Xiaoyan Qiu

Association of MDR1, CYP3A4*18B, and CYP3A5*3 polymorphisms with cyclosporine pharmacokinetics in Chinese renal transplant recipients

ObjectiveThe objective of this study was to retrospectively evaluate the effects of MDR1, CYP3A4*18B, and CYP3A5*3 genetic polymorphisms on cyclosporine A (CsA) pharmacokinetics in Chinese renal transplant patients during the first month after transplantation.MethodsA total of 103 renal transplant recipients receiving CsA were genotyped for MDR1 (C1236T, G2677T/A, and C3435T), CYP3A4*18B, and CYP3A5*3. The predose and 2-h postdose concentrations of CsA (C0 and C2, respectively) were determined by fluorescence polarization immunoassay, and their relationships with corresponding genotypes and haplotypes were investigated.ResultsPatients with a CYP3A4*1/*1 genotype were found to have a higher dose-adjusted concentration compared with those with CYP3A4*18B/*18B, as follows: for C2, 19.3% (P = 0.008) during days 8-15, 35.2% (P = 0.008) during days 16–30, and for C0, 39.7% (P = 0.012) during days 16–30. The dose-adjusted C0 was higher in patients with MDR1 1236CC compared with those with 1236TT in the first month postoperation. The dose-adjusted C0 in patients with the CYP3A5*3/*3 genotype was 25.5% and 30.7% higher than those with the wild-type genotype during days 8–15 (P = 0.011) and days 16–30 (P = 0.015), respectively. Haplotype analysis revealed that the dose-adjusted C0 was higher in the first month following surgery in carriers of haplotype MDR1 CAC than in noncarriers. Polymorphisms of MDR1 and CYP3A5*3 did not affect dose-adjusted C2.ConclusionThe data suggests that the CYP3A4*18B genotype affects CsA pharmacokinetics during the first month following surgery in Chinese renal transplant recipients. Patients with CYP3A4*18B alleles may require higher doses of CsA to reach the target levels. Large prospective studies may be needed to further explore the impact of MDR1 and CYP3A5*3 polymorphisms on CsA pharmacokinetics in renal transplant recipients.

Association of ABCB1, CYP3A4*18B and CYP3A5*3 genotypes with the pharmacokinetics of tacrolimus in healthy Chinese subjects: a population pharmacokinetic analysis

What is known and Objective:  Tacrolimus (TAC) is metabolized mainly by the CYP3A subfamily and extruded into the intestine by P‐glycoprotein, which is encoded by the ABCB1 gene. Several studies have suggested that the CYP3A5*3 genotype influenced the pharmacokinetics (PK) of TAC. The CYP3A4*18B and CYP3A5*3 alleles are clinically important in Chinese subjects because of their relatively high frequency. The present study aimed at evaluating the effects of ABCB1 (C1236T‐G2677T/A‐C3435T), CYP3A4*18B and CYP3A5*3 genetic polymorphisms on TAC PK in healthy Chinese subjects.

Genetic association of FOXP3 gene polymorphisms with allograft rejection in renal transplant patients.

Aim:  FOXP3 gene is known to be important for regulatory T cell development and function, and is associated with the rejection of human kidney transplants. The present study was therefore conducted to determine the effect of FOXP3 polymorphisms on allograft rejection in renal transplant recipients.

External evaluation of published population pharmacokinetic models of tacrolimus in adult renal transplant recipients

AIM Several tacrolimus population pharmacokinetic models in adult renal transplant recipients have been established to facilitate dose individualization. However, their applicability when extrapolated to other clinical centres is not clear. This study aimed to (1) evaluate model external predictability and (2) analyze potential influencing factors. METHODS Published models were screened from the literature and were evaluated using an external dataset with 52 patients (609 trough samples) collected by postoperative day 90 via methods that included (1) prediction-based prediction error (PE%), (2) simulation-based prediction- and variability-corrected visual predictive check (pvcVPC) and normalized prediction distribution error (NPDE) tests and (3) Bayesian forecasting to assess the influence of prior observations on model predictability. The factors influencing model predictability, particularly the impact of structural models, were evaluated. RESULTS Sixteen published models were evaluated. In prediction-based diagnostics, the PE% within ±30% was less than 50% in all models, indicating unsatisfactory predictability. In simulation-based diagnostics, both the pvcVPC and the NPDE indicated model misspecification. Bayesian forecasting improved model predictability significantly with prior 2-3 observations. The various factors influencing model extrapolation included bioassays, the covariates involved (CYP3A5*3 polymorphism, postoperative time and haematocrit) and whether non-linear kinetics were used. CONCLUSIONS The published models were unsatisfactory in prediction- and simulation-based diagnostics, thus inappropriate for direct extrapolation correspondingly. However Bayesian forecasting could improve the predictability considerably with priors. The incorporation of non-linear pharmacokinetics in modelling might be a promising approach to improving model predictability.

External evaluation of population pharmacokinetic models for ciclosporin in adult renal transplant recipients

AIMS Several population pharmacokinetic (popPK) models for ciclosporin (CsA) in adult renal transplant recipients have been constructed to optimize the therapeutic regimen of CsA. However, little is known about their predictabilities when extrapolated to different clinical centres. Therefore, this study aimed to externally evaluate the predictive ability of CsA popPK models and determine the potential influencing factors. METHODS A literature search was conducted and the predictive performance was determined for each selected model using an independent data set of 62 patients (471 predose and 500 2-h postdose concentrations) from our hospital. Prediction-based diagnostics and simulation-based normalized prediction distribution error were used to evaluate model predictability. The influence of prior information was assessed using Bayesian forecasting. Additionally, potential factors influencing model predictability were investigated. RESULTS Seventeen models extracted from 17 published popPK studies were assessed. Prediction-based diagnostics showed that ethnicity potentially influenced model transferability. Simulation-based normalized prediction distribution error analyses indicated misspecification in most of the models, especially regarding variance. Bayesian forecasting demonstrated that the predictive performance of the models substantially improved with 2-3 prior observations. The predictability of nonlinear Michaelis-Menten models was superior to that of linear compartmental models when evaluating the impact of structural models, indicating the underlying nonlinear kinetics of CsA. Structural model, ethnicity, covariates and prior observations potentially affected model predictability. CONCLUSIONS Structural model is the predominant factor influencing model predictability. Incorporation of nonlinear kinetics in CsA popPK modelling should be considered. Moreover, Bayesian forecasting substantially improved model predictability.

NFATC1 genotypes affect acute rejection and long-term graft function in cyclosporine-treated renal transplant recipients

AIM To investigate the effects of SNPs in the cyclophilin A/calcineurin/nuclear factor of activated T-cells (NFATs) pathway genes (PPIA, PPP3CB, PPP3R1, NFATC1 and NFATC2) on cyclosporine (CsA) efficacy in renal transplant recipients. MATERIALS & METHODS Seventy-six tag SNPs were detected in 155 CsA-treated renal recipients with at least a 5-year follow-up. The associations of SNPs with acute rejection, nephrotoxicity, pneumonia and estimated glomerular filtration rate post transplant were explored. RESULTS NFATC1 rs3894049 GC was a risk factor for acute rejection compared with CC carriers (p = 0.0005). NFATC1 rs2280055 TT carriers had a more stable estimated glomerular filtration rate level than CC (p = 0.0004). CONCLUSION Detecting NFATC1 polymorphisms could help predict CsA efficacy in renal transplant patients.

FOXP3 rs3761549 polymorphism predicts long-term renal allograft function in patients receiving cyclosporine-based immunosuppressive regimen

AIM The present study was conducted to determine the effect of FOXP3 single nucleotide polymorphisms (SNPs) on clinical outcomes in CsA-treated renal transplant patients. METHODS A total of 166 renal transplant patients with at least 5years of follow-up were included. SNPs of FOXP3 gene (rs3761547, rs3761548, rs3761549, rs2232365 and rs2280883) were detected by Taqman probe technique. The associations of SNPs with acute rejection, CsA-induced nephrotoxicity, pneumonia and post-transplantation estimated glomerular filtration rate (eGFR) were explored. RESULTS Patients with rs3761549 T/TT genotype showed a more rapid decline in the eGFR level during the 5years following transplantation than those with the C/CC genotype (24.0% vs. 6.3%, P=0.004). All the SNPs and site-site interaction were not related to the occurrence of acute rejection, nephrotoxicity, and pneumonia. CONCLUSIONS FOXP3 rs3761549 was significantly correlated with the renal allograft function. It could be used to predict and improve the outcome of renal transplant patients taking CsA as an immunosuppressant.