Maturation and growth of renal function: Dosing renally cleared drugs in children

Hayton, William L.

doi:10.1208/ps020103

Cited by 120 publications

(134 citation statements)

References 10 publications

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“…Although impossible to answer definitively with these data, the question of whether there is a "universal" b value is of interest. Does the distribution shown in Figure 1 both mammalian glomerular filtration rate and effective renal plasma flow [91][92][93] , although it was consistent with a b value of 0.66 reported for intraspecies scaling of inulin-based glomerular filtration rate in humans 94 and with a b value of 0.69 for scaling creatinine clearance 95 .…”

Section: Discussionsupporting

confidence: 86%

Allometric scaling of xenobiotic clearance: Uncertainty versus universality

Hayton

2001

AAPS PharmSci

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Statistical analysis and Monte Carlo simulation were used to characterize uncertainty in the allometric exponent (b) of xenobiotic clearance (CL). CL values for 115 xenobiotics were from published studies in which at least 3 species were used for the purpose of interspecies comparison of pharmacokinetics. The b value for each xenobiotic was calculated along with its confidence interval (CI). For 24 xenobiotics (21%), there was no correlation between log CL and log body weight.

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Section: Discussionsupporting

confidence: 86%

Allometric scaling of xenobiotic clearance: Uncertainty versus universality

Hayton

2001

AAPS PharmSci

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“…Hayton, for example, estimated an allometric exponent of 0.662 (coefficient of variance 20%) in healthy children (2 days-12 years) when maturation was described by an exponential asymptotic model based on PNA [36]. We prefer to rely on the theory and extensive confirmatory observations supporting an exponent of 0.75 [14,[37][38][39][40][41] rather than accept the empirical coefficient on the basis of a change in objective function without any supporting visual evidence of better predictive performance.…”

Section: Discussionmentioning

confidence: 99%

Human renal function maturation: a quantitative description using weight and postmenstrual age

et al. 2009

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This study pools published data to describe the increase in glomerular filtration rate (GFR) from very premature neonates to young adults. The data comprises measured GFR (using polyfructose, (51)Cr-EDTA, mannitol or iohexol) from eight studies (n = 923) and involved very premature neonates (22 weeks postmenstrual age) to adulthood (31 years). A nonlinear mixed effects approach (NONMEM) was used to examine the influences of size and maturation on renal function. Size was the primary covariate, and GFR was standardized for a body weight of 70 kg using an allometric power model. Postmenstrual age (PMA) was a better descriptor of maturational changes than postnatal age (PNA). A sigmoid hyperbolic model described the nonlinear relationship between GFR maturation and PMA. Assuming an allometric coefficient of 3/4, the fully mature (adult) GFR is predicted to be 121.2 mL/min per 70 kg [95% confidence interval (CI) 117-125]. Half of the adult value is reached at 47.7 post-menstrual weeks (95%CI 45.1-50.5), with a Hill coefficient of 3.40 (95%CI 3.03-3.80). At 1-year postnatal age, the GFR is predicted to be 90% of the adult GFR. Glomerular filtration rate can be predicted with a consistent relationship from early prematurity to adulthood. We propose that this offers a clinically useful definition of renal function in children and young adults that is independent of the predictable changes associated with age and size.

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“…The effects of maturation and growth on renal function were examined in a seminal paper by Hayton (29). The study proposed a series of equations to estimate renal function parameters, such as glomerular filtration rate (GFR) and active secretion, in children as a function of age and weight.…”

Section: Age-dependent Scaling Of Pbpk Model Parametersmentioning

confidence: 99%

A Workflow Example of PBPK Modeling to Support Pediatric Research and Development: Case Study with Lorazepam

Maharaj

Barrett

Edginton

2013

AAPS J

105

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Abstract. The use of physiologically based pharmacokinetic (PBPK) models in the field of pediatric drug development has garnered much interest of late due to a recent Food and Drug Administration recommendation. The purpose of this study is to illustrate the developmental processes involved in creation of a pediatric PBPK model incorporating existing adult drug data. Lorazepam, a benzodiazepine utilized in both adults and children, was used as an example. A population-PBPK model was developed in PK-Sim v4.2® and scaled to account for age-related changes in size and composition of tissue compartments, protein binding, and growth/maturation of elimination processes. Dose (milligrams per kilogram) requirements for children aged 0-18 years were calculated based on simulations that achieved targeted exposures based on adult references. Predictive accuracy of the PBPK model for producing comparable plasma concentrations among 63 pediatric subjects was assessed using average-fold error (AFE). Estimates of clearance (CL) and volume of distribution (V ss ) were compared with observed values for a subset of 15 children using fold error (FE). Pediatric dose requirements in young children (1-3 years) exceeded adult levels on a linear weight-adjusted (milligrams per kilogram) basis. AFE values for model-derived concentration estimates were within 1.5-and 2-fold deviation from observed values for 73% and 92% of patients, respectively. For CL, 60% and 80% of predictions were within 1.5 and 2 FE, respectively. Comparatively, predictions of V ss were more accurate with 80% and 100% of estimates within 1.5 and 2 FE, respectively. Using the presented workflow, the developed pediatric model estimated lorazepam pharmacokinetics in children as a function of age.

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Maturation and growth of renal function: Dosing renally cleared drugs in children

Cited by 120 publications

References 10 publications

Allometric scaling of xenobiotic clearance: Uncertainty versus universality

Allometric scaling of xenobiotic clearance: Uncertainty versus universality

Human renal function maturation: a quantitative description using weight and postmenstrual age

A Workflow Example of PBPK Modeling to Support Pediatric Research and Development: Case Study with Lorazepam

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