Developmental Changes in Pharmacokinetics and Pharmacodynamics

Abstract

Effective drug therapy to optimally influence disease requires an understanding of a drug's pharmacokinetic, pharmacodynamic, and pharmacogenomic interrelationships. In pediatrics, age is a continuum that can and does add variability in drug disposition and effect. This article addresses the many important factors that influence drug disposition and effect relative to age. What is known about the influence of maturation on the processes of drug absorption, distribution, metabolism, excretion, and drug receptor dynamics are outlined. Our state of understanding of many of these factors remains in flux, however, and only with additional study will we be able to better anticipate and model drug‐response relationships across the age continuum. Being able to continuously improve our care of the ill pediatric patient while simultaneously being able to accurately determine the utility of new drugs and chemical entities in this population requires our enhanced understanding of these disposition characteristics.

Ontogeny of Phase I Metabolism of Drugs

“…Similar, different maturational patterns for different elimination processes may result in relevant differences in the phenotypic routes of elimination. Consequently, the interpretation and extrapolation of an isoenzyme‐specific function on the phenotypic drug disposition in children must be applied cautiously and, most importantly, confirmed by in vivo observations …”

“…Compared to the adult MPGGL value of about 40 mg/g, these values are significantly lower in neonates (20‐25 mg/g), with a subsequent increase to peak around the age of 30 years. Using an interlaboratory data pooling effort (n = 129 samples), Barter et al generated an MPGGL age‐dependent function (MPGGL [mg/g] = 10^1.407 + 0.0158*age – 0.00038*age + 0.00000*age [age in years]). Although a function obviously makes data much more operational for modeling tools, we should be aware that this function has been constructed in the absence of MPGGL data in the first 2 years of life, extrapolating from fetal data to individual observations at the age of 2, 4, and 9 years, and neither considers the variability observed unrelated to age.…”

“…The primary goal of clinical pharmacology is to understand the factors that determine dose‐concentration and concentration‐effect relationships, and to use this knowledge to tailor drug selection and dosing to the individual patient . This process of drug selection and dosing should reflect the (patho)physiologic characteristics of the population considered but should also consider the specific characteristics of the individual patient . When applied to children, accurate selection of an effective and safe dose of a specific drug prescribed to an individual newborn, infant, child, or adolescent depends on sufficient understanding of the developmental pharmacokinetics (PK) and pharmacodynamics (PD) of that particular drug, as well as the clinical characteristics of the unique patient (maturational and nonmaturational covariates) being treated with this drug for a given indication .…”

Developmental Pharmacotherapy: The Interface Between Ontogeny and Drug Effect

“…The first paper, written by us and two distinguished colleagues, addresses the dynamic maturational changes that occur following birth through adolescence. Age and size are two very important clinical predictors of drug disposition and effect as both change dramatically as the child develops and grows.…”

“…Age and size are two very important clinical predictors of drug disposition and effect as both change dramatically as the child develops and grows. Only after integrating a patient's severity of illness(es), age, size, and pharmacogenetic makeup with a drug's PK and PD characteristics can one attempt to implement the best pharmacotherapeutic regimen . However, without age‐appropriate drug formulations, drug therapy is severely hampered.…”