Multiscale Modeling of Antibody-Drug Conjugates: Connecting Tissue and Cellular Distribution to Whole Animal Pharmacokinetics and Potential Implications for Efficacy

Antibody-drug conjugates exhibit complex pharmacokinetics due to their combination of macromolecular and small molecule properties. These issues range from systemic concerns, such as deconjugation of the small molecule drug during the long antibody circulation time or rapid clearance from nonspecifi...

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Bibliographic Details
Published in:The AAPS journal 2016-09, Vol.18 (5), p.1117-1130
Main Authors: Cilliers, Cornelius, Guo, Hans, Liao, Jianshan, Christodolu, Nikolas, Thurber, Greg M.
Format: Article
Language:English
Subjects:
Animals
Antibodies, Monoclonal, Humanized - administration & dosage
Antibodies, Monoclonal, Humanized - pharmacokinetics
Antineoplastic Agents - administration & dosage
Antineoplastic Agents - pharmacokinetics
Biochemistry
Biomedical and Life Sciences
Biomedicine
Biotechnology
Cell Line, Tumor
Dose-Response Relationship, Drug
Immunotoxins - administration & dosage
Immunotoxins - pharmacokinetics
Maytansine - administration & dosage
Maytansine - analogs & derivatives
Maytansine - pharmacokinetics
Mice
Mice, Nude
Models, Theoretical
Pharmacology/Toxicology
Pharmacy
Research Article
Theme: Systems Pharmacokinetics Models for Antibody-Drug Conjugates
Tissue Distribution - drug effects
Tissue Distribution - physiology
Trastuzumab - administration & dosage
Trastuzumab - pharmacokinetics
Treatment Outcome
Tumor Burden - drug effects
Tumor Burden - physiology
Xenograft Model Antitumor Assays - methods
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Summary:Antibody-drug conjugates exhibit complex pharmacokinetics due to their combination of macromolecular and small molecule properties. These issues range from systemic concerns, such as deconjugation of the small molecule drug during the long antibody circulation time or rapid clearance from nonspecific interactions, to local tumor tissue heterogeneity, cell bystander effects, and endosomal escape. Mathematical models can be used to study the impact of these processes on overall distribution in an efficient manner, and several types of models have been used to analyze varying aspects of antibody distribution including physiologically based pharmacokinetic (PBPK) models and tissue-level simulations. However, these processes are quantitative in nature and cannot be handled qualitatively in isolation. For example, free antibody from deconjugation of the small molecule will impact the distribution of conjugated antibodies within the tumor. To incorporate these effects into a unified framework, we have coupled the systemic and organ-level distribution of a PBPK model with the tissue-level detail of a distributed parameter tumor model. We used this mathematical model to analyze new experimental results on the distribution of the clinical antibody-drug conjugate Kadcyla in HER2-positive mouse xenografts. This model is able to capture the impact of the drug-antibody ratio (DAR) on tumor penetration, the net result of drug deconjugation, and the effect of using unconjugated antibody to drive ADC penetration deeper into the tumor tissue. This modeling approach will provide quantitative and mechanistic support to experimental studies trying to parse the impact of multiple mechanisms of action for these complex drugs.
ISSN:1550-7416
1550-7416
DOI:10.1208/s12248-016-9940-z