A Workflow Example of PBPK Modeling to Support Pediatric Research and Development: Case Study with Lorazepam
Journal Title: The AAPS Journal - Year 2013, Vol 15, Issue 2
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 (Vss) 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 Vss 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.
Authors and Affiliations
A. R. Maharaj, J. S. Barrett, A. N. Edginton
Keywords
Related Articles
- EP ID EP681097
- DOI 10.1208/s12248-013-9451-0
- Views 76
- Downloads 0
Detergent-resistant membrane microdomains in the disposition of the lipid signaling molecule anandamide
The endogenous cannabinoid anandamide is an agonist of the cannabinoid receptors CB1 and CB2, as well as transient receptor potential vanilloid type 1 and type 4 ion channels. In recent years, there has been a great deal...
RGS6 as a Novel Therapeutic Target in CNS Diseases and Cancer
Regulator of G protein signaling (RGS) proteins are gatekeepers regulating the cellular responses induced by G protein-coupled receptor (GPCR)-mediated activation of heterotrimeric G proteins. Specifically, RGS proteins...
Physical Approaches for Nucleic Acid Delivery to Liver
The liver is a key organ for numerous metabolic pathways and involves many inherited diseases that, although being different in their pathology, are often caused by lack or overproduction of a critical gene product in th...
Epigenetic Cancer Prevention Mechanisms in Skin Cancer
Epigenetics is an important emerging area for study of mechanisms of cancer prevention. In recent years, it has been realized that cancer prevention agents, derived from natural dietary sources, impact cancer cell surviv...
Updated Announcement—AAPS and FDA Agreement to Build Quantitative Alzheimer’s Disease Model