Therapeutic protein-drug interactions: plausible mechanisms and assessment strategies

ABSTRACT

Introduction: Over the last three decades, therapeutic proteins have played an increasingly important role in pharmacotherapy. Owing to an expected significant increase in the coadministration of biotherapeutics with established pharmacotherapy regimens or even with other biotherapeutic agents, there is an increasing likelihood for the occurrence of clinically relevant drug interactions, so called therapeutic protein-drug interactions (TP-DIs).

Areas covered: Our current understanding of TP-DIs and recent collaborations among industry, academia and regulatory agencies are reviewed in this article. Although most of the observed TP-DIs are mediated by disease states, immune status, and/or target physiology, TP-DI assessments are still done empirically. Plausible mechanisms of major TP-DIs involving therapeutic proteins (primarily monoclonal antibodies), either as victims or as perpetrators, are proposed, with mechanism-based strategies and assessment approaches to better evaluate their propensity are recommended.

Expert opinion: Our current understanding of the mechanisms of TP-DIs is in its infancy. Much of the basic research needs to be conducted to verify existing TP-DI hypotheses or help predict and manage potential ones, whose efforts are not considered trivial and may be better achieved through close collaborations among scientists from academia, industry, and regulatory agencies.

KEYWORDS:

• Cocktail
• CYP
• cytochrome P450
• efflux transporter
• uptake transporter
• cytokine-mediated
• cytokine profiling
• disease burden
• disease state
• disease-drug interaction
• drug-disease-drug interaction
• interleukin (IL)
• IL-1β
• IL-6
• IFNγ
• immunogenicity
• infection
• inflammation
• mAb
• mechanism
• mediator
• monoclonal antibody
• perpetrator
• physiologically based pharmacokinetic model (PBPK)
• proinflammatory cytokines
• target expression
• target physiology
• therapeutic protein-drug interaction
• TNFα
• TP-DI
• victim

Article highlights

• Our current understanding of the mechanisms of therapeutic protein-drug interactions (TP-DIs) is in its infancy. More basic research in this area is needed to help better formulate the TP-DI assessment strategies.

• Most of the observed TP-DIs are indirect and are mediated via factors such as disease states, disease burden, immune status, or target physiology (e.g., target expression).

• In general, the preclinical approaches to assess the clinical TP-DI propensity are not predictive and are qualitative at the best.

• The need for designing and conducting a clinical TP-DI study should be science-driven, risk-based, and on a case-by-case basis.

• Most of the observed TP-DIs to date are not considered clinically relevant and no dose adjustment is warranted for therapeutic proteins.

• Due to the wide therapeutic windows of most of the therapeutic proteins, alteration in systemic exposure of therapeutic proteins may not necessarily be clinically meaningful.

This box summarizes key points contained in the article.

Acknowledgments

Part of the article was presented at Gordon Research Conference of Drug Metabolism in July 2015.

Declaration of interest

The authors are employees of Johnson & Johnson. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This paper was not funded.