Target-mediated drug disposition (TMDD)
In target-mediated drug disposition, binding to the pharmacological target contributes to the drug’s distribution and elimination. Because the target can saturate, clearance falls at higher concentrations and PK is nonlinear.
Definition
Target-mediated drug disposition (TMDD) is the situation in which binding of the drug to its pharmacological target, with internalization and degradation of the complex, contributes to the drug's elimination and distribution. It is typical for antibodies against abundant, internalizing targets.
Nonlinear PK
The binding capacity of the target is limited. At low concentrations a large share of the drug is cleared through the target, so clearance is high; at higher concentrations the target saturates and clearance falls toward the linear, non-specific value. Clearance, and therefore the AUC per dose, depends on dose.
Models
A full TMDD model describes free drug, free target and the complex. Approximations replace it when the binding is fast: a quasi-steady-state model, or a Michaelis–Menten (nonlinear) elimination term.
On this site
The nimotuzumab population PK analysis compares a linear one-compartment model, a linear two-compartment model and a two-compartment model with nonlinear elimination, and asks which structure is needed to compare exposure across dosing conditions. The nonlinear candidate is not presented as a reproduction of the original TMDD model. See also population PK models.
Frequently asked questions
Why does TMDD make PK nonlinear?
The target can saturate. At low concentrations the target-mediated route clears a large share of the drug; at high concentrations it is saturated, so clearance falls.
Is a nonlinear elimination model the same as a TMDD model?
No. A Michaelis–Menten elimination term approximates the saturable route, but a TMDD model describes the binding explicitly, with free drug, free target and complex.