Pharmacokinetics and pharmacodynamics of antibody-drug conjugates for the treatment of patients with breast cancer

ABSTRACT

Introduction

Currently three antibody-drug-conjugates (ADC) are approved by the European Medicines Agency (EMA) for treatment of breast cancer (BC) patient: trastuzumab-emtansine, trastuzumab-deruxtecan and sacituzumab-govitecan. ADC are composed of a monoclonal antibody (mAb) targeting a specific antigen, a cytotoxic payload and a linker. Pharmacokinetics (PK) and pharmacodynamics (PD) distinguish ADC from conventional chemotherapy and must be understood by clinicians.

Areas covered

Our review delineates the PK/PD profiles of ADC approved for the treatment of BC with insight for future development. This is an expert opinion literature review based on the EMA’s Assessment Reports, enriched by a comprehensive literature search performed on Medline in August 2023.

Expert opinion

All three ADC distributions are described by a two-compartment structure: tissue and serum. Payload concentration peak is immediate but remains at low concentration. The distribution varied for all ADC only with body weight. mAb will be metabolised firstly by the saturable complex formation of ADC/Tumour-Receptor and secondly by binding of FcgRs in immune cells. They are all excreted in the bile and faeces with minimal urine elimination. Dose adjustments, apart from weight, are not recommended. Novel ADC are composed of cleavable linkers with various targets/payloads with the same PK/PD properties, but novel structures of ADC are in development.

KEYWORDS:

• Antibody-drug conjugates
• breast cancer
• drug development
• pharmacodynamics
• pharmacokinetics
• trastuzumab-deruxtecan
• trastuzumab-emtansine
• sacituzimab-govitecan

Article highlights

• Trastuzumab-emtansine (T-DM1), Trastuzumab-deruxtecan (T-DXd) and Sacituzimab-govitecan (SG) are antibody-drug conjugates (ADC) approved by the European Medicines Agency for the treatment of patients with breast cancer.

• They have roughly the same distribution and elimination properties. Metabolism varies according to the payload.

• Body weight is the unique clinically significant covariate of PK/PD properties.

• No dose adjustment is required for special populations and few drug–drug interactions are clinically relevant.

• Most ADC under development share the same PK/PD as the approved ADC

• New ADC are being engineered and may have completely new PK/PD properties as well as interaction with cancer cells and the tumor microenvironment.

Declaration of interest

D Martins-Branco : full-time employment from the European Society for Medical Oncology since 1 September 2023; speaker’s engagement from AstraZeneca, Daiichi Sankyo; meeting/travel grant from Novartis; institutional research funding from Eli Lilly, F. Hoffmann- La Roche Ltd., Novartis; non-remunerated activity as a member of the board of directors for Associaҫão de Investigaҫão e Cuidados de Suporte em Oncologia; non-remunerated leadership role as prior Portuguese Young Oncologists Committee Chair of Sociedade Portuguesa de Oncologia (all outside the submitted work).

A Awada: Advisory role: Amgen, AstraZeneca, Bayer, Daiichi, EISAI, Genomic Health, Hengrui, Innate, Ipsen, Leo Pharma, Lilly, Merck, MSD, Novartis, Pfizer, Seattle Genetics, Menarini. Speaker fees: Amgen, AstraZeneca, Bayer, Daiichi, EISAI, Genomic Health, Ipsen, Leo Pharma, Lilly, Merck, MSD, Novartis, Pfizer, Seattle Genetics. Research grants to my Institute: BMS, Roche (all outside the submitted work)

G Nader-Marta: Support to attend medical conferences: Roche, AstraZeneca and Bayer (all outside the submitted work)

F Cherifi and A Da Silva : No relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript; this includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosure

One reviewer has been recruited by Research Square. Reviewers with declared or apparent competing interests are not utilized for these reviews. This reviewer was paid a small honorarium for completing the review within a specified timeframe. Honoraria for reviews such as this are paid regardless of the reviewer recommendation. The remaining reviewers have no other relevant financial relationships or otherwise to disclose.

Authors’ contribution

All authors participated in the writing of the original draft, provided critical feedback and contributed to data acquisition, interpretation of data, and approved the final version for submission.

Additional information

Funding

This paper was not funded.