Liam V Brown 1, Alberto Ippolito 2, Mark Penney 1, Rhys DO Jones 1
1 AstraZeneca (Cambridge, United Kingdom), 2 Merck Group (London, United Kingdom)
Target-mediated drug distribution (TMDD) is typically classified by accelerated removal of drug after serum concentration drops below a critical level [1,2]. 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 degradation. 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 [3].
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 characterise 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.
References:
0. Brown et al: A simple algebraic expression can determine if a drug’s clearance is non-specific or target-mediated. Submitted (2026)
1. Peletier and Gabrielsson: Dynamics of target-mediated drug disposition: characteristic profiles and parameter identification. J PKPD 39, 429–451 (2012)
2. Gabrielsson et al: In vivo potency revisited – Keep the target in sight. Pharmacology and Therapeutics 184, 177–188 (2018)
3. Penney et al: Predicting the pharmacokinetics of T-Cell Engagers as a function of Target-Mediated Drug Disposition. Clin Transl Sci. 18(11) (2025)
Reference: PAGE 34 (2026) Abstr 11942 [www.page-meeting.org/?abstract=11942]
Poster: Drug/Disease Modelling - Absorption & PBPK