as a case and independently subjected to subsequent analyses. The blood concentration of TCR at steady state (Css), ratio of Css to daily TCR dose (C/D), and clinical laboratory data were compared before and after therapeutic IV-MTX administration. In addition, dose changes in the TCR after therapeutic IV-MTX administration were evaluated.ResultsTen patients (23 cases) were included in this study. The C/D value significantly increased after therapeutic IV-MTX administration (median: 697 vs. 771 (ng/mL)/(mg/kg), 1.16-fold increase, P < 0.05), indicating a reduction in the apparent clearance of TCR. Along with the increase in C/D, significant increases were observed in aspartate transaminase level (median: 51.0 vs. 92.9 U/L, P < 0.01) and alanine aminotransferase level (median: 74.5 vs. 99.4 U/L, P < 0.01) indicating that liver injury after therapeutic IV-MTX administration contributes to the observed C/D increase. In addition, the daily dose of TCR was reduced in 11 cases (47.8%) after therapeutic IV-MTX administration, and the relative frequency of dose reduction tended to be higher than that of dose increase (median: 37.5% vs. 0.0%, P = 0.0519, permuted Brunner-Munzel test). The magnitude of dose reduction was 18.8% (7.4–50.0%) in the 11 cases with dose reduction.ConclusionsTherapeutic IV-MTX administration cause a significant increase in C/D, which requires TCR dose reduction. Careful therapeutic drug monitoring of TCR is needed after therapeutic IV-MTX administration in patients receiving immunosuppressive therapy with TCR after allo-HSCT.

Clinical Effects of Tacrolimus Blood Concentrations Early after Allogeneic Hematopoietic Stem Cell Transplantation

Tacrolimus (TAC) plus short-term methotrexate (stMTX) is used for graft-versus-host disease (GVHD) prophylaxis after allogeneic hematopoietic stem cell transplantation (allo-HSCT). TAC blood concentrations are frequently adjusted to enhance the graft-versus-leukemia/lymphoma effect or attenuate severe GVHD. Limited information is available on the clinical impact of these adjustments and the optimal time to perform them in order to achieve good clinical outcomes. We retrospectively analyzed 211 patients who underwent allo-HSCT at our institutes. Higher TAC concentrations in week 3 correlated with a significantly higher cumulative incidence of relapse (CIR) (p=0.03) and lower non-relapse mortality (p=0.04). The clinical impact of high TAC concentrations in week 3 on CIR was detected in the refined disease risk index: low/intermediate (p=0.04) and high (p&amp;lt;0.01), and conditioning regimens other than cyclophosphamide/total body irradiation and busulfan/cyclophosphamide (p=0.07). Higher TAC concentrations in week 1 correlated with a lower grade 2-4 acute GVHD rate (p=0.01). Higher TAC concentrations in weeks 2 and 3 correlated with slightly lower (p=0.05) and significantly lower (p=0.02) grade 3-4 acute GVHD rates, respectively. Higher TAC concentrations in weeks 1 and 3 were beneficial for severe acute GVHD in patients with a human leukocyte antigen-matched donor (p=0.03 and p&amp;lt;0.01, respectively), not treated with anti-thymocyte globulin (p=0.02 and p=0.02, respectively), and receiving three stMTX doses (p=0.03 and p=0.02, respectively). The clinical impact of TAC concentrations varied according to patient characteristics, including disease malignancy, conditioning regimens, donor sources, and GVHD prophylaxis. These results suggest that TAC management needs to be based on patient profiles.

Influencing factors of post-transplantation diabetes mellitus in kidney transplant recipients and establishment of a risk prediction model.

The aim was to explore the influencing factors of post-trans-plantation diabetes mellitus (PTDM) in kidney transplant recipients and to es-tablish a risk prediction model. A retrospective analysis was performed on the clinical data of 408 patients subjected to kidney transplantation from May 2015 to March 2022. With the simple random sampling method, they were divided into a training set (n=306) and a test set (n=102) at a ratio of 3:1. According to the occurrence of PTDM, the training set was further classified into PTDM and non-PTDM groups. The influencing factors of PTDM were identified by least absolute shrinkage and selection operator and multivariate logistic regression analysis. A nomogram prediction model was constructed and validated. Non-PT-DM and PTDM groups had significantly different preoperative body mass index (BMI), family history of diabetes mellitus, 2-h preoperative and postprandial blood glucose, 2-hpreoperative and postprandial peptide index, postoperative hypomagnesemia, whole blood concentration of tacrolimus, triacylglycerol, glycated albumin and fasting blood glucose (P&lt;0.05). BMI, family history of diabetes mellitus, 2-h preoperative and postprandial blood glucose, and post-operative whole blood tacrolimus concentration were independent risk factors for PTDM. In contrast, the 2-h preoperative and postprandial peptide index was an independent protective factor (P&lt;0.05). The incidence of PTDM in patients receiving kidney transplantation correlates with the family history of diabetes mellitus, preoperative BMI, 2-h postprandial blood glucose, 2-h postprandial peptide index, and postoperative whole blood tacrolimus concentration.

Effects of CYP3A5 Genotypes on Thrombocytopenia in Liver Transplantation Patients Treated with Tacrolimus.

Thrombocytopenia is a complication after liver transplantation. This study's aims were to evaluate the role of CYP3A5 genotypes on tacrolimus-induced thrombocytopenia after orthotopic liver transplantation. In this retrospective case-control study, data from 100 patients who underwent deceased-donor liver transplantation (DDLT) were divided into CYP3A5*3 genotype (donor/recipient) tacrolimus fast- (A*/A*, n = 22), intermediate- (A*/GG, n = 20; GG/A*, n = 31) and slow-metabolizer (GG/GG, n = 27) groups. Platelet count changes and prognosis for 180 days after surgery were compared. Platelet counts declined significantly after DDLT, especially on postoperative day (POD) 3, and continued at low levels for a week thereafter in all groups. In the GG/GG group, platelet counts on POD3 (50.29 ± 5.44 × 109/L) were the lowest among the groups (A*/A*, 71.00 ± 6.22 × 109/L; A*/GG, 57.95 ± 6.21 × 109/L; GG/A*, 75.90 ± 5.56 × 109/L) (p = 0.006). Compared with the A*/A* genotype, tacrolimus nadir levels were significantly higher in GG/GG genotype patients, who also exhibited a higher incidence of hemorrhage (22.2%, p = 0.011). A combination of a nadir blood concentration of tacrolimus ≥ 4.74 ng/mL and spleen size ≥ 165.5 mm was a risk factor for increased thrombocytopenia after DDLT on POD3, with an AUC of 0.735 (sensitivity, 77.2%; specificity, 41.7%). A high blood concentration of tacrolimus after the early stage of DDLT is a major risk factor for hemorrhage. For the CYP3A5 genotype (GG/GG), controlling the blood concentration of tacrolimus below the target concentration until POD3 can avoid thrombocytopenia-related complications.