Analytical Solution and Exposure Analysis of a Pharmacokinetic Model with Simultaneous Elimination Pathways and Endogenous Production: The Case of Multiple Dosing Administration.

In this paper, a typical pharmacokinetic (PK) model is studied for the case of multiple intravenous bolus-dose administration. This model, of one-compartment structure, not only exhibits simultaneous first-order and Michaelis-Menten elimination, but also involves a constant endogenous production. For the PK characterization of the model, we have established the closed-form solution of concentrations over time, the existence and local stability of the steady state. Using analytical approaches and the concept of corrected concentration, we have shown that the area under the curve ([Formula: see text]) at steady state is higher compared to that at the single dose ([Formula: see text]). Moreover, by splitting the dose and dosing interval into halves, we have revealed that it can result in a significant decrease in the steady-state average concentration. These model-based findings, which contrast with the current knowledge for linear PK, confirm the necessity to revisit drugs exhibiting nonlinear PK and to suggest a rational way of using mathematical analysis for the dosing regimen design.