title: AAPS workshop report: strategies to address therapeutic protein-drug interactions during clinical development.
abstract: Therapeutic proteins (TPs) are increasingly combined with small molecules and/or with other TPs. However preclinical tools and in vitro test systems for assessing drug interaction potential of TPs such as monoclonal antibodies, cytokines and cytokine modulators are limited. Published data suggests that clinically relevant TP-drug interactions (TP-DI) are likely from overlap in mechanisms of action, alteration in target and/or drug-disease interaction. Clinical drug interaction studies are not routinely conducted for TPs because of the logistical constraints in study design to address pharmacokinetic (PK)- and pharmacodynamic (PD)-based interactions. Different pharmaceutical companies have developed their respective question- and/or risk-based approaches for TP-DI based on the TP mechanism of action as well as patient population. During the workshop both company strategies and regulatory perspectives were discussed in depth using case studies; knowledge gaps and best practices were subsequently identified and discussed. Understanding the functional role of target, target expression and their downstream consequences were identified as important for assessing the potential for a TP-DI. Therefore, a question-and/or risk-based approach based upon the mechanism of action and patient population was proposed as a reasonable TP-DI strategy. This field continues to evolve as companies generate additional preclinical and clinical data to improve their understanding of possible mechanisms for drug interactions. Regulatory agencies are in the process of updating their recommendations to sponsors regarding the conduct of in vitro and in vivo interaction studies for new drug applications (NDAs) and biologics license applications (BLAs).
authors.affiliation: Clinical Pharmacology, Department of Pharmacokinetics and Pharmacodynamics, gRED, Genentech, South San Francisco, California, USA. sandhyag@gene.com
authors.forename: Sandhya
authors.initials: S
authors.lastname: Girish
authors.forename: Steven W
authors.initials: SW
authors.lastname: Martin
authors.forename: Mark C
authors.initials: MC
authors.lastname: Peterson
authors.forename: Lei K
authors.initials: LK
authors.lastname: Zhang
authors.forename: Hong
authors.initials: H
authors.lastname: Zhao
authors.forename: Joseph
authors.initials: J
authors.lastname: Balthasar
authors.forename: Raymond
authors.initials: R
authors.lastname: Evers
authors.forename: Honghui
authors.initials: H
authors.lastname: Zhou
authors.forename: Min
authors.initials: M
authors.lastname: Zhu
authors.forename: Lewis
authors.initials: L
authors.lastname: Klunk
authors.forename: Chao
authors.initials: C
authors.lastname: Han
authors.forename: Eva Gil
authors.initials: EG
authors.lastname: Berglund
authors.forename: Shiew-Mei
authors.initials: SM
authors.lastname: Huang
authors.forename: Amita
authors.initials: A
authors.lastname: Joshi
mesh_terms: D002986:Clinical Trials as Topic; D055808:Drug Discovery / Q000379:methods*; D004345:Drug Industry / Q000379:methods / Q000592:standards; D004347:Drug Interactions; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D011506:Proteins / Q000009:adverse effects*
chemical_list: D011506:Proteins