A systematic review on disease-drug-drug interactions with immunomodulating drugs: A critical appraisal of risk assessment and drug labelling.

Abstract

AIM:

Use of immunomodulating therapeutics for immune-mediated inflammatory diseases may cause disease-drug-drug interactions (DDDIs) by reversing inflammation-driven alterations in the metabolic capacity of cytochrome P450 enzymes. European Medicine Agency (EMA) and US Food and Drug Administration (FDA) guidelines from 2007 recommend that the DDDI potential of therapeutic proteins should be assessed. This systematic analysis aimed to characterize the available DDDI trials with immunomodulatory drugs, experimental evidence for a DDDI risk and reported DDDI risk information in FDA/EMA approved drug labelling.

METHOD:

For this systematic review, the EMA list of European Public Assessment Reports of human medicine was used to select immunomodulating monoclonal antibodies (mAbs) and tyrosine kinase inhibitors (TKIs) marketed after 2007 at risk for a DDDI. Selected drugs were included in PubMed and Embase searches to extract reported interaction studies. The Summary of Product Characteristics (SPCs) and the United States Prescribing Information (USPIs) were subsequently used for analysis of DDDI risk descriptions.

RESULTS:

Clinical interaction studies to evaluate DDDI risks were performed for 12 of the 24 mAbs (50%) and for none of the TKIs. Four studies identified a DDDI risk, of which three were studies with interleukin-6 (IL-6) neutralizing mAbs. Based on (non)clinical data, a DDDI risk was reported in 32% of the SPCs and in 60% of the USPIs. The EMA/FDA documentation aligned with the DDDI risk potential in 35% of the 20 cases.

CONCLUSION:

This systematic review reinforces that the risk for DDDI by immunomodulating drugs is target- and disease-specific. Drug labelling information designates the greatest DDDI risk to mAbs that neutralize the effects of IL-6, Tumor Necrosis Factor alfa (TNF-α) and interleukin-1 bèta (IL-1β) in diseases with systemic inflammation.

• Authors: Laura M de Jong, Sylvia D Klomp, Nicoline Treijtel, Robert Rissmann, Jesse J Swen, Martijn L Manson
• Journal: British journal of clinical pharmacology (Br J Clin Pharmacol) Vol. 88 Issue 10 Pg. 4387-4402 (10 2022) ISSN: 1365-2125 [Electronic] England
• PMID: 35484780 (Publication Type: Journal Article, Review, Systematic Review, Research Support, Non-U.S. Gov't)
• Copyright: © 2022 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

Chemical References

• Antibodies, Monoclonal
• Immunomodulating Agents
• Interleukin-1beta
• Interleukin-6
• Pharmaceutical Preparations
• Protein Kinase Inhibitors
• Tumor Necrosis Factor-alpha

Topics

• Antibodies, Monoclonal (adverse effects)
• Drug Approval
• Drug Interactions
• Drug Labeling
• Humans
• Immunomodulating Agents (adverse effects)
• Inflammation (drug therapy)
• Interleukin-1beta
• Interleukin-6
• Pharmaceutical Preparations
• Protein Kinase Inhibitors (adverse effects)
• Risk Assessment
• Tumor Necrosis Factor-alpha
• United States
• United States Food and Drug Administration