Viera Lukacova, Michael B. Bolger, Walter S. Woltosz
Simulations Plus, Inc., Lancaster, CA, USA
Objectives: An amoxicillin PBPK model was previously developed and validated in several adult populations. The purpose of this study was to explore the utility of the model in describing amoxicillin pharmacokinetics (PK) in neonates and infants.
Methods: An absorption/PBPK model for amoxicillin PK in adult populations was previously developed and validated [1-2] using GastroPlus™ 8.0 (Simulations Plus, Inc.). The program’s Advanced Compartmental Absorption and Transit (ACAT™) model described the absorption of the drug, while PK was simulated with its PBPKPlus™ module. Intestinal absorption and tissue distribution accounted for both passive diffusion and carrier-mediated transport. Total clearance consisted of renal (major) and hepatic (minor) components. Physiologies for infants and neonates were based on information collected from literature. These account for body weight, height, tissue sizes and blood flows, as well as rapid changes in extracellular water and renal function during first few weeks of life. Plasma protein and red blood cell binding was adjusted to account for infant plasma protein levels and hematocrit. The PBPK model, along with observed Cp-time profiles after i.v. administration was used to estimate the ontogeny of renal transporters.
Results: The PBPK model for amoxicillin correctly predicted volume of distribution in infants. The age-dependent glomerular filtration rate (GFR) was incorporated as reported in the literature for full-term and pre-term infants [3-4]. Renal transporter expression levels were fitted against observed Cp-time profiles from some studies and validated by using the final model to simulate amoxicillin PK in subjects of similar age from different studies. The differences in scaling for GFR and renal transporters are in line with the reported rates of maturation of GFR and active tubular secretion [5].
Conclusions: Amoxicillin is eliminated primarily by renal secretion. A physiological model that included relevant distribution and clearance mechanisms was previously fitted and validated in different adult populations. In the current work the model was applied to simulations of amoxicillin PK in neonates and infants: (1) to fill-in missing pieces of physiological information (ontogeny of renal transporters) using available in vivo data; and (2) to explore sources of variability in amoxicillin PK and provide insights into the drug’s behavior in populations where large scale clinical studies are not feasible.
References:
[1] Lukacova V., Poster presentation (#6366), AAPS Annual Meeting 2012, Chicago IL
[2] [2] Lukacova V., Poster presentation (#6367), AAPS Annual Meeting 2012, Chicago IL
[3] DeWoskin R.S., Regul Toxicol Pharmacol 2008, 51 : 66-86
[4] Arant B.S., J Pediatr 1978, 92: 705-712
[5] Huisman-de Boer, J.J., Antimicrob Agents Chemother 1995, 39(2): 431-434
Reference: PAGE 22 () Abstr 2953 [www.page-meeting.org/?abstract=2953]
Poster: Paediatrics