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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. [ABSTRACT FROM AUTHOR]

1. Several tacrolimus population pharmacokinetic (PPK) models in hematopoietic stem cell transplantation (HSCT) patients have been set up to recommend an optimal dosage schedule. However, the PPK model of Chinese pediatric HSCT patients has not been reported. The study is to investigate whether published PPK models of HSCT patients can be used to simulate Chinese pediatric HSCT patients and establish the tacrolimus PPK model of Chinese pediatric HSCT patients. 2. Published PPK models were collected from the literature and assessed using Chinese pediatric HSCT patients via the individual prediction error method. The establishment of tacrolimus PPK model in Chinese pediatric HSCT patients was characterized with nonlinear mixed-effects modeling (NONMEM). 3. Three published HSCT PPK models were identified, two of which could be applied to our external dataset. However, these models were dissatisfactory in terms of individual prediction error and, hence, inadequate for extrapolation. Finally, a new tacrolimus PPK model in Chinese pediatric HSCT patients was established. Based on the simulation results of our model, new initial dosage suggestions were recommended. In conclusion, the tacrolimus PPK model in Chinese pediatric HSCT patients was presented and the model could be used to predict individualized dosing regimens in children with HSCT. [ABSTRACT FROM AUTHOR]

Survival for pediatric liver transplantation patients is limited by nephrotoxicity of calcineurin inhibitors tacrolimus. The present study was to explore the association of genetic factors with nephrotoxicity of pediatric liver transplantation patients treated with tacrolimus. Chinese pediatric liver transplantation patients under tacrolimus therapy between March 2014 and August 2018 from Children's Hospital of Fudan University were retrospectively analyzed. A total of 15 patients, including 6 patients with nephrotoxicity induced by tacrolimus and 9 patients without nephrotoxicity, were detected by pharmacogenomics (PGxOne®160). Demographic characteristics and laboratory testing were collected from medical logs. Tacrolimus blood concentrations were extracted from therapeutic drug monitoring (TDM) documents. The risk of renal toxicity induced by tacrolimus in Chinese pediatric liver transplantation patients were positively associated with T allele of cytochrome P450 1A2 (CYP1A2) rs2470890 (RR = 2.857, 95% confidence interval = [1.392–5.863]), A allele of dopamine D2 (DRD2) rs1076560 (RR = 4.375, 95% confidence interval = [1.148–16.676]), T allele of paraoxonase-1 (PON1) rs662 (RR = 2.800, 95% confidence interval= [1.184–6.622]), respectively. Pharmacogenomics analysis in Chinese pediatric liver transplantation patients with renal toxicity induced by tacrolimus was firstly reported. The SNPs in 3 genes (CYP1A2, DRD2, and PON1) were associated with risk of tacrolimus-induced nephrotoxicity [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: To investigate the mRNA and protein expression of FK506-binding protein 52 (FKBP52) in the chorionic villi of patients with recurrent spontaneous abortion (RSA) and normal women during early pregnancy. Methods: Fresh chorionic villus tissues were collected from 60 subjects. A total of 30 patients with a history of RSA were enrolled into the RSA group and 30 normal pregnant women were enrolled into the control group. The FKBP52 mRNA expression levels in chorionic villi of the RSA patients and healthy controls were measured via semiquantitative RT-PCR. The protein distribution and expression levels of FKBP52 in chorionic villi were analyzed through immunohistochemistry (IHC). The correlation between FKBP52 expression and RSA was analyzed. Results: We demonstrated that FKBP52 mRNA is expressed in chorionic villi samples of normal pregnancy and RSA. RSA patients exhibited significantly lowerFKBP52gene expression levels compared with those in normal pregnancies (p < 0.05). FKBP52 immunoreactivity in chorionic villi was mainly observed in trophoblast cell cytoplasm. The FKBP52 protein expression levels in the chorionic villi of RSA patients was significantly lower than in normal women during pregnancy (p < 0.05). Conclusions: FKBP52 protein levels were decreased in the chorionic villi of RSA patients, which indicate that the decrease in FKBP52 may be associated with RSA. The low FKBP52 mRNA expression level, which is consistent with the IHC result, may affect embryonic development and even lead to abortion. FKBP52 may be involved in the pathogenesis of RSA and new therapies that increase the FKBP52 expression may help treat RSA. [ABSTRACT FROM AUTHOR]