Population pharmacokinetics of tacrolimus in children with nephrotic syndrome

Hao, Guo‐Xiang; Huang, Xin; Zhang, Dongfeng; Zheng, Yi; Shi, Haiyan; Li, Yan; Jacqz-Aigrain, Évelyne; Zhao, Wei

doi:10.1111/bcp.13605

Cited by 25 publications

(23 citation statements)

References 56 publications

(56 reference statements)

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“…Moreover, genetic polymorphism was not obtained in our previous study . The CYP3A5*3 genotype was identified as an important factor affecting TAC PPK in children after organ transplant Jacobo-Cabral et al, 2015;Prytuła et al, 2016;Andrews et al, 2018), which was also demonstrated in a previous study (Hao et al, 2018) mentioned above in children with PNS. Smaller TAC doses are usually required for CYP3A5*3/*3 carrier than for CYP3A5*1 carrier.…”

Section: Introductionsupporting

confidence: 73%

Population pharmacokinetic study of tacrolimus in pediatric patients with primary nephrotic syndrome: A comparison of linear and nonlinear Michaelis–Menten pharmacokinetic model

Huang

Liu

Jiao

et al. 2020

European Journal of Pharmaceutical Sciences

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BackgroundLittle is known about the population pharmacokinetics (PPK) of tacrolimus (TAC) in pediatric primary nephrotic syndrome (PNS). This study aimed to compare the predictive performance between nonlinear and linear PK models and investigate the significant factors of TAC PK characteristics in pediatric PNS. MethodsData were obtained from 71 pediatric patients with PNS, along with 525 TAC trough concentrations at steady state. The demographic, medical, and treatment details were collected. Genetic polymorphisms of CYP3A4*1G, CYP3A5*3, and ABCB1-C3435T were analyzed. The PPK models were developed using nonlinear mixed-effects model (NONMEM ® ) software. Two modeling strategies, linear compartmental and nonlinear Michaelis-Menten (MM) models, were evaluated and compared. ResultsBody weight, age, daily dose of TAC, co-therapy drugs (including azole antifungal agents and diltiazem), and CYP3A5*3 genotype were important factors in the final linear model (one-compartment model), whereas only body weight, co-therapy drugs, and CYP3A5*3 genotype were the important factors in the nonlinear MM model. Apparent clearance and volume of distribution in the final linear model were 7.13 L/h and 142 L, respectively.The maximal dose rate (Vmax) of the nonlinear MM model was 1.92 mg/day and the average concentration at steady state at half-Vmax (Km) was 1.98 ng/mL. The nonlinear model described the data better than the linear model.Dosing regimens were proposed based on the nonlinear PK model. ConclusionOur findings demonstrate that the nonlinear MM model showed better predictive performance than the linear compartmental model, providing reliable support for optimizing TAC dosing and adjustment in children with PNS.

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Section: Introductionsupporting

confidence: 73%

Population pharmacokinetic study of tacrolimus in pediatric patients with primary nephrotic syndrome: A comparison of linear and nonlinear Michaelis–Menten pharmacokinetic model

Huang

Liu

Jiao

et al. 2020

European Journal of Pharmaceutical Sciences

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“…45 T A B L E 2 Number and proportion of adverse drug events in clinical studies of tacrolimus in the treatment of nephrotic syndrome in children 31,32,[36][37][38][39][40][41][42][47][48][49][50]66 In the first population pharmacokinetic model of tacrolimus in children with nephrotic syndrome, body weight, CYP3A5 genotype had significant impact on tacrolimus pharmacokinetics. 93 The mean clearance/bioavailability (CL/F) of tacrolimus is in agreement with previously reported values of tacrolimus in paediatric kidney transplant patients. 94 However, tacrolimus appeared to have a much shorter half-life in paediatric nephrotic syndrome patients (about 9 h) than in children receiving kidney transplants (about 24 h).…”

Section: Pharmacokineticssupporting

confidence: 90%

“…In the first population pharmacokinetic model of tacrolimus in children with nephrotic syndrome, body weight, CYP3A5 genotype had significant impact on tacrolimus pharmacokinetics . The mean clearance/bioavailability (CL/F) of tacrolimus is in agreement with previously reported values of tacrolimus in paediatric kidney transplant patients .…”

Section: Introductionsupporting

confidence: 83%

Off‐label use of tacrolimus in children with glomerular disease: Effectiveness, safety and pharmacokinetics

Hao

Song

Zhang

et al. 2020

Brit J Clinical Pharma

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Glomerular diseases are leading causes of end‐stage renal disease in children. Tacrolimus is frequently used off‐label in the treatment of glomerular diseases. The effectiveness, safety and pharmacokinetic data of tacrolimus in the treatment of glomerular diseases in children are reviewed in this paper to provide evidence to support its rational use in clinical practice. The remission rates in previously published studies were different. In 19 clinical trials on children with nephrotic syndrome, the overall remission rate was 52.6‐97.6%. In four clinical trials on children with lupus nephritis, the overall remission rate was 81.8‐89.5%. In a pilot study with paediatric Henoch‐Schönlein purpura nephritis patients, the overall remission rate was 100.0%. Infection, nephrotoxicity, gastrointestinal symptoms and hypertension are the most common adverse events. Body weight, age, CYP3A5 genotype, cystatin‐C and daily dose of tacrolimus may have significant effects on the pharmacokinetics of tacrolimus in children with glomerular disease. More prospective controlled trials with long follow‐up are needed to demonstrate definitely the effectiveness, safety and pharmacokinetics of tacrolimus in children with glomerular diseases.

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“…The proportion of trials involving infants and newborns in China is lower than that in the paediatric randomised controlled drug trials published in 2007 11. In recent years, opportunistic sampling design, population pharmacokinetics model and model-based bridging approach have provided technical support for clinical trials of children’s drugs 12–14. China has also launched the construction of a clinical evaluation technology platform for children’s medicine, which will enhance the overall level of clinical research on children’s medicine in China 15.…”

Section: Discussionmentioning

confidence: 99%

Paediatric drugs trials in China

Hao

Yuan

Guo

et al. 2020

bmjpo

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ObjectiveClinical trials of children’s drugs are of great significance to rational drug use in children. However, paediatric drugs trials in China are facing complex challenges. At present, the investigation data on registration status of paediatric drug trials in China are still relatively lacking, and relevant research is urgently needed.MethodsThe advanced retrieval function is used to retrieve clinical trials data in the Clinical Trial.gov and Chinese Clinical Trial Registry databases in 22 April 2019. Fifteen key items were analysed to describe trial characteristics, including: registration number, study start date (year), mode of funding, type of disease, medicine type, research stage, research design, sample size, number of experimental groups, placebo group, blind method, implementation centre, child specific, newborn specific and participant age.ResultsA total of 1388 clinical trials of paediatric drugs conducted in China were registered. The number of paediatric drug trials grew steadily over time, from less than 20 per year before 2005 to more than 100 per year after 2012. Most clinical trials were postmarketing (n=800, 57.6%), single-centre (n=1045, 75.3%), intervention studies (n=1161, 83.6%) without blinded methods (1169, 84.2%) and funded by non-profit organisations (n=838, 60.4%). The number of clinical trials for antineoplastic agents (n=254, 18.3%), anti-infectives (n=156, 11.2%) and vaccines (n=154, 11.1%) is the largest.ConclusionPaediatric drug trials in China made a significant progress in recent years. Innovative method and trial design optimisation should be encouraged to accelerate paediatric clinical research. Pharmaceutical companies need to be further stimulated to carry out more high-quality paediatric clinical trials with support of paediatric drug legislation.

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Population pharmacokinetics of tacrolimus in children with nephrotic syndrome

Abstract: The PPK of TAC was estimated in children with NS and a CYP3A5 genotype-based dosing regimen was set up based on simulations.

Cited by 25 publications

References 56 publications

Population pharmacokinetic study of tacrolimus in pediatric patients with primary nephrotic syndrome: A comparison of linear and nonlinear Michaelis–Menten pharmacokinetic model

Population pharmacokinetic study of tacrolimus in pediatric patients with primary nephrotic syndrome: A comparison of linear and nonlinear Michaelis–Menten pharmacokinetic model

Off‐label use of tacrolimus in children with glomerular disease: Effectiveness, safety and pharmacokinetics

Paediatric drugs trials in China

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