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Creatinine-Based Renal Function Assessment in Pediatric Drug Development: An Analysis Using Clinical Data for Renally Eliminated Drugs.

ABSTRACT: The estimated glomerular filtration rate (eGFR) equations based on serum creatinine (SCR) have been used for pediatric dose adjustment in drug labeling. This study evaluated the performance of those equations in estimating individual clearance of drugs that are predominantly eliminated by glomerular filtration, using clinical data from the renally eliminated drugs gadobutrol, gadoterate, amikacin, and vancomycin. The eGFR was compared with the observed drug clearance (CL) in 352 pediatric patients from birth to 12 years of age. Multiple eGFR equations overestimated the drug CL on average, including the original and bedside Schwartz equations, which showed an average eGFR/CL ratio between 1 and 3. Further analysis with bedside Schwartz equation showed a higher eGFR/CL ratio in the subjects with a lower SCR or CL. Supraphysiological eGFR as high as 380 mL/min/1.73 m² was obtained using the bedside Schwartz equation for some of the subjects, most of whom are children < 2 years of age with SCR < 0.2 mg/dL. Excluding the subjects with supraphysiological eGFR from the analysis did not change the overall trend of overestimation. In conclusion, Schwartz equations led to an overestimation of drug clearance for the drugs evaluated. When greater precision is required in predicting eGFR for pediatric patients, such as in drug dosing, revised k constants for the Schwartz equation or new methods of glomerular filtration rate estimation may be necessary.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC7855729 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Creatinine-Based Renal Function Assessment in Pediatric Drug Development: An Analysis Using Clinical Data for Renally Eliminated Drugs.

Zhang Yifei Y Sherwin Catherine M CM Gonzalez Daniel D Zhang Qunshu Q Khurana Mona M Fisher Jeffrey J Burckart Gilbert J GJ Wang Yaning Y Yao Lynne P LP Ganley Charles J CJ Wang Jian J

Clinical pharmacology and therapeutics 20200829 1

The estimated glomerular filtration rate (eGFR) equations based on serum creatinine (SCR) have been used for pediatric dose adjustment in drug labeling. This study evaluated the performance of those equations in estimating individual clearance of drugs that are predominantly eliminated by glomerular filtration, using clinical data from the renally eliminated drugs gadobutrol, gadoterate, amikacin, and vancomycin. The eGFR was compared with the observed drug clearance (CL) in 352 pediatric patien ...[more]

PMID: 32696977

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Project description:IntroductionAge-related changes occurring in the kidney can lead to a reduction in Glomerular Filtration Rate (GFR); especially in older adults with multimorbidity and/or frailty, an accurate evaluation of kidney function is critical. For the estimation of GFR in patients over 70 years, CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) is often used. However, validated equations exist for old-age populations like BIS1 (Berlin Initiative Study 1) and FAS (Full Age Spectrum). Here we aimed to compare the performance of CKD-EPI, MDRD (Modification of Diet in Renal Disease), BIS1, and FAS in assessing eGFR in a population of patients over 70, to evaluate which equations show the most accurate performance in our setting.Materials and methodsA total of 499 older adults were consecutively recruited in the Orthogeriatric ward and Oncogeriatrics clinic of IRCCS Polyclinic San Martino in Genoa Italy. eGFR was calculated using CKD-EPI, MDRD, BIS1, and FAS, calculating mean, median, standard deviation, and interquartile range. Bland-Altman graphs were used to evaluate how each equation performs with respect to the others and the concordance of the attribution of the KDIGO CKD stage was performed with Cohen's K constant and chi-squared test.ResultsPatients' mean age was 82.6 years (± 7.44), and the mean creatinine value was 0.97 (± 0.71) mg/dl. The mean value of eGFR was 70 mL/min with CKD-EPI (± 20.6) and MDRD (± 25.7), 57 mL/min with BIS1 (± 16.7) and FAS (± 19.0), respectively. BIS1 and FAS estimated lower eGFR values than CKD-EPI and MDRD. As age increases, a steady decrease in filtrate value is observed with BIS1 and FAS. MDRD and CDK-EPI do not show the same trend. The performance of the equations at a fixed eGFR value of 30 mL/min is more linear for BIS1 and FAS compared with CKD-EPI and MDRD. Upon evaluation with chi-square, the attribution of KDIGO stage was statistically different among the various equations.DiscussionAn appropriate assessment of renal function is of key clinical relevance to prevent adverse outcomes and risk of drug accumulation in older adults. Our study originally showed that in persons aged more than 70 years old BIS1 is the most accurate formula in calculating eGFR values when only serum creatinine is available.

Project description:BackgroundTeicoplanin is used to treat serious gram-positive infections. Optimal teicoplanin trough levels are considered to be ≥ 10 μg/mL. Despite its wide use in various clinical settings, data on teicoplanin trough level in pediatric patients are limited. Therefore, the aim of this study was to investigate the therapeutic drug level monitoring of teicoplanin in Korean pediatric patients, including those with impaired renal function.MethodsA retrospective study was performed in pediatric patients (age ≤ 18 years old) who received teicoplanin from September 2014 to April 2018. The regimen included a loading dose of 10 mg/kg/dose at 12 hours' interval three times in a row, and a maintenance dose of 10 mg/kg/dose commenced at 24 hours of interval after the loading dose, with a maximum of 400 mg/dose, respectively. The first therapeutic drug levels were measured. Distribution and characteristics of trough levels in patients with decreased renal function and those with bacteremia were also assessed.ResultsA total of 187 trough levels were collected from 143 patients. Hematologic and oncologic diseases were the most common underlying diseases (83.2%, n = 119). One hundred eighty trough levels were first measured, and their median value was 16.2 μg/mL (range, 2.3-100 μg/mL) and the median interval between initial teicoplanin injection and 1st trough level was 96.5 hours (range 47.6-179.3 hours). Lower steady-state levels were observed in younger age group (median, 13.5 vs. 18.0 μg/mL, P = 0.038). Median trough levels were higher in patients with decreased renal functions (P < 0.001). In addition, among eight with gram-positive bacteremia, seven of them had a favorable outcome.ConclusionThis study provides additive information on trough level monitoring of teicoplanin in children with impaired renal function and treatment effect in patients with gram-positive bacteremia. Careful monitoring for steady state trough levels of teicoplanin is warranted.

Dataset Information

Creatinine-Based Renal Function Assessment in Pediatric Drug Development: An Analysis Using Clinical Data for Renally Eliminated Drugs.

Publications

Creatinine-Based Renal Function Assessment in Pediatric Drug Development: An Analysis Using Clinical Data for Renally Eliminated Drugs.

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