Predicting the Onset of Nonlinear Pharmacokinetics

Abstract

When analyzing the pharmacokinetics (PK) of drugs, one is often faced with concentration Cvs. time curves, which display a sharp transition at a critical concentration Ccrit. For C> Ccrit, the curve displays linear clearance and for C < Ccritclear-ance increases in a nonlinear manner as Cdecreases. Often, it is important to choose a high enough dose such that PK re-mains 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 Ccritfor models involving linear and nonlinear (saturable) clearance, such as Michaelis-Menten and target- mediated drug disposition (TMDD) models.