A Workflow Example of PBPK Modeling to Support Pediatric Research and Development: Case Study with Lorazepam

Abstract

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.

Physiologically Based Pharmacokinetic Predictions of Tramadol Exposure Throughout Pediatric Life: an Analysis of the Different Clearance Contributors with Emphasis on CYP2D6 Maturation

“…Physiologically based pharmacokinetic (PBPK) modeling enables pediatric pharmacological research to proceed to the next level, by guiding dose finding studies and the formulation design for the different stages in pediatric life (1)(2)(3)(4). The stronghold of PBPK models is that they separate intrinsic from extrinsic patient factors, i.e., drug-independent (system) factors versus drug-dependent factors and study design, so that a physiologically plausible generic human model structure can be applied for any drug under various study conditions (3,5).…”

Sorafenib metabolism, transport, and enterohepatic recycling: physiologically based modeling and simulation in mice

“…Because of their mechanistic basis a PBPK model allows us to test hypotheses, with extrapolation being the most commonly applied hypothesis testing process. This has been used to assess the relevance of a drug-drug interaction [29] or the first-in-pediatric dose using extrapolation from an adult model [30]. Hypothesis generation on the other hand is a process to help us understand mechanisms.…”

Development of a Pediatric Physiologically-Based Pharmacokinetic Model of Clindamycin Using Opportunistic Pharmacokinetic Data

“…We followed the FDA guidance on PBPK model development and workflow in children to build our pediatric PBPK model (Figure 1) (9-11). We first developed an adult PBPK model and extracted clindamycin IV concentration versus time data from 3 adult PK studies (12-14).…”