Aim: Purpose of the study was to predict amoxicillin pharmacokinetics in populations with altered renal function to further validate an absorption/PBPK model for amoxicillin.
Methods: An absorption/PBPK model for amoxicillin was developed using GastroPlusTM 8.0 (Simulations Plus, Inc., Lancaster, CA). The program’s Advanced Compartmental Absorption and Transit (ACAT™) model described the passive and carrier-mediated absorption of the drug, while pharmacokinetics were simulated with its PBPKPlusTM module. Both intestinal absorption and tissue distribution included components of passive diffusion and carriermediated transport. Total clearance consisted of renal (major) and hepatic (minor) components. Physiological parameters (tissue sizes, blood flows, relative expression levels of transporters, etc.) were generated by the program or were obtained from literature. A number of 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. To verify that the model included correct contributions of different processes affecting the Cp-time profile, the model was used to predict the amoxicillin pharmacokinetics in different populations. In this prediction, renal clearance was adjusted according to reported changes in renal function in pregnant women and in subjects with impaired renal function. The remaining fitted drug-dependent parameter values were retained as fitted earlier against Cp-time profiles in healthy volunteers.
American Association of Pharmaceutical Scientists (AAPS), October 14-18, 2012, Chicago, IL
By Viera Lukacova, Walter S. Woltosz, Michael B. Bolger