title: Strategies to address drug interaction potential for antibody-drug conjugates in clinical development.
abstract: Antibody-drug conjugates (ADCs) are a unique class of therapeutic proteins with both small and large molecular components. In vivo, ADCs are processed to multiple clinically relevant analytes, each with distinct PK properties. This increases the complexity for ADC drug interaction (DI) assessment. Furthermore, given the usually narrow therapeutic range for ADCs, a thorough risk assessment is essential to establish benefit/risk for patients. Therefore, an early understanding of the ADC catabolism and elimination pathways and cytochrome P450 reaction phenotyping, cytochrome P450 inhibition and induction potential, transporter interaction and inhibition potential for the cytotoxic drug catabolites assessed by in vitro and preclinical studies is essential. This information would be integrated with the clinical PK and PD properties of the ADC-related analytes for a theoretical risk assessment of ADC DI in combination therapy. ADC DI assessment in clinical studies will further support the theoretical risk assessment and the conclusions for the labeling statement.
authors: Department of Clinical Pharmacology, Genentech Inc., 1 DNA Way, Mail Stop 46-3a, South San Francisco, CA 94080, USA. lu.dan@gene.com
authors: Dan
authors: D
authors: Lu
authors: Srikumar
authors: S
authors: Sahasranaman
authors: Yi
authors: Y
authors: Zhang
authors: Sandhya
authors: S
authors: Girish
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000032:analysis / Q000378:metabolism / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000032:analysis / Q000378:metabolism / Q000494:pharmacology*; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006801:Humans; D018796:Immunoconjugates / Q000032:analysis / Q000378:metabolism / Q000494:pharmacology*; D018570:Risk Assessment
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D018796:Immunoconjugates; D003577:Cytochrome P-450 Enzyme System