Physiologically based pharmacokinetic modeling of oseltamivir in pregnant rhesus macaques to inform clinical dosing across trimesters

Abstract

Oseltamivir phosphate is a lipophilic prodrug that is metabolized to the active form, oseltamivir carboxylate, by carboxylesterase 1 enzymes in the liver in humans and in the liver and gut in rhesus macaques. Oseltamivir carboxylate is hydrophilic and distributes extensively in extracellular fluids, including plasma, and is eliminated primarily by the kidneys through glomerular filtration and tubular secretion. Pregnant women have lower systemic exposure to oseltamivir carboxylate due to an increase in plasma volume and total body water, leading to an increased apparent volume of distribution and increased renal excretion. To evaluate the differences in oseltamivir pharmacokinetics during pregnancy, a study was conducted previously using rhesus monkeys that were administered oseltamivir phosphate via intravenous and nasogastric routes at doses of 2.5 mg/kg body weight during the three trimesters of pregnancy. In the current study, we present a physiologically based pharmacokinetic (PBPK) model to help characterize the pharmacokinetic data that were collected in the previous study and demonstrate how the model can be used to predict the pharmacokinetics of oseltamivir and oseltamivir carboxylate in pregnant women. As it can be challenging to obtain rich clinical data in pregnant women, evaluating drug pharmacokinetics in preclinical species using tools such as PBPK models can provide reliable estimates of drug disposition across species during sensitive life stages such as pregnancy. Using the PBPK modeling approach, we were able to successfully characterize a reduction in oseltamivir carboxylate exposure during pregnancy in rhesus macaques (20–25 % decrease in AUC) and satisfactorily extend the model predictions to humans by accounting for physiological changes that occur throughout the different stages of pregnancy. The rhesus macaque can thus be considered a promising animal model for extrapolating pharmacokinetic predictions during pregnancy, especially for drugs or chemicals that are metabolized by hydrolysis reactions and primarily eliminated by renal excretion.