Prediction of Human Glomerular Filtration Rate from Preterm Neonates to Adults: Evaluation of Predictive Performance of Several Empirical Models

Abstract

Abstract. The objective of this study was to evaluate the predictive performance of several allometric empirical models (body weight dependent, age dependent, fixed exponent 0.75, a data-dependent single exponent, and maturation models) to predict glomerular filtration rate (GFR) in preterm and term neonates, infants, children, and adults without any renal disease. In this analysis, the models were developed from GFR data obtained from inulin clearance (preterm neonates to adults; n = 93) and the predictive performance of these models were evaluated in 335 subjects (preterm neonates to adults). The primary end point was the prediction of GFR from the empirical allometric models and the comparison of the predicted GFR with measured GFR. A prediction error within ±30% was considered acceptable. Overall, the predictive performance of the four models (BDE, ADE, and two maturation models) for the prediction of mean GFR was good across all age groups but the prediction of GFR in individual healthy subjects especially in neonates and infants was erratic and may be clinically unacceptable.

Population Pharmacokinetics of Milrinone in Infants, Children, and Adolescents

“…Interestingly, acyclovir, a drug cleared through active renal secretion, likely organic anion transporters 1 and 3, exhibits maturational properties that are more similar to our observations, with a reported TM 50 of 58 weeks PMA . This is significantly greater than the TM 50 previously reported to characterize the maturation of glomerular filtration rate . A greater sample size of subjects, particularly neonates, would be needed to more precisely estimate the TM 50 value and clarify whether maturation of milrinone clearance is in fact reflective of transporter maturation and to what extent this maturation differs from that of glomerular filtration processes.…”

“…24,35 This is significantly greater than the TM 50 previously reported to characterize the maturation of glomerular filtration rate. 30,31 A greater sample size of subjects, particularly neonates, would be needed to more precisely estimate the TM 50 value and clarify whether maturation of milrinone clearance is in fact reflective of transporter maturation and to what extent this maturation differs from that of glomerular filtration processes. Alternatively or perhaps concomitantly, additional covariates beyond age and renal function may affect milrinone elimination and could be further elucidated in a larger, more granular data set.…”

A Comparative Study Between Allometric Scaling and Physiologically Based Pharmacokinetic Modeling for the Prediction of Drug Clearance From Neonates to Adolescents

“…The exponents of ADE are based on the observations of many authors from the past, body weightdependent exponent (BDE) models, [36][37][38][39] and the results of the previous studies based on the application of ADE. 12,14,17,35 In humans, Brody 42,43 found different slopes for basal metabolism. For example, in male subjects aged 0-3 years, 3-16 years, 16-31 years, 31-60 years, and over 60 years, the exponents of basal metabolism were 1.02, 0.59, 0.65, 0.56, and 0.55, respectively.…”

“…The allometric exponents are not universal, have no biological or physiological meaning, are data dependent, and vary widely based on several factors such as weight, age, and species. 14,17,26,[35][36][37][38][39] In other words, in many instances nonlinear allometry exists. 40 Due to this very nature of the exponents of allometry, it is not surprising that 1 single exponent cannot be used for interspecies scaling, nor does it predict drug clearance in children across all age groups.…”

Children in clinical trials: towards evidence-based pediatric pharmacotherapy using pharmacokinetic-pharmacodynamic modeling

“…Furthermore, depending on the drug properties, drug metabolism is also affected by hepatic blood flow and/or the unbound drug fraction (22), which also change throughout childhood. GFR is mostly influenced by renal blood flow (23) as has been described by many empirical formulas and models (24). Total renal clearance is also affected by passive and active transporters in the tubular epithelium.…”