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  • Title: Predicting the Onset of Nonlinear Pharmacokinetics.
    Author: Stein AM, Peletier LA.
    Journal: CPT Pharmacometrics Syst Pharmacol; 2018 Oct; 7(10):670-677. PubMed ID: 30196577.
    Abstract:
    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 Ccrit . For C > Ccrit , the curve displays linear clearance and for C < Ccrit 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 Ccrit for models involving linear and nonlinear (saturable) clearance, such as Michaelis-Menten and target-mediated drug disposition (TMDD) models. Study Highlights.
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