Target-mediated drug disposition

Target-mediated drug disposition (TMDD) is a term used in pharmacokinetics to describe the phenomenon where the pharmacokinetics of a drug are significantly affected by its own pharmacodynamics. This typically occurs when a drug has a high affinity for a specific target such as a receptor, enzyme, or transporter, and the drug-target interaction significantly influences the drug's distribution and elimination.

Overview

TMDD is often observed with biologic drugs, including monoclonal antibodies, recombinant proteins, and gene therapies. These drugs often have high affinities for their targets, and the targets can be present in limited quantities. As a result, the drug-target interaction can significantly influence the drug's pharmacokinetics.

Mechanism

The mechanism of TMDD involves the binding of the drug to its target. This binding can lead to the internalization and degradation of the drug-target complex, effectively removing the drug from circulation. This can result in nonlinear pharmacokinetics, where the drug's clearance rate changes with its concentration.

In some cases, the target can be upregulated in response to drug binding, leading to an increase in the drug's clearance rate. This is known as target-mediated drug induction.

Mathematical modeling

Mathematical models have been developed to describe and predict the pharmacokinetics of drugs exhibiting TMDD. These models typically involve differential equations that describe the rates of drug absorption, distribution, metabolism, and excretion, as well as the rates of target binding and internalization.

Clinical implications

Understanding TMDD is important for the development and dosing of new drugs. If a drug exhibits TMDD, its dose-response relationship may be nonlinear, and its optimal dose may depend on the patient's target levels. Additionally, TMDD can lead to variability in drug response between patients, which can complicate drug development and dosing strategies.

See also

• Pharmacokinetics
• Pharmacodynamics
• Biologic drugs
• Monoclonal antibodies
• Recombinant proteins
• Gene therapies