Publication Cover
Xenobiotica
the fate of foreign compounds in biological systems
Volume 49, 2019 - Issue 9
3,176
Views
60
CrossRef citations to date
0
Altmetric
Animal Pharmacokinetics and Metabolism

Comprehensive preclinical pharmacokinetic evaluations of trastuzumab deruxtecan (DS-8201a), a HER2-targeting antibody-drug conjugate, in cynomolgus monkeys

, , &
Pages 1086-1096 | Received 03 Aug 2018, Accepted 28 Sep 2018, Published online: 04 Jan 2019
 

Abstract

  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.

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.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.