Renal clearance parameters for PBPK model analysis of early lifestage differences in the disposition of environmental toxicants

Physiologically-based pharmacokinetic (PBPK) models are being developed to evaluate whether humans in early life are more or less susceptible to adverse effects than adults from exposure to chemicals because of reduced renal clearance. To support the development of such models, data on the rates of glomerular filtration, tubular secretion, tubular reabsorption, and renal blood flow in neonates and infants were compiled and summarized. All three processes are deficient in the newborn with varying maturation rates during the first months and years of life. Glomerular filtration rate (GFR) has traditionally been the primary indicator of kidney function, and in full-term neonates (<1-month-old) is about 30% of the adult level, subsequently approaching adult rates between 6 months and 1 year of age. Tubular secretion is around 25% of adult levels at birth, and increases more slowly and more variably than GFR, not approaching adult levels until 1–5 years of age. Limited data on renal plasma flow indicate neonatal rates of only 10–20% of adult values that rapidly increase to 50% by 6 months, and then approach adult levels by 1–2 years of age. Examples of PBPK model representations of renal clearance for chemicals that are primarily cleared by the kidneys are discussed in terms of their use in evaluating early life stage susceptibility.