Target–Mediated Drug Disposition Model
This document presents a SimBiology implementation of Mager and Jusko’s generic Target-Mediated Drug Disposition model (TMDD) as described in General pharmacokinetic model for drugs exhibiting target-mediated drug disposition. Target-mediated drug disposition is a common source of nonlinearity in PK profiles for biotherapeutics. Nonlinearities are introduced because drug-target bindings saturate at therapeutic dosing levels.
In 2001, Mager and Jusko  proposed a generic TMDD model that accounted for saturable drug-target binding, as well as target (or receptor) mediated elimination.
Drug in the
Plasma reversibly binds with the unbound
Target to form drug-target
koff are the association and dissociation rate constants, respectively. Clearance of free
Complex from the
Plasma is described by first-order processes with rate constants,
km, respectively. Free target turnover is described by a zero-order synthesis rate,
ksyn, and a first order elimination (rate constant,
kdeg). The model also includes an optional
Tissue compartment to account for non-specific tissue binding or distribution. Variants of this TMDD model have been since used to characterize the pharmacokinetics of numerous drugs.
 Mager DE and Jusko WJ (2001) General pharmacokinetic model for drugs exhibiting target-mediated drug disposition. J Pharmacokinetics and Pharmacodynamics 28: 507–532.