What is the best size predictor for dose in the obese child?

Abstract

SummaryLean body mass is commonly proposed for anesthesia maintenance drug dosing calculations. However, total body mass used with allometric scaling has been shown to be better for propofol in obese adults and children. Fat-free mass has also been used instead of lean body mass. Fat-free mass is essentially the same as lean body mass but excludes a small percentage of mass of lipids in cell membranes, CNS, and bone marrow. Normal fat mass is a size descriptor that partitions total body mass into fat-free mass and fat mass calculated from total body mass minus fat-free mass.The relative influence of fat mass compared with fat-free mass is described by the fraction of fat mass that makes fat equivalent to fat-free mass in terms of allometric size. This fraction (Ffat) will differ for each drug and each parameter affected by body size (eg, clearance and volume of distribution). This fraction is based on the concept of theory-based allometric size. The normal fat mass based on allometric theory and partition of body mass into fat and fat-free components provides a principle-based approach explaining size and body composition effects on pharmacokinetics of all drugs in children and in adults. 1 This speculation is difficult to test because of the well-known biologically driven relationship between body structure and function driven by body mass. 2 In order to evaluate the influence of obesity, it is necessary to find a means to distinguish between size and the independent effects of obesity.We have proposed using a theory-based relationship between body mass and size-related differences in clearance to distinguish between size and age-related effects in early life that reflect maturation of organ function. 3 This approach has proved useful for describing glomerular filtration rate and clearance of many drugs. 4We have also suggested using a similar theory-based approach to distinguish the influence of fat and fat-free components of body mass used to predict clearance and volume of distribution. 5 In this review, we expand on these concepts to develop a framework for determining if there is an influence of obesity on pharmacokineticparameters. We also demonstrate how pharmacokinetic parameters may be predicted using fat mass with application to drug dosing in children and adults.

Population Pharmacokinetics and Pharmacodynamics of Teicoplanin and C‐Reactive Protein in Hospitalized Patients With Gram‐Positive Infections

“…32,48 Teicoplanin exhibited a hydrophilic character, and few teicoplanin distributed organic phases in a previous study. NFM was used for the index of body size to consider the influence of both body size and composition.…”

A manual propofol infusion regimen for neonates and infants

“…The authors analyzed propofol PK data and BIS data from 1033 patients of a wide age range (27 weeks postmenstrual age to 88 years) with data obtained from 30 published studies. Although growth and maturational aspects of propofol disposition are incorporated in the estimated parameters, the assessment of pharmacokinetic covariates such as fat mass and the use of BIS as a surrogate electroencephalographic measure of depth of anesthesia remains uncertain in neonates and infants and might bias model predictions in this population …”

“…Although growth and maturational aspects of propofol disposition are incorporated in the estimated parameters, the assessment of pharmacokinetic covariates such as fat mass and the use of BIS as a surrogate electroencephalographic measure of depth of anesthesia remains uncertain in neonates and infants and might bias model predictions in this population. 12,13 We aimed to evaluate the manual propofol infusion regimens 9 published for neonates and infants using the pharmacokinetic propofol parameter set estimated by the general purpose model. 11 This general purpose model included a limited cohort of neonates and so we developed a simple pharmacokinetic model from previously published propofol studies in children 0-11 years to propose alternative manual infusion guidelines that targeted a plasma concentration of 3 µg.mL −1 in neonates and infants; infusion regimens consistent with previously used pediatric manual infusion regimens.…”

Acetaminophen pharmacokinetics in severely obese adolescents and young adults

“…Those doses were determined by concerns regarding hepatotoxicity caused by chronic administration rather than by pharmacokinetic‐pharmacodynamic considerations . The best size descriptor for determination of acetaminophen dose in obese and severely obese adolescents remains uncertain …”

“…8 The best size descriptor for determination of acetaminophen dose in obese and severely obese adolescents remains uncertain. 9,10 The objective of this study was to investigate acetaminophen serum concentrations following the administration of a single intravenous dose of the manufacturer's recommended maximum of 1000 mg in obese adolescents and young adults following sleeve gastrectomy. Pharmacokinetic analysis of time-concentration profiles included assessment of size descriptors 9 for obese adolescents in order to predict a dose that might achieve a target concentration of 10 mg·L −1 at steady-state.…”