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USFDA Guidance: Clinical Pharmacology Considerations for Antibody-Drug Conjugates

The U.S. Food and Drug Administration (FDA) Center for Drug Evaluation and Research and Center for Biologics Evaluation and Research released a final guidance "Clinical Pharmacology Considerations for Antibody-Drug Conjugates" that details the recommendations to assist industry and other parties involved in the development of antibody-drug conjugates (ADCs) with a cytotoxic small-molecule drug or payload.


In this guidance, FDA recommends bioanalytical methods, dosing strategies, dose- and exposure-response analysis, intrinsic factors, QTc assessments, immunogenicity, and drug-drug interactions (DDIs) based on its current understanding of clinical pharmacology.


The principles outlined in this guidance may not be relevant to the development of other types of ADCs (such as ADCs with payloads different from cytotoxic small molecule drugs and/or intended for uses other than oncology).


Understanding Antibody-Drug Conjugates (ADCs)

ADCs consist of three main components: a monoclonal antibody that targets a specific antigen on cancer cells, a linker molecule that attaches the antibody to a cytotoxic drug, and the cytotoxic drug itself. This targeted approach allows for the delivery of potent cytotoxic agents directly to cancer cells, while minimizing damage to healthy tissues.


ADCs combine an antibody's selectivity for a specific target with a small molecule drug's potency. Therefore, selecting optimal dosing strategies for ADCs requires careful consideration of the differences in pharmacokinetics (PK) and pharmacodynamics (PD) between the antibody and the payload.


Each component of the ADC can independently impact safety and/or efficacy. Even a small increase in the systemic exposure of the cytotoxic payload or the ADC can lead to significant adverse reactions that may limit the dose from a safety perspective.


Due to these challenges, it is crucial to gain a thorough understanding of the PK and PD of the ADC and its components early in development, as well as their relationships to safety and efficacy outcomes, to optimize the ADC dosage. Data contributing to this understanding may include findings from nonclinical studies.


Pharmacokinetic, efficacy, and safety information that can inform dosage recommendations for ADCs can be obtained from:

  1. Patients with organ impairment or interacting concomitant medications enrolled in the dose-escalation studies (e.g., as a staggered cohort at lower doses compared to patients with normal organ function or no interacting concomitant drug)

  2. Patients with organ impairment or interacting concomitant medications enrolled in safety and efficacy studies

  3. Dedicated organ impairment or DDI studies


By following this guidance, industry sponsors can enhance their understanding of the pharmacokinetic and pharmacodynamic properties of ADCs and optimize their clinical development programs.

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