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

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Nagai Y, Oitate M, Shiozawa H, Ando O

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

Xenobiotica. 2019 Sep;49(9):1086-1096. doi: 10.1080/00498254.2018.1531158. Epub 2019 Jan 4.

PubMed ID

30351177 [ View in PubMed

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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.

DrugBank Data that Cites this Article

Drugs

Trastuzumab deruxtecan

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Trastuzumab deruxtecan	High affinity immunoglobulin gamma Fc receptor I	Protein	Humans	Yes	Antibody	Details

Drug Transporters

Drug	Transporter	Kind	Organism	Pharmacological Action	Actions
Trastuzumab deruxtecan	P-glycoprotein 1	Protein	Humans	No	Substrate	Details