Derivation of new equations to estimate glomerular filtration rate in pediatric oncology patients

Millisor, Vanessa E.; Roberts, Jessica K.; Sun, Yilun; Li, Tang; Daryani, Vinay M.; Gregornik, David; Cross, Shane J; Ward, Deborah; Pauley, Jennifer L.; Molinelli, Alejandro R.; Brennan, Rachel C.; Stewart, Clinton F.

doi:10.1007/s00467-017-3693-5

Cited by 19 publications

(29 citation statements)

References 21 publications

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“…The curve is the model estimated covariate relation between systemic clearance and age. Although initially patient age was a significant covariate in the univariate analysis, after inclusion of BSA and eGFR in the model, age was no longer a significant covariate, probably due to the inclusion of age in the 5‐covariate St. Jude equation used to estimate GFR in infants and young children . (C) concomitant administration of dexamethasone increased MTX clearance by 19%.…”

Section: Resultsmentioning

confidence: 99%

“…Demographic and lab chemistries tested as covariates included weight, BSA, estimated glomerular filtration rate (eGFR) estimated via the 5 covariate (i.e. height, serum creatinine, age, blood urea nitrogen) St. Jude equation, total bilirubin, alanine aminotransferase, age as a continuous covariate, and age as a categorical covariate (≤31 days at time of HDMTX treatment, between 31 days and 6 months, 6 months and 1 year, 1 and 2 years, and >2 years old). Concomitant medications evaluated as covariates were administered within 48 h of the initiation of the HDMTX infusion, and are listed in Supplemental Table 2.…”

Section: Methodsmentioning

confidence: 99%

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Pharmacokinetic basis for dosing high‐dose methotrexate in infants and young children with malignant brain tumours

Panetta

Roberts

Huang

et al. 2020

Brit J Clinical Pharma

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Aims No population pharmacokinetic studies of high‐dose methotrexate (HDMTX) have been conducted in infants with brain tumours, which are a vulnerable population. The aim of this study was to evaluate HDMTX disposition in these children to provide a rational basis for MTX dosing. Methods Patients received 4 monthly courses of HDMTX (5 g/m2 or 2.5 g/m2 for infants aged ≤31 days) as a 24‐h infusion. Serial samples were analysed for MTX by an enzyme immunoassay method. Pharmacokinetic parameters were estimated using nonlinear mixed effects population modelling. Demographics, concomitant medications and genetic polymorphisms were considered as pharmacokinetic covariates while MTX exposure and patient age were considered as covariates for Grade 3 and 4 toxicities. Results The population pharmacokinetics of HDMTX were estimated in 178 patients (age range 0.02–4.7 years) in 648 courses. The population clearance and volume were 90 mL/min/m2 and 14.4 L/m2, respectively. Significant covariates on body surface area adjusted MTX clearance included estimated glomerular filtration rate and co‐treatment with dexamethasone or vancomycin. No significant association was observed between MTX toxicity and MTX exposure, patient age, leucovorin dosage or duration. MTX clearance in infants ≤31 days at enrolment was 44% lower than in older infants, but their incidence of toxicity was not higher since they also received a lower MTX dosage. Conclusions By aggressively following institutional clinical guidelines, HDMTX‐related toxicities were low, and using covariates from the population pharmacokinetic model enabled the calculation of a rational dosage for this patient population for future clinical trials.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Pharmacokinetic basis for dosing high‐dose methotrexate in infants and young children with malignant brain tumours

Panetta

Roberts

Huang

et al. 2020

Brit J Clinical Pharma

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“…As the relationship between mGFR and the reciprocal of the marker concentration is not perfectly linear, more recent approaches performed multiple linear regression analysis on logarithmic data [112,115,[194][195][196][197].…”

Section: Statistical Approach To the Development Of Egfr Equationsmentioning

confidence: 99%

“…During the last 30 years, a large number of different eGFR equations have been developed for children that use one or several of the endogenous markers of GFR discussed in this review. A selection of equations, which were developed at least in part in pediatric populations, is presented in Table 2 [112,115,141,145,191,196,197,201,202,204,[211][212][213][214][215][216][217][218]. With respect to creatinine and cystatin C, we have restricted our selection to equations using current IFCC calibrated assays in order to provide clinically useful rather than historical information.…”

Section: Egfr Equations In Childrenmentioning

confidence: 99%

Endogenous markers for kidney function in children: a review

Bakker

Gemke

Bökenkamp

2018

Critical Reviews in Clinical Laboratory Sciences

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Although glomerular filtration rate (GFR) in children can be measured using a gold-standard technique following injection of an exogenous marker, this invasive and cumbersome technique is not widely available and GFR is commonly estimated using serum levels of endogenous markers. Creatinine, urea, cystatin C, beta-trace protein, and beta-2 microglobulin are well-established endogenous markers of kidney function. These markers differ in site of production and effects of diet and medication, as well as renal-tubular handling and extra-renal elimination. For each marker, different methods are available for measurement. Importantly, the measurements of creatinine and cystatin C have recently been standardized with the introduction of international reference standards. In order to allow estimation of GFR from serum marker concentrations, different equations for estimated GFR (eGFR) have been developed in children, using simple or more complex regression strategies with gold standard GFR measurements as a dependent variable. As a rule, estimation strategies relying on more than one marker - either by calculating the average of single parameter equations or by using more complex equations incorporating several parameters - outperform eGFR estimations using only a single marker. This in-depth review will discuss the physiology, measurement and clinical use of creatinine, urea, cystatin C, beta-trace protein, and beta-2 microglobulin in children. It will also address the generation of eGFR equations in children and provide an overview of currently available eGFR equations for the pediatric age group.

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“…At least four other pediatric dosing formulas, commonly based on adult studies, have been described for adaptive dosing of carboplatin, [8][9][10][11] and many of these formulas continue to be used in children with cancer. [12][13][14][15][16][17][18] As part of an effort by the Children's Oncology Group (COG) to standardize cancer drug administration across protocols, 19 we reexamined the data supporting adaptive dosing of carboplatin in children. We found that previously described methodological problems with nuclear-medicine-based estimates of GFR in children, 20,21 including variation in the number and timing of plasma samples obtained and in the methods used to calculate GFR (ie, clearance of the tracer), continue to exist in current practice.…”

Section: Who Demonstrated Amentioning

confidence: 99%

Fundamental problems with pediatric adaptive dosing of carboplatin using nuclear‐medicine‐based estimates of renal function

Adamson

Veal

Womer

et al. 2019

Pediatric Blood & Cancer

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Background Carboplatin is often adaptively dosed based on glomerular filtration rate (GFR), usually estimated by nuclear medicine tests. At least five pediatric adaptive dosing formulas have been developed. In an effort to standardize dosing in Children's Oncology Group protocols, we explored methodologic variation in GFR estimation and adaptive‐dosing formula performance. Procedure Nuclear medicine GFR data from published series of ≥100 children with cancer were compared. Data from patients for whom body surface area, weight, GFR, and tracer half‐life were available were used to compare formulas. Results Differences in methods used to estimate GFR in children with cancer resulted in highly variable population results, with median GFRs ranging from 96 to 150 mL/min/1.73m2. The choice of adaptive formula had a major impact on calculated dose. When targeting an area under the curve of 7.9 mg/mL • min, the median difference between the formula yielding the lowest and highest carboplatin dose for individual subjects was 289 (range 96‐1 737) mg/m2. Conclusions Wide variation in GFR obtained with nuclear‐medicine‐based tests in children with cancer primarily results from systematic methodologic errors. Formulas for calculating carboplatin dose produce additional and substantial variation that may place children with cancer at unnecessary risk for excessive toxicity or underdosing. These findings indicate a need for the development of a uniform, validated method for GFR determination in children that should be utilized in all centers. Currently, adaptive dosing of carboplatin based on GFR has serious limitations and in most clinical settings should arguably not be used in place of body‐surface‐area‐based dosing.

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Derivation of new equations to estimate glomerular filtration rate in pediatric oncology patients

Cited by 19 publications

References 21 publications

Pharmacokinetic basis for dosing high‐dose methotrexate in infants and young children with malignant brain tumours

Pharmacokinetic basis for dosing high‐dose methotrexate in infants and young children with malignant brain tumours

Endogenous markers for kidney function in children: a review

Fundamental problems with pediatric adaptive dosing of carboplatin using nuclear‐medicine‐based estimates of renal function

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