Predicting the Onset of Nonlinear Pharmacokinetics

This is the authors' abstract. We don't add key points for this paper.

When analyzing the pharmacokinetics ( PK ) of drugs, one is often faced with concentration C vs. time curves, which display a sharp transition at a critical concentration C crit . For C > C crit , the curve displays linear clearance and for C < C crit clearance increases in a nonlinear manner as C decreases. Often, it is important to choose a high enough dose such that PK remains linear in order to help ensure that continuous target engagement is achieved throughout the duration of therapy. In this article, we derive a simple expression for C crit for models involving linear and nonlinear (saturable) clearance, such as Michaelis‐Menten and target‐mediated drug disposition ( TMDD ) models.