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Purpose: The present study aims to explore the effects of tacrolimus on proteinuria in patients with idiopathic membranous nephropathy (IMN) and recommend an appropriate dosage schedule via machine learning method., Methods: The E max model was constructed to analyze the effects of tacrolimus on proteinuria in patients with IMN. Data were mined from published literature and machine learning was built up with E max model, among which the efficacy indicator was proteinuria change rates from baseline. 463 IMN patients were included for modeling, and tacrolimus therapeutic window concentrations were 4-10 ng/ml., Results: In machine learning model, the E max from tacrolimus effecting proteinuria in IMN patients was -72.7%, the ET 50 was 0.43 months, and the time to achieving 25% E max , 50% E max , 75% E max , and 80% (plateau) E max of tacrolimus on proteinuria in patients with IMN were 0.15, 0.43, 1.29, and 1.72 months, respectively., Conclusion: For achieving better therapeutic effects from tacrolimus on proteinuria in patients with IMN, tacrolimus concentration range need to be maintained at 4-10 ng/ml for at least 1.72 months., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: The treatment of tacrolimus-induced post-transplantation diabetes mellitus (PTDM) has become a hot topic to improve the long-term survival of organ transplant patients, however whose pathogenesis has not been fully elucidated. In pancreas, the up-regulation of NF-κB has been reported to stimulate cytokine IL-1β/TNF-α secretion, inducing pancreatic injury, meanwhile other studies have reported the inhibitory effect of rapamycin on NF-κB., Purpose: The aim of this study was to clarify the mechanism of tacrolimus-induced pancreatic injury and to explore the potential effect from small dose of sirolimus., Methods: Wistar rats were randomly divided normal control (NC) group, PTDM group, sirolimus intervention (SIR) group. Transcriptomic analysis was used to screen potential mechanism of PTDM. Biochemical index detections were used to test the indicators of pancreatic injury. Pathological staining, immumohistochemical staining, immunofluorescent staining, western blot were used to verify the underlying mechanism., Results: Compared with NC group, the level of insulin was significant reduction (P < 0.01), inversely the level of glucagon was significantly increase (P < 0.01) in PTDM group. Transcriptomic analysis indicated Syk/BLNK/NF-κB signaling was significantly up-regulated in PTDM group. Pathological staining, immumohistochemical staining, immunofluorescent staining, western blot verified Syk/BLNK/NF-κB and TNF-α/IL-1β were all significantly increased (P < 0.05 or P < 0.01), demonstrating the mechanism of tacrolimus-induced pancreatic injury via Syk/BLNK/NF-κB signaling. In addition, compared with PTDM group, the levels of weight, FPG, AMY, and GSP in SIR group were significant ameliorative (P < 0.05 or P < 0.01), and the expressions of p-NF-κB, TNF-α/IL-1β in SIR group were significantly reduction (P < 0.05 or P < 0.01), showing Syk/BLNK/NF-κB signaling promoted pancreatic injury induced by tacrolimus and potential protective effect from rapamycin reducing NF-κB., Conclusion: Syk/BLNK/NF-κB signaling promotes pancreatic injury induced by tacrolimus and rapamycin has a potentially protective effect by down-regulating NF-κB. Further validation and clinical studies are needed in the future., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

What Is Known and Objectives: The initial tacrolimus dose regimen in paediatric lung transplant recipients is unknown. The present study optimized the initial tacrolimus dose regimen for paediatric lung transplant recipients., Methods: This study was based on a published population pharmacokinetic model of tacrolimus in lung transplant recipients and used Monte Carlo simulations to recommend an initial dose regimen of tacrolimus in paediatric lung transplant recipients., Results: Without voriconazole, the tacrolimus doses recommended for paediatric lung transplant recipients who were not CYP3A5*1 carriers were 0.02, 0.03, and 0.04 mg/kg/day, split into two doses, for weights of 10-16, 16-30, and 30-40 kg, respectively. For paediatric lung transplant recipients who were CYP3A5*1 carriers, the tacrolimus doses of 0.03, 0.04, 0.05, and 0.06 mg/kg/day, split into two doses, were recommended for weights of 10-16, 16-25, 25-30, and 30-40 kg, respectively. With voriconazole, the tacrolimus dose recommended for paediatric lung transplant recipients who were not CYP3A5*1 carriers was 0.02 mg/kg/day, split into two doses, for weights of 10-40 kg. For paediatric lung transplant recipients who were CYP3A5*1 carriers, tacrolimus doses of 0.02 and 0.03 mg/kg/day, split and two doses, were recommended for weights of 10-24 and 24-40 kg, respectively., What Is New and Conclusions: This study developed tacrolimus dose regimens for the first time for paediatric lung transplant recipients using Monte Carlo simulation and optimized initial dosage in paediatric lung transplant recipients., (© 2022 John Wiley & Sons Ltd.)

What Is Known and Objectives: Tacrolimus is used to treat patients with lupus nephritis; however, its time course and dose effect on proteinuria in lupus nephritis patients remain unknown. The purpose of this study was to determine the time course and dose effect of tacrolimus on proteinuria in lupus nephritis patients via model-based meta-analysis (MBMA)., Methods: PubMed, Web of Science, Cochrane Library and ClinicalTrials.gov databases were systematically searched for information on the efficacy of tacrolimus against proteinuria in lupus nephritis patients. Useful data were extracted to build a model for the population studied using a non-linear mixed-effect model (NONMEM). This model was applied to simulate time course of tacrolimus on proteinuria using Monte Carlo simulations., Results: Ten clinical studies that recruited 222 patients with lupus nephritis were included. Based on various diagnostic plots, we found that the established model described the observed data reasonably well. In addition, the typical E max and ET 50 of tacrolimus for 24-hour proteinuria in lupus nephritis patients were -5.88 g and 0.37 months, respectively. The baseline value of 24-hour proteinuria affected E max . No significant dose-response relationship was observed in the range of tacrolimus concentration used in the present study (3-10 ng/mL), indicating that the effect of tacrolimus on proteinuria depends on effective concentration range and not the dose. However, the time course relationship was obvious; the efficacy of tacrolimus increased over time, reaching a plateau (80% E max ) at approximately 1.48 months from the beginning of treatment., What Is New and Conclusion: When the concentration range of tacrolimus is maintained at 3-10 ng/mL, at least 1.48 months of treatment is required to achieve a better outcome with regard to proteinuria in lupus nephritis patients., (© 2020 John Wiley & Sons Ltd.)

The present study aimed to optimize the tacrolimus initial dosing scheme in pediatric refractory nephrotic syndrome patients based on population pharmacokinetics and pharmacogenomics.Demographic characteristics, concomitant medication, laboratory data, pharmacogenomics were collected to build the model and Monte Carlo was used to simulate the optimization of initial dosing scheme.Weight, the polymorphisms of CYP3A5 , and concomitant medication of wuzhi-capsule were included into the covariates affecting tacrolimus clearance. In addition, with the same weight, there was difference in tacrolimus clearance in patients who carry CYP3A5*3/*3 and no coadministration of wuzhi-capsule, patients who carry CYP3A5*1 allele and no coadministration of wuzhi-capsule, patients who carry CYP3A5*3/*3 and coadministration of wuzhi-capsule, patients who carry CYP3A5*1 allele and coadministration of wuzhi-capsule, and their clearance ratios were 1:1.5:0.697:1.0455, respectively. Based on the differences of clearance in the above cases, we simulated different dosing regimens and obtained the optimal initial dose in each case.The present study recommended the tacrolimus initial dosing scheme in pediatric refractory nephrotic syndrome patients based on CYP3A5 genotype and coadministration with wuzhi-capsule.

Background: The purpose of our research was to recommend the initial tacrolimus dosage for Chinese pediatric patients undergoing kidney transplantation based on population pharmacokinetics and pharmacogenetics., Methods: Demographic data, laboratory results, drug combinations, and pharmacogenetics from Chinese pediatric patients undergoing kidney transplantation were analyzed using non-linear mixed-effects modeling. A Monte Carlo simulation was performed to evaluate the optimal initial dose of tacrolimus., Results: Body weight and post-transplant days, combined with wuzhi-capsule (WZ, extracted from schisandra sphenanthera, whose primary efficient constituents are schisantherin A, schisandrol B, schisandrin, etc., and often used to treat drug-induced hepatitis in Chinese organ transplant patients) and CYP3A5 polymorphisms, influenced the clearance of tacrolimus in these patients. With same weight and post-transplant days, tacrolimus clearance rates from patients carrying CYP3A5*3/*3 and without WZ, carrying CYP3A5*1 allele and without WZ, carrying CYP3A5*3/*3 and with WZ, carrying CYP3A5*1 allele and with WZ were 1, 1.6, 0.72, and 1.152, respectively. In addition, the initial dose for each condition is recommended., Conclusions: The initial dosage recommendations in the tacrolimus instructions were not individualized, and we have developed more accurate initial doses based on weight and the CYP3A5 genotype. In addition, lower initial doses are recommended with concurrent use of WZ.

1. Numerous tacrolimus population pharmacokinetic (PPK) models in pediatric liver transplantation patients have been established to define an optimal dose schedule. However, the applicability of extrapolating these PPK models to our clinical center remains unknown. The goals of the present study was to evaluate model external predictiveness and establish a new model applicable to traditional therapeutic drug monitoring data.2. Published PPK models were collected from the literature and assessed using our real-world dataset including 41 pediatric liver transplantation patients via the individual prediction error method. The establishment of a new model was characterized using non-linear mixed-effects modeling.3. Nine published pediatric liver transplantation PPK models were identified, three of which could be applied to our real-world dataset. However, these models were dissatisfactory in terms of individual prediction error and hence, inadequate for extrapolation. Finally, a new model applicable to our real-world dataset was established as follows: CL/ F  = 22.9 × (WT/70) 0.75 × (1 - WZ × 0.264) × (1 - FCZ × 0.338) × (1 + ASPI × 0.281) × (POD/41) 0.0486 L/h; V / F  = 906 × (WT/70) L. Where WT, WZ, FCZ, ASPI and POD were weight, Wuzhi capsule, fluconazole, aspirin and post-transplantation day, respectively. In conclusion, published models were inadequate for application to our real-world dataset. The present study produced a new model applicable to our real-world study data.

What Is Known and Objectives: Tacrolimus is widely used for kidney transplantation in children. However, the narrow therapeutic window and considerable interindividual and intraindividual variabilities make tacrolimus untoward to design an optimum dosage for paediatric personalized medicine. Our research aims to establish the tacrolimus population pharmacokinetics (PPK) of Chinese paediatric kidney transplantation patients and to distinguish covariates impacting variabilities., Methods: Chinese paediatric kidney transplantation patients treated with tacrolimus between January 2014 and April 2018 from Children's Hospital of Fudan University were retrospectively analysed. A total of 51 Chinese paediatric kidney transplantation patients were analysed using non-linear mixed effects modelling (NONMEM). The effects of population characteristics, biological features and drug combination were assessed. The final PPK model was evaluated using visual inspection of routine diagnostic plots and the internal validation method of bootstrap., Results: Our data met the condition of a one-compartment model, and the final model was CL/F = 32.7 × (WT/70) 0.75  × (1 - WZ × 0.341) × (HGB/97) -0.508 ; V/F = 1890 × (WT/70) × (POD/57) 0.816 , where WT, WZ, HGB and POD were weight, Wuzhi capsule (extracted from schisandra sphenanthera, whose primary efficient constituents are schisantherin A, schisandrol B, schisandrin etc, and often used to treat drug-induced hepatitis in Chinese organ transplant patients), haemoglobin and post-transplant day, respectively., What Is New and Conclusion: The tacrolimus PPK model in Chinese paediatric kidney transplantation patients was developed, and Wuzhi capsule and haemoglobin influence tacrolimus elimination in paediatric kidney transplantation patients., (© 2019 John Wiley & Sons Ltd.)

Aim: To investigate the effect of the ''minimizing tacrolimus'' strategy on long-term survival of patients after liver transplantation (LT)., Methods: We conducted a retrospective study of 319 patients who received LT between January 2009 and December 2011 at the First Affiliated Hospital of Zhejiang University School of Medicine. Following elimination of ineligible patients, 235 patients were included in the study. The relationship between early tacrolimus (TAC) exposure and survival period was analyzed by Kaplan Meier curves. Adverse effects related to TAC were evaluated by the χ(2) test. Routine monitoring of blood TAC concentration (TC) was performed using the PRO-Trac(TM) II Tacrolimus Elisa Kit (Diasorin, United States)., Results: Of 235 subjects enrolled in the study, 124 (52.8%) experienced adverse effects due to TAC. When evaluating mean TC, the survival time of patients with a mean TC < 5 ng/mL was significantly shorter than that in the other groups (911.3 ± 131.6 d vs 1381.1 ± 66.1 d, 911.3 ± 131.6 d vs 1327.3 ± 47.8 d, 911.3 ± 131.6 d vs 1343.2 ± 83.1 d, P < 0.05), while the survival times of patients with a mean TC of 5-7, 7-10 and 10-15 ng/mL were comparable. Adverse effects due to TAC in all four groups were not significantly different. When comparing the standard deviation (SD) of TC among the groups, the survival time of patients with a SD of 2-4 was significantly longer than that in the other groups (1388.8 ± 45.4 d vs 1029.6 ± 131.3 d, 1388.8 ± 45.4 d vs 1274.9 ± 57.0 d, P < 0.05), while in patients with a SD < 2 and SD > 4, the survival time was not statistically different. Adverse effects experienced in all three groups were not statistically different. In Cox regression analysis, male patients and those with a primary diagnosis of benign disease, mean TC > 5 ng/mL and TC SD 2-4 had better outcomes., Conclusion: The early ''minimizing tacrolimus'' strategy with a mean TC of 5-10 ng/mL and SD of 2-4 was beneficial in terms of long-term survival after LT.

The present study aimed to establish a population pharmacokinetics model of tacrolimus and further optimize the initial dosing regimen of tacrolimus in pediatric and adolescent patients with lupus nephritis (LN). Pediatric and adolescent patients with LN were recruited between August 2014 and September 2019 at the Children's Hospital of Fudan University (Shanghai, China). Relevant information was used to set up a population pharmacokinetics model with a Nonlinear Mixed Effect Model and the initial dosage regimen was simulated with the Monte Carlo method. Body weight and co-administration of wuzhi capsule were indicated to influence tacrolimus clearance in pediatric and adolescent patients with LN, and at the same body weight, the rate of tacrolimus clearance in patients without vs. with co-administration of wuzhi capsule was 1:0.71. In addition, in patients who were not administered wuzhi capsule, an initial dosage regimen of 0.15 mg/kg/day was recommended for a body weight of 10-23 kg and 0.10 mg/kg/day for 23-60 kg; in patients who were administered wuzhi capsule, an initial dosage regimen of 0.10 mg/kg/day was recommended for a body weight of 10-23 kg and 0.05 mg/kg/day for 23-60 kg. To the best of our knowledge, the present study was the first to establish a population pharmacokinetics model of tacrolimus in order to determine the optimal initial dosage regimen of tacrolimus in pediatric and adolescent patients with LN. [ABSTRACT FROM AUTHOR]