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Hepatotoxicity with antibody maytansinoid conjugates: A review of preclinical and clinical findings
Author(s) -
Taplin Sarah,
Vashisht Kapil,
Walles Markus,
Calise David,
Kluwe William,
Bouchard Page,
Johnson Robert
Publication year - 2018
Publication title -
journal of applied toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.784
H-Index - 87
eISSN - 1099-1263
pISSN - 0260-437X
DOI - 10.1002/jat.3582
Subject(s) - pharmacology , drug , conjugate , metabolite , chemistry , antibody drug conjugate , antibody , medicine , biochemistry , immunology , monoclonal antibody , mathematical analysis , mathematics
Abstract Maytansinoids, the potent cytotoxic derivatives of the alkaloid maytansine are used as payloads in antibody maytansinoid conjugates. This article reviews clinical and preclinical hepatotoxicity observed with antibody maytansinoid conjugates used to treat cancer. Specific aspects of drug distribution, metabolism and excretion that may impact hepatotoxicity are reviewed vis‐à‐vis the kind of maytansinoid in the conjugate, cleavable or non‐cleavable linkers, linker–payload combinations, drug to antibody ratio, metabolite formation, hepatic enzyme induction in relation to drug–drug interactions and species, age and gender differences. The article also sheds light on factors that may protect the liver from toxic insults.