Dosage Optimization Based on Population Pharmacokinetic Analysis of Tacrolimus in Chinese Patients with Nephrotic Syndrome

Lu, Tianlan; Zhu, Xu; Xu, Shoufang; Zhao, Mingming; Huang, Xueshi; Wang, Zhan-You; Zhao, Limei

doi:10.1007/s11095-019-2579-6

Cited by 18 publications

(14 citation statements)

References 48 publications

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“…For genetic factors, CYP3A genetic polymorphisms including CYP3A5*3 rs776746, 22 CYP3A4*1G rs2242480, 19 , 20 CYP3A4 rs4646437; 21 genetic polymorphisms of NF-κB/PXR metabolism pathway proteins including NFKB1 rs28362491 24 , 25 and NR1I2 rs2276707; 23–25 and immune-related genes including IL-3 rs181781 21 may influence the expression of CYP3A and play important roles in nifedipine metabolism. In addition, the multidrug resistance gene MDRD1 , which encodes P-gp, was reported to be involved in the transport of nifedipine.…”

Section: Discussionmentioning

confidence: 99%

“…The DNA for genomic analysis was extracted using a commercially available EZNA ® SQ Blood DNA Kit II. Through the Sanger dideoxy DNA sequencing method with the ABI 3730xl sequencer (ABI Co., Sangon Biotech Co. Ltd. Shanghai, China), CYP3A4 * 1G rs2242480, 19 , 20 CYP3A4 rs4646437, 21 CYP3A5 * 3 rs776746, 22 NR1I2 rs2276707, 23–25 NF-κB rs28362491, 24 , 25 IL-3 rs181781, 21 and MDRD1 -C3435T rs1045642 26 , 27 were detected, all of which may influence the expression of CYP3A and/or play important roles in nifedipine disposal.…”

Section: Methodsmentioning

confidence: 99%

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Population Pharmacokinetic Modelling for Nifedipine to Evaluate the Effect of Parathyroid Hormone on CYP3A in Patients with Chronic Kidney Disease

Pei

et al. 2022

DDDT

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Purpose Parathyroid hormone (PTH) can induce the downregulation of CYP3A in chronic kidney disease (CKD). Nevertheless, the effect of PTH on CYP3A-mediated clearance pathways from a clinical perspective remains unclear. Methods This study employed population pharmacokinetic (PopPK) modeling to delineate potential changes in CYP3A activity in patients with CKD. Pharmacokinetic data for nifedipine, a typical CYP3A substrate, as well as covariate information, were prospectively collected from 157 patients with a total of 612 concentrations. PopPK data analysis was performed using a nonlinear mixed-effects model. Results The pharmacokinetics of nifedipine were optimally described according to a one-compartment model with zero-order absorption and first-order elimination. The estimated population parameters (and interindividual variability) were apparent clearance (CL/F) 49.61 L/h (58.33%) and apparent volume of distribution (V/F) 2300.26 L (45.62%), and the PTH level negatively correlated with CL/F. In comparison with the reference level, it was observed that the dosage of nifedipine should be reduced with the maximum boundary value of PTH, after a Monte Carlo simulation. Conclusion This study provides insight into the effects of PTH on CYP3A-mediated clearance pathways. Moreover, PTH could be used as a guide for the appropriate administration of CYP3A eliminated drugs in patients with CKD.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Population Pharmacokinetic Modelling for Nifedipine to Evaluate the Effect of Parathyroid Hormone on CYP3A in Patients with Chronic Kidney Disease

Pei

et al. 2022

DDDT

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“…Research in Chinese patients with nephrotic syndrome found that the NR1I2 rs2276707 TT variant carriers had 1.17-fold CL/F compared with the CC/CT variant carriers. 41 Patients with the CT or TT genotype who are undergoing kidney transplantation may have decreased dose-adjusted trough concentrations of tacrolimus compared with patients with the CC genotype. 9 Although the study subjects are different, the above reports are consistent with our findings in liver transplant patients in China.…”

Section: Discussionmentioning

confidence: 99%

Effects of Postoperative Day and NR1I2 on Tacrolimus Clearance in Chinese Liver Transplant Recipients—A Population Model Approach

Cui³

et al. 2021

Clinical Pharm in Drug Dev

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We aimed to explore the new biomarkers influencing tacrolimus in vivo behavior in Chinese liver transplant recipients. A total of 418 drug concentration samples of 41 liver transplant patients were collected for modeling. A population pharmacokinetic model was developed using the nonlinear mixed-effects modeling approach. The potential covariates, such as postoperative day (POD), age, body weight, hepatic and renal function, and recipient genetic polymorphisms (ABCB1, CYP3A4, CYP3A5, NR1I2) were evaluated using forward-inclusion and backward-elimination methods. A 1-compartment model was used describing the in vivo behavior of tacrolimus in liver transplant patients. The estimates of CL/F and V/F were 8.88 L/h and 495.82 L, respectively. Two covariates, POD and NR1I2 rs2276707 genotypes, were incorporated into the final population pharmacokinetic model, and they could significantly impact the CL/F: CL/F (L/h) = 8.88 × (POD/16) 0.18 × e 0.91 × NR1I2 × e ηCL . The model evaluation and validation indicated a stable and precise performance of the final model. The functional annotation using ENCODE data indicated that rs2276707 was located on the higher peak of the H3K4Me1 and H3K4Me3 histone marker. To our knowledge, this is the first report indicating NR1I2 rs2276707 genotypes is another biomarker impacting tacrolimus clearance in liver transplant recipients. The NR1I2 gene polymorphism may affect the in vivo behavior of tacrolimus by regulating gene expression.

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“…Population pharmacokinetic models may be useful in predicting individualized therapy by integrating different effects of variables on drug exposure ( 76 ), which may determine the initial dosage in different diseases. This includes dose simulation of oxcarbazepine in pediatric patients with epilepsy ( 77 ), dose optimization of vancomycin in neonates and young infants ( 78 ), dose optimization of azithromycin in pediatric patients with community-acquired pneumonia ( 79 ), dose optimization of cyclosporin in pediatric patients with hemophagocytic lymphohistiocytosis ( 80 ) and dose optimization of tacrolimus in patients with nephritic syndrome ( 81 , 82 ). Thus, the present study aimed to establish a population pharmacokinetic model of tacrolimus and further optimize the initial dosage regimen of tacrolimus in pediatric and adolescent patients with LN.…”

Section: Discussionmentioning

confidence: 99%

Population pharmacokinetics model and initial dose optimization of tacrolimus in children and adolescents with lupus nephritis based on real‑world data

Chen

Wang

et al. 2020

Exp Ther Med

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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.

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Dosage Optimization Based on Population Pharmacokinetic Analysis of Tacrolimus in Chinese Patients with Nephrotic Syndrome

Cited by 18 publications

References 48 publications

Population Pharmacokinetic Modelling for Nifedipine to Evaluate the Effect of Parathyroid Hormone on CYP3A in Patients with Chronic Kidney Disease

Population Pharmacokinetic Modelling for Nifedipine to Evaluate the Effect of Parathyroid Hormone on CYP3A in Patients with Chronic Kidney Disease

Effects of Postoperative Day and NR1I2 on Tacrolimus Clearance in Chinese Liver Transplant Recipients—A Population Model Approach

Population pharmacokinetics model and initial dose optimization of tacrolimus in children and adolescents with lupus nephritis based on real‑world data

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