Abstract
Annual Review of Pharmacology and Toxicology
Vol. 48:
303-332
(Volume publication date February 2008)
(doi:10.1146/annurev.pharmtox.48.113006.094708)
First published online as a Review in Advance on October 3, 2007Mechanism-Based Concepts of Size and Maturity in Pharmacokinetics B.J. Anderson1 and N.H.G. Holford21Department of Anaesthesiology 2Department of Pharmacology and Clinical Pharmacology, University of Auckland School of Medicine, Auckland, New Zealand; email: briana@adhb.govt.nz, n.holford@auckland.ac.nz 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 Emax model (Hill equation) describes gradual maturation of clearance in early life leading to a mature adult clearance achieved at a later age. Acronyms and Definitions BSA: body surface area βcl: a parameter estimating the fractional CLstd at a specified PMA CLcr: creatinine clearance CPR: creatinine production rate ECF: extracellular fluid FFM: fat free mass MATCL50: the PMA at which clearance is 50% that of the mature value NFWT: normal fat weight NONMEM: a nonlinear mixed effects modeling program PMA: postmenstrual age PNA: postnatal age Optimizing Pediatric Dosing: A Developmental Pharmacologic Approach Pharmacotherapy 29(6):680-690 (2009) Developmental Pharmacokinetics of Gentamicin in Preterm and Term Neonates Clinical Pharmacokinetics 48(4):253-263 (2009) A Pharmacokinetic and Dosing Study of Intravenous Insulin-Like Growth Factor-I and IGF-Binding Protein-3 Complex to Preterm Infants Pediatric Research 65(5):574-579 (2009) Intravenous neonatal paracetamol dosing: the magic of 10  days Pediatric Anesthesia 19(4):289-295 (2009) A Framework for Assessing Inter-individual Variability in Pharmacokinetics Using Virtual Human Populations and Integrating General Knowledge of Physical Chemistry, Biology, Anatomy, Physiology and Genetics: A Tale of ‘Bottom-Up’ vs ‘Top-Down’ Recognition of Covariates Drug Metabolism and Pharmacokinetics 24(1):53-75 (2009)
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