Differences in Pharmacokinetics Between Children and Adults—II. Children's Variability in Drug Elimination Half‐Lives and in Some Parameters Needed for Physiologically‐Based Pharmacokinetic Modeling

Abstract

In earlier work we assembled a database of classical pharmacokinetic parameters (e.g., elimination half-lives; volumes of distribution) in children and adults. These data were then analyzed to define mean differences between adults and children of various age groups. In this article, we first analyze the variability in half-life observations where individual data exist. The major findings are as follows. The age groups defined in the earlier analysis of arithmetic mean data (0-1 week premature; 0-1 week full term; 1 week to 2 months; 2-6 months; 6 months to 2 years; 2-12 years; and 12-18 years) are reasonable for depicting child/adult pharmacokinetic differences, but data for some of the earliest age groups are highly variable. The fraction of individual children's half-lives observed to exceed the adult mean half-life by more than the 3.2-fold uncertainty factor commonly attributed to interindividual pharmacokinetic variability is 27% (16/59) for the 0-1 week age group, and 19% (5/26) in the 1 week to 2 month age group, compared to 0/87 for all the other age groups combined between 2 months and 18 years. Children within specific age groups appear to differ from adults with respect to the amount of variability and the form of the distribution of half-lives across the population. The data indicate departure from simple unimodal distributions, particularly in the 1 week to 2 month age group, suggesting that key developmental steps affecting drug removal tend to occur in that period. Finally, in preparation for age-dependent physiologically-based pharmacokinetic modeling, nationally representative NHANES III data are analyzed for distributions of body size and fat content. The data from about age 3 to age 10 reveal important departures from simple unimodal distributional forms-in the direction suggesting a subpopulation of children that are markedly heavier than those in the major mode. For risk assessment modeling, this means that analysts will need to consider "mixed" distributions (e.g., two or more normal or log-normal modes) in which the proportions of children falling within the major versus highweight/fat modes in the mixture changes as a function of age. Biologically, the most natural interpretation of this is that these subpopulations represent children who have or have not yet received particular signals for change in growth pattern. These apparently distinct subpopulations would be expected to exhibit different disposition of xenobiotics, particularly those that are highly lipophilic and poorly metabolized.

Elevated internal exposure of children in simulated acute inhalation of volatile organic compounds: effects of concentration and duration

“…Lower metabolism rates in the very young have been reported by several authors (Cresteil 1998, Hattis et al 2003. Pelekis et al (2001) and, more recently, Price et al (2003) and Sarangapani et al (2003) have presented derivations of the adult to child kinetic uncertainty factors for inhalation exposure, based on physiological models.…”

“…in deriving acute exposure guideline levels (AEGLs), the concentration ratios (child/adult) calculated can be used to establish intraspecies assessment factors to account for kinetic differences between children and adults. In cases where chemical-specific data is not available, the default factor of 3.2 is often applied to considertoxicokinetic differences within the human population , Hattis et al 2003. This factor has to be reconsidered: in some cases, a higher factor may be more appropriate to cover highly susceptible populations, such as the newborn.…”

“…Exposure patterns have been considered in various age groups (Cohen Hubal et al 2000). In addition, several authors have described age-dependent kinetics, which show lower metabolic elimination in the very young , Ginsberg et al 2004, Hattis et al 2003, Renwick et al 2000.…”

Expressing urine from a gel disposable diaper for biomonitoring using phthalates as an example

“…Ginsberg et al (2002) compiled these toxicokinetic parameters for children and adults for 45 drugs. Analysing these data, Hattis et al (2003) reported that the half-lives of orally administered drugs in children of 2 months to 18 years were within a factor of 3.2 of the adult half-lives. However, 27% of the zero-to one-week age group and 19% of the one-week to two-month age group had half-lives that should be noted that most of the drugs evaluated by these authors have short half-lives (less than one day).…”

“…This range of longer half-lives exceeds the 3.16 uncertainty factor that is applied to account for interindividual pharmacokinetic variability. Other studies have further evaluated these differences and suggest that an additional factor may be necessary for newborns and neonates (Hattis et al, 2003;Ginsberg et al, 2004a,b). Consequently, the traditional uncertainty factor may be inadequate at this life stage.…”