Saskia Fuhrmann (1,2), Charlotte Kloft (3) and Wilhelm Huisinga (4)
(1) Institute of Biochemistry, Universitaet Potsdam, Germany; (2) Graduate Research Training Program PharMetrX: Pharmacometrics & Computational Disease Modelling, Freie Universitaet Berlin and Universitaet Potsdam, Germany (3) Institute of Pharmacy, Dept. Clinical Pharmacy & Biochemistry, Freie Universitaet Berlin; (4) Institute of Mathematics, Universitaet Potsdam, Germany
Objectives:
Heterogeneous distribution of antibodies within tumor tissue, often discussed in the context of the `binding site barrier’, is still a current topic of debate, in particular for antibody-drug conjugates (ADCs)[1]. Furthermore, for monoclonal antibodies (mAbs) competing with a natural ligand for receptor binding, receptor inhibition is also an important measure for efficacy. The objective was to comprehensively investigate mAb distribution within tumor tissue and its implications on therapeutic efficacy based on a mechanistic modelling framework that allows to study in detail receptor saturation and receptor inhibition.
Methods:
Model development was based on a consensus PBPK (cPBPK) model for mAbs [2] that incorporates total plasma in addition to various tissues with an extravasation-rate limited tissue distribution model for organs except tumor. The cPBPK model is fully specified by readily available physiological and drug-specific parameters for various species, validated ABC values [3] and a-priori median unspecific clearance with one equation per tissue. The model thus allows to a-priori predict target independent mAb disposition processes as well as mAb disposition in concentration ranges, for which the linear unspecific clearance dominates target-mediated clearance processes. This is often the case for mAb therapies at steady state. The cPBPK model has successfully been validated against preclinical and clinical data. For the present study, the cPBPK model was extended by a detailed tumor distribution model (Krogh cylinder geometry). The Krogh cylinder is divided into sub-compartments that represent the tumor tissue around the blood capillary. Tumor parameters were taken from literature [1] and were not fit to data. Furthermore, the tumor model integrates a single cell-level modelling approach [4,5] to account for antibody-receptor-ligand interactions as well as receptor dynamics.
Results:
The experimentally observed heterogeneous drug distribution within solid tumor tissue in xenograft mice following approved clinical dosing regimens of ADCs [1] was confirmed based on the cell-level based tumor cPBPK model and considered as a first validation of the extended approach. Extrapolation to patients, however, predicted a homogenous drug tumor distribution following clinical dosing regimens of ADCs. The qualitative species-differences may be related to a marked difference in tumor volume per kg body weight, which is almost 2-3 orders of magnitude larger in xenograft mice than typically in patients. As a consequence, target-mediated mAb disposition dominates linear clearance in mice, resulting in faster declining PK profiles. In humans, however, linear unspecific mAb clearance is the dominating clearance process, and its inter-individual variability has a marked influence on the duration of receptor saturation. In the context of multiple dosing and if receptor saturation is required for efficacy, this finding has important implications (i) for the first treatment cycle and (ii) in the case of increased unspecific CL (e.g., due to immunogenicity). In addition, if the mAb is competing for receptor binding with a natural ligand we found that residual receptor activity (in contrast to receptor saturation by the mAb) may largely differ.
Conclusions:
The cell-level based tumor cPBPK offers a mechanistic framework to especially investigate the dosing regimen within the initial treatment period of ADCs targeting solid tumors and to study the impact of antibody receptor affinity as well as the tumor micro-environment (e.g., ligand concentration within tumor) on residual receptor inhibition and receptor saturation.
References:
[1] Cilliers and Thurber et al. The AAPS Journal, 18: 1117-30, 2016.
[2] S.Fuhrmann et al. J Pharmacokinet Pharmacodyn, 44: 351-374, 2017.
[3] Shah et al. mAbs, 5:297-305, 2013.
[4] W.Huisinga, S.Fuhrmann, L.Fronton, B.F.Krippendorff
Target-Driven Pharmacokinetics of Biotherapeutics
in Application of ADME and Translational PK/PD in the development of therapeutic biologics (Eds. H. Zhou and F.-P. Theil)
Wiley, 2015.
[5] B.-F. Krippendorff et al. J Pharmacokinet Pharmacodyn, 39: 125-39, 2012.
Reference: PAGE 27 (2018) Abstr 8657 [www.page-meeting.org/?abstract=8657]
Poster: Drug/Disease Modelling - Absorption & PBPK