Walles, Markus and Hainzl, Dominik (2021) Risk-Based Pharmacokinetic and Drug-Drug Interaction Characterization of Antibody-Drug Conjugates in Clinical Development: An IQ Consortium Perspective. Clinical pharmacology and Therapeutics. ISSN 34657311

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 FDA and many more are in the early- and late-phase development. These conjugates combine the target specificity of monoclonal antibodies with the anti-cancer activity of small-molecule therapeutics (also referred to as payload). Due to the complex structure, three analytes, namely conjugate, total antibody and unconjugated payload, are typically quantified during drug development, however. the benefits of measuring all 3 analytes at later stages of clinical development are not clear. The cytotoxic payloads, upon release from the ADC, are expected 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 6 unique payloads. The analyses from IQ ADC database and 9 approved ADCs support the strategy of PK 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.

Item Type:	Article
Keywords:	ADCs, DDI, payload, Pharmacokinetics
Date Deposited:	11 Mar 2022 00:45
Last Modified:	11 Mar 2022 00:45
URI:	https://oak.novartis.com/id/eprint/44297