Objective

Physiologically-based pharmacokinetic models (PBPK) are increasingly utilised since they are more mechanistic than ‘classical’ compartmental PK models as they incorporate anatomical and physiological knowledge into descriptions of pharmacokinetics. Building and validating such models requires measurements of drug concentrations in tissues as well as plasma. However, due to the specific characteristics of antibodies (e.g. common “macro-structure” and molecular weight, non-specific elimination governed by common Fc component, distribution limited to plasma and interstitial liquid, intracellular metabolism, parenteral administration), their ADME profiles are expected to be similar within a mAb isotype and it is possible to extrapolate the PK information from one antibody to another. ‘Lumping’ is a commonly employed approach to reduce the dimensionality and complexity of whole body PBPK models grouping tissues that show similar kinetics together in the same compartment, the ‘lumped’ compartment. Cao et al proposed to lump compartments using two categories of tissues: the leaky and tight tissue in the so-called minimal PBPK model (mPBPK). These models can also embed the target binding features using the target mediated drug disposition (TMDD) concept. In principle, the location of TMDD should be chosen consistent with target expressing tissues. Another approach of interest is to isolate one specific tissue and lump the rest of the tissues in one compartment: the so called hybrid model. These models allow more detailed descriptions of drug exposures or disposition for specific tissues and they can be used to guide dose selection at early phases, when target engagement (TE) is used as pharmacological endpoint (e.g. FIH). A case study for monoclonal antibody against a soluble target will be presented to illustrate how TE data from a FIH can be used to assess the probability of pharmacological success (i.e, TE above 90%) in subsequent studies using clinical trial simulations that take into account study design characteristics Cao Y and Jusko WJ. "Incorporating target-mediated drug disposition in a minimal physiologically-based pharmacokinetic model for monoclonal antibodies." J pharmacokinet pharmacodyn 41.4 (2014): 375-387.