Predicting the Onset of Nonlinear Pharmacokinetics

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. Study Highlights