Physiologically based pharmacokinetic modeling and simulation in pediatric drug development

Abstract

Increased regulatory demands for pediatric drug development research have fostered interest in the use of modeling and simulation among industry and academia. Physiologically based pharmacokinetic (PBPK) modeling offers a unique modality to incorporate multiple levels of information to estimate age-specific pharmacokinetics. This tutorial will serve to provide the reader with a basic understanding of the procedural steps to developing a pediatric PBPK model and facilitate a discussion of the advantages and limitations of this modeling technique.

Figure 1

Pediatric PBPK model development workflow. PBPK, physiologically based pharmacokinetic.

Figure 2

Simulated (lines) and observed (symbols) plasma concentrations of a hypothetical drug administered as a 30-min i.v. infusion of 2 mg to an adult population.

Figure 3

Simulated (lines) and observed (symbols) plasma concentrations of a hypothetical drug administered orally as a 50 mg tablet to an adult population. Eighty-six percent of all individual (n = 6) observed data points are within the simulated 90th percentile.

Figure 4

A box whisker plot of the maximum concentration (C_max) vs. age class for a hypothetical drug administered orally as a 1 mg/kg dose formulated as a suspension (0.1 mg/ml) to a pediatric population (n = 10,000; ages 0–17 years). The boundaries of the box indicate the 25th and 75th percentile with the line representing the median. Error bars indicate the 90th and 10th percentiles, and the symbols indicate outliers.

Figure 5

Simulation of area under the plasma concentration–time curve (AUC) vs. body weight for rivaroxaban administered at 0.143 mg/kg body weight and formulated as an oral suspension as compared with the adult reference population. Simulated data of the pediatric population are represented as a geometric mean (blue line) and 90% prediction interval (gray shaded area). Simulated data of the adult reference population are represented as a geometric mean (thick red line) and 90% confidence interval (red shaded area in the background of the graph). Expected weight ranges for infants, preschool children, children, and adolescents are indicated. Taken from Willmann et al.

Figure 6

A box whisker plot of AUC_inf (y-axis) values as a function of age class for a given dose (in mg/kg) of hypothetical drug administered orally as a suspension to a pediatric population (n = 10,000; ages 0–17 years) that would reach equivalent AUC_inf as a 50 mg tablet in adults. The box is the interquartile range (IQR) representing the 25th to 75th percentile. The whiskers represent the last point within 1.5 times the IQR of the 25th and 75th percentile. Circles represent all points above or below the whiskers. The blue dotted line is the geometric mean AUC_inf, and the shaded area is the 90th percentile of adult values. Red dots are the adult individuals.