Dataset Information

Population pharmacokinetics of tacrolimus in children with nephrotic syndrome.

ABSTRACT: AIMS:Nephrotic syndrome (NS) is the most common clinical manifestation of glomerular disease in children. Currently, tacrolimus (TAC) is widely used in children with NS. However, pharmacokinetic data in children with nephrotic syndrome is limited. This study was intended to evaluate the population pharmacokinetics (PPK) of TAC in paediatric NS and to optimize dosing regimen. METHODS:Blood samples from NS children treated with TAC were collected and the blood concentrations of TAC were detected using HPLC-MS/MS. A PPK model was developed using NONMEM software. Pharmacogenetic analysis was carried out in the CYP3A5 gene. RESULTS:The data from 28 children were used for PPK analysis. A one-compartment model and first-order elimination were accorded with the TAC data in paediatric NS. A covariate analysis showed that body weight and CYP3A5 genotype significantly affected TAC pharmacokinetics. Monte Carlo simulation indicated that NS children with CYP3A5*3/*3 receiving 0.10 mg kg-1 dose-1 twice daily and NS children with CYP3A5*1 receiving 0.25 mg kg-1 dose-1 twice daily TAC could achieve the target concentrations of 5-10 ng ml-1 . CONCLUSION:The PPK of TAC was estimated in children with NS and a CYP3A5 genotype-based dosing regimen was set up based on simulations.

SUBMITTER: Hao GX

PROVIDER: S-EPMC6046506 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Population pharmacokinetics of tacrolimus in children with nephrotic syndrome.

Hao Guo-Xiang GX Huang Xin X Zhang Dong-Feng DF Zheng Yi Y Shi Hai-Yan HY Li Yan Y Jacqz-Aigrain Evelyne E Zhao Wei W

British journal of clinical pharmacology 20180522 8

<h4>Aims</h4>Nephrotic syndrome (NS) is the most common clinical manifestation of glomerular disease in children. Currently, tacrolimus (TAC) is widely used in children with NS. However, pharmacokinetic data in children with nephrotic syndrome is limited. This study was intended to evaluate the population pharmacokinetics (PPK) of TAC in paediatric NS and to optimize dosing regimen.<h4>Methods</h4>Blood samples from NS children treated with TAC were collected and the blood concentrations of TAC ...[more]

PMID: 29637588

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Project description:Background and objectivesChildren with nephrotic syndrome can develop life-threatening complications, including infection and thrombosis. While AKI is associated with adverse outcomes in hospitalized children, little is known about the epidemiology of AKI in children with nephrotic syndrome. The main objectives of this study were to determine the incidence, epidemiology, and hospital outcomes associated with AKI in a modern cohort of children hospitalized with nephrotic syndrome.Design, setting, participants, & measurementsRecords of children with nephrotic syndrome admitted to 17 pediatric nephrology centers across North America from 2010 to 2012 were reviewed. AKI was classified using the pediatric RIFLE definition.ResultsAKI occurred in 58.6% of 336 children and 50.9% of 615 hospitalizations (27.3% in stage R, 17.2% in stage I, and 6.3% in stage F). After adjustment for race, sex, age at admission, and clinical diagnosis, infection (odds ratio, 2.24; 95% confidence interval, 1.37 to 3.65; P=0.001), nephrotoxic medication exposure (odds ratio, 1.35; 95% confidence interval, 1.11 to 1.64; P=0.002), days of nephrotoxic medication exposure (odds ratio, 1.10; 95% confidence interval, 1.05 to 1.15; P<0.001), and intensity of medication exposure (odds ratio, 1.34; 95% confidence interval, 1.09 to 1.65; P=0.01) remained significantly associated with AKI in children with nephrotic syndrome. Nephrotoxic medication exposure was common in this population, and each additional nephrotoxic medication received during a hospitalization was associated with 38% higher risk of AKI. AKI was associated with longer hospital stay after adjustment for race, sex, age at admission, clinical diagnosis, and infection (difference, 0.45 [log]days; 95% confidence interval, 0.36 to 0.53 [log]days; P<0.001).ConclusionsAKI is common in children hospitalized with nephrotic syndrome and should be deemed the third major complication of nephrotic syndrome in children in addition to infection and venous thromboembolism. Risk factors for AKI include steroid-resistant nephrotic syndrome, infection, and nephrotoxic medication exposure. Children with AKI have longer hospital lengths of stay and increased need for intensive care unit admission.

Project description:ImportanceCalcineurin inhibitors are an established first-line corticosteroid-sparing therapy for patients with corticosteroid-dependent nephrotic syndrome (CDNS), whereas B-lymphocyte-depleting therapy is mostly used as a rescue for calcineurin inhibitor-resistant cases. The positive efficacy and safety profile of rituximab raises the question of whether it could be used as a first-line alternative to calcineurin inhibitor therapy.ObjectiveTo compare the efficacy of rituximab and tacrolimus in maintaining relapse-free survival among children with CDNS.Design, setting, and participantsA parallel-arm, open-label, randomized clinical trial was performed from May 8, 2015, to September 20, 2016, with 1-year follow-up in a single-center, tertiary care unit. A total of 176 consecutive children aged 3 to 16 years with CDNS not previously treated with corticosteroid-sparing agents were screened for eligibility.InterventionsThe children received either tacrolimus (along with tapering alternate-day prednisolone) for 12 months or a single course of rituximab (2 infusions of 375 mg/m2).Main outcomes and measuresTwelve-month relapse-free survival in the intention-to-treat population.ResultsOf the 176 children screened for eligibility, 120 were randomized and all but 3 patients completed 1 year of follow-up. The groups were comparable, with mean (SD) age of 7.2 (2.8) years, 32 boys (53.3%) in each group, mean (SD) disease duration of 2.5 (1.5) years and 2.3 (1.7) in the tacrolimus and rituximab groups, respectively, disease duration less than 1 year among 15 children (25.0%) in each group, median (interquartile range) of 4 (3-5) relapses in each group, and mean (SD) cumulative prednisolone dose of 246 (48) mg/kg and 239 (52) mg/kg in the prestudy year in the tacrolimus and rituximab groups, respectively. Rituximab therapy was associated with a higher 12-month relapse-free survival rate than tacrolimus (54 [90.0%] vs 38 [63.3%] children; P < .001; odds ratio, 5.21; 95% CI, 1.93-14.07). Among the patients who experienced relapse, median time to first relapse was 40 weeks in the rituximab group and 29 weeks in the tacrolimus group. Only 2 patients in the rituximab group had more than 1 relapse during the study period compared with 10 patients in the tacrolimus group. The cumulative corticosteroid dose during the 12-month study period was lower with rituximab compared with tacrolimus (mean [SD], 25.8 [27.8] vs 86.3 [58.0] mg/kg). Although both treatments were well tolerated, mild to moderate infections were twice as common in the tacrolimus group (26 [43.3%] vs 13 [21.7%] events).Conclusions and relevanceIn children with CDNS, rituximab appears to be more effective than tacrolimus in maintaining disease remission and minimizing corticosteroid exposure and, given its good tolerability and lack of nephrotoxic effects, may be considered as first-line corticosteroid-sparing therapy.Trial registrationClinicalTrials.gov Identifier: NCT02438982; Clinical Trial Registry of India: CTRI/2014/01/004355.

Dataset Information

Population pharmacokinetics of tacrolimus in children with nephrotic syndrome.

Publications

Population pharmacokinetics of tacrolimus in children with nephrotic syndrome.

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