Abstract
The development of antibody–drug conjugates (ADCs) represents a novel approach to improving the therapeutic index of cytotoxic agents by selectively delivering potent cytotoxic drugs to tumors while minimizing exposure and toxicity to normal tissues. The past decade has seen a significant progress in the development of ADCs as anticancer therapeutics. Although there are more than 40 ADCs currently being evaluated in clinical trials, the clinical pharmacology roadmap for the development of ADCs is not well defined. With the example of T-DM1, an ADC comprised of a unique combination of trastuzumab, linker, and cytotoxic agent DM1, some development challenges unique to ADCs are discussed in this chapter. A clinical pharmacology strategy, comprised of both large and small molecule drug development paradigms, including population pharmacokinetics and exposure–response (safety/efficacy) analysis, QTc, drug interaction, organ dysfunction, and integrated metabolism strategies, was applied to characterize the clinical pharmacology of T-DM1. Antitherapeutic antibody responses to molecular components of the ADC were also assessed. T-DM1 is currently being tested in multiple Phase Ib/II and III studies, either as a single agent or in combination with taxane and pertuzumab in HER2+ MBC and gastric cancer patients. This chapter focuses primarily on clinical pharmacology assessments in the development of T-DM1 for HER2+ metastatic breast cancer.
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Girish, S., Gupta, M. (2013). Clinical Pharmacology Strategies in the Development of Antibody–Drug Conjugates. In: Phillips, G. (eds) Antibody-Drug Conjugates and Immunotoxins. Cancer Drug Discovery and Development. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-5456-4_4
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