In Vitro Plasma Stability Related to In Vivo Pharmacokinetics and Metabolism

Predicting in vivo PK and metabolism is challenging because of a lack of sufficient analytical means to track complex and often heterogeneous ADC molecules; the effort is further hampered by an incomplete understanding of ADC metabolism. Most factors that impact ADC PK are not amenable for in vitro studies; among these are solid tumor burden, tissue distribution, and shed antigen. In contrast, the systemic stability, as one potential clearance pathway, can be assessed easily through the use of in vitro plasma stability studies. High plasma stability encourages the maximum total accumulation at tumor sites and minimizes systemic toxicity due to free drug release. It also provides an initial assessment of linker stability and overall metabolic stability. A good example is the use of plasma stability to aid in the selection of appropriate ADC linkers. In an effort to develop potent mAb-auristatin conjugates for cancer therapy, Dor-onina et al. compared the in vitro plasma stabilities between a conventional peptide (i.e., amide) linker and a less stable acid-labile hydrazone linker (148). These results were related to in vivo efficacy studies that showed better in vivo efficacy in a tumor model for the more stable linker relative to the acid-labile linker derivatives (148). These results emphasize that in vitro plasma stability may be used as a predictive tool for candidate ranking and selection.

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