title: Evolution of Antibody-Drug Conjugate Tumor Disposition Model to Predict Preclinical Tumor Pharmacokinetics of Trastuzumab-Emtansine (T-DM1).
abstract: A mathematical model capable of accurately characterizing intracellular disposition of ADCs is essential for a priori predicting unconjugated drug concentrations inside the tumor. Towards this goal, the objectives of this manuscript were to: (1) evolve previously published cellular disposition model of ADC with more intracellular details to characterize the disposition of T-DM1 in different HER2 expressing cell lines, (2) integrate the improved cellular model with the ADC tumor disposition model to a priori predict DM1 concentrations in a preclinical tumor model, and (3) identify prominent pathways and sensitive parameters associated with intracellular activation of ADCs. The cellular disposition model was augmented by incorporating intracellular ADC degradation and passive diffusion of unconjugated drug across tumor cells. Different biomeasures and chemomeasures for T-DM1, quantified in the companion manuscript, were incorporated into the modified model of ADC to characterize in vitro pharmacokinetics of T-DM1 in three HER2+ cell lines. When the cellular model was integrated with the tumor disposition model, the model was able to a priori predict tumor DM1 concentrations in xenograft mice. Pathway analysis suggested different contribution of antigen-mediated and passive diffusion pathways for intracellular unconjugated drug exposure between in vitro and in vivo systems. Global and local sensitivity analyses revealed that non-specific deconjugation and passive diffusion of the drug across tumor cell membrane are key parameters for drug exposure inside a cell. Finally, a systems pharmacokinetic model for intracellular processing of ADCs has been proposed to highlight our current understanding about the determinants of ADC activation inside a cell.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, The State University of New York at Buffalo, 455 Kapoor Hall, Buffalo, New York, 14214-8033, USA.
authors.forename: Aman P
authors.initials: AP
authors.lastname: Singh
authors.affiliation: Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|David H. Koch Institute of Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Katie F
authors.initials: KF
authors.lastname: Maass
authors.affiliation: Translational Research Group, Department of Pharmacokinetics Dynamics and Metabolism, Pfizer, Groton, Connecticut, USA.
authors.forename: Alison M
authors.initials: AM
authors.lastname: Betts
authors.affiliation: Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|David H. Koch Institute of Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: K Dane
authors.initials: KD
authors.lastname: Wittrup
authors.affiliation: Oncology Medicinal Chemistry, Worldwide Medicinal Chemistry, Pfizer, Groton, Connecticut, USA.
authors.forename: Chethana
authors.initials: C
authors.lastname: Kulkarni
authors.affiliation: Translational Research Group, Department of Pharmacokinetics Dynamics and Metabolism, Pfizer, Groton, Connecticut, USA.
authors.forename: Lindsay E
authors.initials: LE
authors.lastname: King
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, The State University of New York at Buffalo, 455 Kapoor Hall, Buffalo, New York, 14214-8033, USA.
authors.forename: Antari
authors.initials: A
authors.lastname: Khot
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, The State University of New York at Buffalo, 455 Kapoor Hall, Buffalo, New York, 14214-8033, USA. dshah4@buffalo.edu.
authors.forename: Dhaval K
authors.initials: DK
authors.lastname: Shah
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000493:pharmacokinetics; D000970:Antineoplastic Agents / Q000493:pharmacokinetics; D001943:Breast Neoplasms / Q000188:drug therapy; D006801:Humans; D018796:Immunoconjugates / Q000627:therapeutic use; D008453:Maytansine / Q000493:pharmacokinetics*; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D000068878:Trastuzumab
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D018796:Immunoconjugates; D008453:Maytansine; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab
keywords: T-DM1; antibody-drug conjugate; cellular pharmacokinetics; global sensitivity analysis; mechanistic model; model-based drug development; tumor disposition; tumor pharmacokinetics