Risk‐Based Pharmacokinetic and Drug–Drug Interaction Characterization of Antibody–Drug Conjugates in Oncology Clinical Development: An International Consortium for Innovation and Quality in Pharmaceutical Development Perspective

Abstract

Antibody-drug conjugates (ADCs) represent a rapidly evolving area of drug development and hold significant promise. To date, nine ADCs have been approved by the US Food and Drug Administration (FDA). These conjugates combine the target specificity of monoclonal antibodies with the anticancer activity of small-molecule therapeutics (also referred to as payload). Due to the complex structure, three analytes, namely ADC conjugate, total antibody, and unconjugated payload, are typically quantified during drug development; however, the benefits of measuring all three analytes at later stages of clinical development are not clear. The cytotoxic payloads, upon release from the ADC, are considered to behave like small molecules. Given the relatively high potency and low systemic exposure of cytotoxic payloads, drug-drug interaction (DDI) considerations for ADCs might be different from traditional small molecule therapeutics. The International Consortium for Innovation and Quality in Pharmaceutical Development (IQ Consortium) convened an ADC working group to create an IQ ADC database that includes 26 ADCs with six unique payloads. The analysis of the ADC data in the IQ database, as well as nine approved ADCs, supports the strategy of pharmacokinetic characterization of all three analytes in early-phase development and progressively minimizing the number of analytes to be measured in the late-phase studies. The systemic concentrations of unconjugated payload are usually too low to serve as a DDI perpetrator; however, the potential for unconjugated payloads as a victim still exists. A data-driven and risk-based decision tree was developed to guide the assessment of a circulating payload as a victim of DDI.

Therapeutic Protein Drug Interactions: A White Paper From the International Consortium for Innovation and Quality in Pharmaceutical Development

“…The analysis concluded that due to extremely low circulating levels of the unconjugated payloads following administration of ADCs the DI risk is low for these payloads to inhibit or induce CYP enzymes, UGTs, or transporters. The IQ ADC review article did not comment on the DI risk for proteins or payloads that are either pro‐inflammatory cytokines directly causing increases in cytokine levels, or that affect a disease state that may indirectly change pro‐inflammatory cytokine levels 54 . As discussed in the review articles by Li et al .…”

“…As discussed in the review articles by Li et al . and Boni et al 54,55 . many ADCs that are currently in development have moieties that could act as immune modulators.…”

“…Recently, the IQ consortium published an in-depth review of DI potential for ADCs utilizing both data from the literature on the approved ADCs as well as from an IQ database consisting of 26 ADCs in development. 54 This review concluded that there was no DI risk from mAbs that are part of an ADC. The payloads that were considered were cytotoxic small molecules.…”

Antibody Drug Conjugates

“…It is speculated that given the low systemic exposure, cytotoxic payload molecules are unlikely to cause clinically meaningful interactions but can be significantly affected by enzymes and transporters. Unique considerations may be needed when designing PK studies to evaluate interactions with cytotoxic payloads [45].…”

Recent Advances in Translational Pharmacokinetics and Pharmacodynamics Prediction of Therapeutic Antibodies Using Modeling and Simulation

“…(3) The complex payload release process in tumor including the bystander effect [ 146 ] makes it harder for PD modeling. (4) Each payload shows distinct PKPD profile that includes drug–drug interaction (DDI) [ 147 , 148 ]. With these complexities, modeling ADC PKPD has peculiar challenges while being an indispensable tool for ADC drug discovery and development.…”