A simple algebraic expression can determine if a drug's clearance is non-specific or target-mediated

Target-mediated drug distribution (TMDD) is typically classified by accelerated removal of drug after serum concentration drops below a critical level. Susceptible drugs would be dosed to a schedule that maintains exposure above this level, where concentration drops monoexponentially. Out-dosing TMDD often implies that target binding is saturated or degraded. T-cell engagers and other biologics are often given with low dosages which make out-dosing TMDD unrealistic, yet are also typically observed to have monoexponential elimination. It can be challenging to determine whether such a concentration-time relationship is due to TMDD or standard non-specific (intrinsic) routes of clearance, and more so to scale this clearance from preclinical settings, as TMDD-driven clearance may not scale allometrically like intrinsic clearance. In this work, we derived an algebraic expression for the proportion of clearance that is target-mediated or intrinsic, which requires only the intrinsic half-life and the target receptor's concentration, turnover rate and binding affinity for the drug. We further show that the typical transition from monoexponential decline of serum concentrations to accelerated, target-driven clearance occurs at concentrations given by two expressions in those same parameters. We apply the equations to published data for monoclonal antibodies and T-cell engagers, finding that we consistently characterize their clearance as expected. These expressions can be used to determine if a drug's clearance would be expected to be driven by target-mediated or non-specific routes at pharmacologically active concentrations, and hence how to accurately translate pharmacokinetic properties from preclinical species to human, a process that is essential for drug development.