TMDd

TMDD stands for Target-Mediated Drug Disposition, a pharmacokinetic phenomenon and modeling approach used when a drug interacts with a specific biological target, such as a receptor or enzyme, in a manner that meaningfully alters its clearance and distribution. This effect is particularly important for biologics like monoclonal antibodies and other high-affinity agents, but can also arise with small molecules that strongly bind to a target.

The core idea of TMDD is that drug clearance can be driven, at least in part, by binding to the target. The drug and target form a complex that may be internalized, degraded, or recycled, creating an additional, saturable clearance pathway. Because binding is saturable, drug kinetics become nonlinear at therapeutic concentrations: clearance is higher when the target is unsaturated and tends to level off as binding sites become saturated, while target occupancy influences pharmacodynamic responses.

Modeling TMDD typically involves full mechanistic frameworks that track free drug, free target, and the drug-target complex, with rate constants for binding (kon and koff) and for internalization or degradation of the complex, as well as target production and loss. Simplified TMDD approaches, such as quasi-equilibrium or quasi-steady-state approximations, reduce complexity. These models are often integrated with PK/PD data to predict dose-Exposure and exposure-occupancy relationships, and to aid dose selection for biologics.

Applications of TMDD include development and characterization of monoclonal antibodies, fusion proteins, and other targeted therapies, where nonlinear PK and target engagement are critical for understanding efficacy and safety. Limitations include model complexity, data requirements, and potential identifiability challenges, which can limit practical use in some settings.