Abstract
Methods: We have developed a novel pharmacokinetic model, termed dynamic TMDD, to mechanistically describe the phenomenon of drug induced changes in target expression and resultant TMDD. The model is based on first principle reaction kinetics and contains easily interpretable and biology-based parameters, linking target engagement to changes in synthesis.
Results: We demonstrate how tuning a single parameter can convert between a static-, target-depleting-, and target inducing-TMDD. Ease of utility is demonstrated by reproducing PK profiles of two drugs: Rituximab (anti-CD20) for target-depleting TMDD, wherein clearance decreases over successive cycles, and CEA-IL2 for target-inducing TMDD, wherein clearance increases over time. We explore properties of these differing classes of molecules through simulations of the effect of dose and affinity on PK/PD profiles.
This work was initially presented by Applied BioMath. Applied BioMath was acquired by Certara in 2023.