Pharmacokinetic pharmacodynamic modeling of analgesics and sedatives in children

Abstract

Pharmacokinetic pharmacodynamic modeling is an important tool which uses statistical methodology to provide a better understanding of the relationship between concentration and effect of drugs such as analgesics and sedatives. Pharmacokinetic pharmacodynamic models also describe between-subject variability that allows identification of subgroups and dose adjustment for optimal pain management in individual patients. This approach is particularly useful in the pediatric population, where most drugs have received limited evaluation and dosing is extrapolated from adult practice. In children, the covariates of weight and age are used to describe size- and maturation-related changes in pharmacokinetics. It is important to consider both size and maturation in order to develop an accurate model and determine the optimal dose for different age groups. An adequate assessment of analgesic and sedative effect using pain scales or brain activity measures is essential to build reliable pharmacokinetic pharmacodynamic models. This is often challenging in children due to the multidimensional nature of pain and the limited sensitivity and specificity of some measurement tools. This review provides a summary of the pharmacokinetic and pharmacodynamic methodology used to describe the dose-concentration-effect relationship of analgesics and sedation in children, with a focus on the different pharmacodynamic endpoints and the challenges of pharmacodynamic modeling.

Keywords: children; pain; pharmacodynamic; pharmacokinetic; sedation.

FIGURE 1

Plot of an $E_{\max }$ model of drug concentration versus effect; $E_{\max }$ is the maximum effect and $\mathrm{E}{\mathrm{C}}_{50}$ is the drug concentration for 50% E _max effect observed.

FIGURE 2

Plot of a sigmoidal E _max model with a logarithmic abscissa and three different values of n. n refers to the slope factor (Hill factor) and measures sensitivity of the response to the dose range of the drug, determining the steepness of the dose–response curve. The dotted line represents the E _max.

FIGURE 3

Schematic diagram of compartmental PK models; each rectangle represents a compartment, V and V₁ represent the central compartment, V₂ and V₃ represent the peripheral compartments. Q and CL represent the inter‐compartmental and elimination clearances, respectively.