Growth and development can be investigated using readily observable demographic factors such as weight and age. Size is the primary covariate and can be referenced to a 70-kg person with allometry using a coefficient of 0.75 for clearance and 1 for volume. The use of these coefficients is supported by fractal geometric concepts and observations from diverse areas in biology. Fat free mass (FFM) might be expected to do better than total body weight when there are wide variations in fat affecting body composition. Clearance pathways develop in the fetus before birth. The use of postnatal age as a descriptor of maturation is unsatisfactory because birth may occur prematurely; therefore postmenstrual age is a superior predictor of elimination function. A sigmoid E(max) model (Hill equation) describes gradual maturation of clearance in early life leading to a mature adult clearance achieved at a later age.

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.

Growth and development are two major aspects of children not readily apparent in adults. Clearance in the paediatric population should be investigated using models that describe size, maturation and organ function influences. Size is the primary covariate and although lean body weight is argued as a better measure than total body weight, the use of different fractions of fat mass to explain how pharmacokinetic parameters vary with body composition has been proposed. Allometric scaling using an empiric power exponent of 3/4 is superior to scaling using body surface area. The sigmoid hyperbolic model has proven useful to describe maturation. An extra parameter that describes asymmetry can be incorporated into this model. These descriptors are used to illustrate creatinine, morphine and paracetamol clearance in children. Simultaneous investigation of pooled GFR, paracetamol and morphine data enabled testing for shared common features of maturation processes. Results suggest that GFR matures before paracetamol or morphine clearance, consistent with phase II conjugation processes that convert xenobiotics to water soluble forms that can subsequently be eliminated from the body through the renal system. The use of such mechanistic approaches improves understanding of paediatric pharmacokinetics; improving dosing predictions and allowing projection in exploratory drug development.

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