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Abstract
Trastuzumab deruxtecan (DS-8201a) is an antibody-drug conjugate (ADC) composed of a monoclonal antibody targeting human epidermal growth factor receptor 2 (HER2) conjugated to a topoisomerase I inhibitor (DXd) at a drug-to-antibody ratio (DAR) of 7-8. Here, we examined the pharmacokinetic (PK) profiles of DS-8201a and DXd in cynomolgus monkeys, a cross-reactive species.
Following intravenous (iv) administration of DS-8201a, the linker was stable in plasma, and systemic DXd exposure was low. DXd was rapidly cleared following iv dosing. Biodistribution studies revealed that intact DS-8201a was present mostly in the blood without tissue-specific retention. The major pathway of excretion for DXd was the faecal route following iv administration of radiolabelled DS-8201a. The only detectable metabolite in the urine and faeces was unmetabolized DXd. DXd is a substrate of organic anion transporting polypeptides, P-gp, and breast cancer resistance protein.
In conclusion, the stable linker in circulation and the high clearance of DXd upon release resulted in the low systemic exposure to DXd. Furthermore, the minimal tissue-specific retention and rapid excretion of DXd into faeces as its unmetabolized form with potentially limited impact on drug − drug interaction as a victim were also critical elements of the PK profile of DS-8201a.
Acknowledgements
We are grateful to Ms Chiaki Ishii for providing the data on DS-8201a affinity to cynomolgus monkey and human HER2 proteins. We wish to thank Ms Masako Soma and Ms Yoko Urasaki for their kind help in describing the bioanalytical method.
Disclosure statement
Yoko Nagai, Masataka Oitate, Hideyuki Shiozawa and Osamu Ando are employees of Daiichi Sankyo Co., Ltd.