A workflow example of PBPK modeling to support pediatric research and development: case study with lorazepam

Abstract

The use of physiologically based pharmacokinetic (PBPK) models in the field of pediatric drug development has garnered much interest of late due to a recent Food and Drug Administration recommendation. The purpose of this study is to illustrate the developmental processes involved in creation of a pediatric PBPK model incorporating existing adult drug data. Lorazepam, a benzodiazepine utilized in both adults and children, was used as an example. A population-PBPK model was developed in PK-Sim v4.2® and scaled to account for age-related changes in size and composition of tissue compartments, protein binding, and growth/maturation of elimination processes. Dose (milligrams per kilogram) requirements for children aged 0-18 years were calculated based on simulations that achieved targeted exposures based on adult references. Predictive accuracy of the PBPK model for producing comparable plasma concentrations among 63 pediatric subjects was assessed using average-fold error (AFE). Estimates of clearance (CL) and volume of distribution (V(ss)) were compared with observed values for a subset of 15 children using fold error (FE). Pediatric dose requirements in young children (1-3 years) exceeded adult levels on a linear weight-adjusted (milligrams per kilogram) basis. AFE values for model-derived concentration estimates were within 1.5- and 2-fold deviation from observed values for 73% and 92% of patients, respectively. For CL, 60% and 80% of predictions were within 1.5 and 2 FE, respectively. Comparatively, predictions of V(ss) were more accurate with 80% and 100% of estimates within 1.5 and 2 FE, respectively. Using the presented workflow, the developed pediatric model estimated lorazepam pharmacokinetics in children as a function of age.

Fig. 1

Proposed workflow for scaling adult PBPK models toward children

Fig. 2

a Predicted (solid line corresponds to geometric mean; dashed lines corresponds to 5th and 95th percentiles; virtual population n=100) versus observed (symbols – (, –22)) plasma concentration versus time data following a 2-mg IV lorazepam bolus in adults. Log (concentration) versus Log (time) plot is displayed in insert. b Predicted (solid line corresponds to geometric mean; dashed lines corresponds to 5th and 95th percentiles; virtual population n=1140) versus observed (symbols – (30)) plasma concentration versus time data following a 0.05 mg/kg IV lorazepam bolus in children aged 0 to 18 years. Log (concentration) versus Log (time) plot is displayed in insert

Fig. 3

Pediatric dose (milligrams per kilogram) required to achieve an equivalent AUC_0→∞ of a 2-mg dose in adults. a Entire pediatric age-range. b Children between 0 and 1 years old

Fig. 4

Mean tissue concentration-time profiles for selected organs among a virtual population (n = 100) of 2-year-old subjects

Fig. 5

Predictive accuracy plots: Individual AFE values for PBPK model concentration-time predictions for the 63 pediatric patients (plot A), fold error associated PBPK model clearance predictions for the 15 elective patients (plot B), and fold error associated PBPK model volume of distribution predictions for the 15 elective patients (plot C) (dotted line represents 1.5-fold error. Dashed line represents twofold error)