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Comprehensive Preclinical Pharmacokinetic Evaluations of Trastuzumab Deruxtecan (DS-8201a), a HER2-targeting antibody-drug conjugate, in Cynomolgus…

A new interesting article has been published in Xenobiotica. 2018 Oct 23:1-39. doi: 10.1080/00498254.2018.1531158. [Epub ahead of print] and titled:

Comprehensive Preclinical Pharmacokinetic Evaluations of Trastuzumab Deruxtecan (DS-8201a), a HER2-targeting antibody-drug conjugate, in Cynomolgus…

Authors of this article are:

Nagai Y, Oitate M, Shiozawa H, Ando O.

A summary of the article is shown below:

1. 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. 2. 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. 3. 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.

Check out the article’s website on Pubmed for more information:



This article is a good source of information and a good way to become familiar with topics such as:

Antibody drug conjugate (ADC);DS-8201a;DXd;QWBA;Topoisomerase I inhibitor;drug-to-antibody ratio (DAR);trastuzumab deruxtecan

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