Preclinical pharmacokinetics, distribution, metabolism and excretion of disitamab vedotin

TL;DR

This study examines how disitamab vedotin, an antibody-drug conjugate, behaves in the body, focusing on its absorption, distribution, metabolism, and elimination in preclinical models.

Contribution

The study provides new insights into the pharmacokinetics and elimination pathways of disitamab vedotin and its payload MMAE in preclinical animal models.

Findings

Disitamab vedotin and MMAE show higher and longer exposure in tumor tissue.

Disitamab vedotin is primarily eliminated through renal excretion, while MMAE is mainly excreted via the biliary fecal route.

MMAE is identified as the major metabolite in excreta, along with 10 minor species.

Abstract

Disitamab vedotin is an antibody-drug conjugate (ADC) composed of a humanized IgG1 monoclonal antibody (mAb) targeting HER2 conjugated to monomethyl auristatin E(MMAE) via a cleavable dipeptide linker.

The pharmacokinetics, distribution, catabolism/metabolism and elimination properties of disitamab vedotin and its payload MMAE were characterized in rats and tumour-bearing mice.

The configured mAb and total antibody showed linear dynamic characteristics. Moreover, the molecular structure of disitamab vedotin effectively reduces the exposure of MMAE, which has a fast clearance. Two radiolabeled probes were developed to track the fate of different components of the disitamab vedotin, including 125I labelled antibody and 3H labelled MMAE payload of the ADC. Following a single intravenous administration of the radiolabeled probes to the tumour-bearing mice and rats, blood, various tissues, and excreta samples were collected and analyzed for radioactivity and to characterize the metabolites/catabolites. Disitamab vedotin and free MMAE (FM) were majorly distributed in tissues and organs with rich blood flow. Moreover, both disitamab vedotin and MMAE have higher and longer exposure in tumour tissue. Disitamab vedotin was mainly eliminated through renal excretion, while the FM was mainly eliminated through the biliary faecal route (>70 %) and a small fraction (<10 %) was eliminated through renal excretion in the form of catabolites/metabolites, among which, MMAE was identified as the major species, along with 10 other minor species.

These studies provided significant insight into disitamab vedotin pharmacokinetics, distribution, metabolism and elimination properties, which supports the clinical development of disitamab vedotin.

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