Dynamic Target-Mediated Drug Disposition (TMDD)


Objectives: Clearance of biologics is mediated by two routes: non-specific (linear) protein catabolism and target-mediated (saturable) endocytosis. The hallmark of such target-mediated drug disposition (TMDD) is non-linear clearance, wherein drug clearance and resulting exposure is concentration-dependent.  Pharmacokinetic (PK) models incorporating TMDD in common use presume target synthesis rate to be constant.  While this is generally a reasonable assumption, there are documented cases where it does not hold.  If target synthesis changes over time due to pharmacological activity of the drug, the rate of TMDD and clearance will thus change with successive doses, affecting drug concentration profiles and activity.  This creates a nonintuitive phenomenon, wherein pharmacodynamics (PD) affect pharmacokinetics – a PD/PK model. This phenomenon is especially important in oncology/immuno-oncology. For drugs which deplete target expressing cells, target expression and drug clearance over time (e.g. Anti-CD20).&n For biologics which induce expansion of target expressing cells, target expression and drug clearance over time (e.g. immuno-cytokines such as IL-2). A modeling framework which quantifies drug-induced changes in target synthesis may be important to capture pharmacokinetic profiles of such agents.

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.

Conclusion: For molecules exhibiting target-depleting TMDD, higher affinity always results in greater biological activity.  However, for the case of target-inducing TMDD, a lower affinity drug can provide improved biological activity by balancing TMDD-mediated clearance vs target engagement. Non-linear clearance profiles typical of TMDD are however not produced in the latter case, which may mask this phenomenon when examining single ascending dose-PK profiles. In both cases, doses may need to be adjusted over successive cycles to maintain consistent exposure and target engagement.

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