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.