Physiologically Based Pharmacokinetic (PBPK) Modeling of Amoxicillin in Neonates and Infants

Authors: Lukacova V, Bolger MB, Woltosz WS
Conference: ACoP
Keywords: Advanced Compartmental Absorption and Transit (ACAT™) model, Amoxicillin, Cp-Time, PBPK, PBPKPlus, pediatrics
Software: GastroPlus®
Division: Simulations Plus

Abstract

Objective: An amoxicillin PBPK model was previously developed and validated in healthy adults as well as adults with altered renal function [1-2]. The purpose of this study was to explore the utility of the model in describing amoxicillin pharmacokinetics (PK) in neonates and infants.

Methods: An adult absorption/PBPK model for amoxicillin was previously developed [1] using GastroPlus™ 8.0 (Simulations Plus, Inc., Lancaster, CA). The program’s Advanced Compartmental Absorption and Transit (ACAT™) model described the absorption of the drug, while PK was simulated with its PBPKPlus™ module. In the adult model, both intestinal absorption and tissue distribution included passive diffusion and carrier-mediated transport (PepT1/PepT2 influx and MRP4 efflux in kidney, liver and brain; PepT1/PepT2 influx in intestine; and a basolateral influx transporter in kidney). Total clearance consisted of renal (major) and hepatic (minor) components. Physiological parameters were generated by the program or obtained from literature. Certain drug-dependent parameters were obtained by fitting against reported plasma concentration-time (Cp-time) profiles and amounts secreted in urine after amoxicillin i.v. and p.o. administration in healthy volunteers. The model was further validated by predicting amoxicillin PK in different adult populations [2]. For this study, infant and neonate physiologies were based on information collected from literature. Aside from body weight, height, and individual tissue sizes and blood flows, parameters with a large effect on amoxicillin pharmacokinetics included changes in extracellular water in very young infants, glomerular filtration rate, and renal transporters. Fraction unbound in plasma and blood-to-plasma concentration ratio were adjusted to account for infant plasma protein levels and hematocrit. Literature information on ontogeny of relevant transporters was not found. The PBPK model, along with observed amoxicillin Cp-time profiles after i.v. administration, was used to estimate transporter expression levels in different groups of infants.

American Conference on Pharmacometrics (ACoP), May 12-15, 2013, Fort Lauderdale, Florida

By Viera Lukacova, Michael B. Bolger, Walter S. Woltosz