Is PEGylation of Drugs Associated with Hypersensitivity Reactions? An Analysis of the Italian National Spontaneous Adverse Drug Reaction Reporting System.

Content Provider	Europe PMC
Author	Crisafulli, Salvatore Cutroneo, Paola Maria Luxi, Nicoletta Fontana, Andrea Ferrajolo, Carmen Marchione, Pasquale Sottosanti, Laura Zanoni, Giovanna Moretti, Ugo Franzè, Silvia Minghetti, Paola Trifirò, Gianluca
Abstract	Background and objectiveEvidence highlights the allergenic potential of PEGylated drugs because of the production of anti-polyethylene glycol immunoglobulins. We investigated the risk of hypersensitivity reactions of PEGylated drugs using the Italian spontaneous adverse drug reaction reporting system database.MethodsWe selected adverse drug reaction reports attributed to medicinal products containing PEGylated active substances and/or PEGylated liposomes from the Italian Spontaneous Reporting System in the period between its inception and March 2021. As comparators, we extracted adverse drug reaction reports of medicinal products containing the same non-PEGylated active substances and/or non-PEGylated liposomes (or compounds belonging to the same mechanistic class). A descriptive analysis of reports of hypersensitivity reactions was performed. Reporting rates and time to onset of hypersensitivity reactions were also calculated in the period between January 2009 and March 2021. As a measure of disproportionality, we calculated the reporting odds ratio.ResultsOverall, 3865 adverse drug reaction reports were related to PEGylated medicinal products and 11,961 to their non-PEGylated comparators. Around two-thirds of patients were female and reports mostly concerned patients aged between 46 and 64 years. The frequency of hypersensitivity reactions reporting was higher among PEGylated versus non-PEGylated medicinal products (11.7% vs 9.4%, p < 0.0001). The hypersensitivity reaction reporting rates were higher for PEGylated medicinal products versus non-PEGylated medicinal products, with reporting rate ratios that ranged from 1.4 (95% confidence interval 0.8–2.5) for pegfilgrastim versus filgrastim to 20.0 (95% confidence interval 2.8–143.5) for peginterferon alpha-2a versus interferon alpha-2a. The median time to onset of hypersensitivity reactions was 10 days (interquartile range: 0–61) for PEGylated medicinal products, and 36 days (interquartile range: 3–216) for non-PEGylated comparators. Statistically significant reporting odds ratios were observed when comparing the reporting of hypersensitivity reactions for PEGylated versus non-PEGylated medicinal products (reporting odds ratio: 1.3; 95% confidence interval 1.1–1.4). However, when using all other drugs as comparators, the disproportionality analysis showed no association with hypersensitivity reactions for PEGylated nor non-PEGylated medicinal products, thus suggesting that many other triggers of drug-induced hypersensitivity reactions play a major role.ConclusionsThe findings of this analysis of the Italian spontaneous adverse drug reaction database suggest a potential involvement for PEGylation in triggering drug-related hypersensitivity reactions, especially clinically relevant reactions. However, when comparing both PEGylated and non-PEGylated drugs under study to all other drugs no disproportionate reporting of hypersensitivity reactions was observed, probably due to a masking effect owing to the presence in the same database of other medicinal products increasing the threshold required to highlight a safety signal when the entire database is used as a reference.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40264-023-01277-5.
Related Links	https://europepmc.org/backend/ptpmcrender.fcgi?accid=PMC9930046&blobtype=pdf
ISSN	01145916
Journal	Drug Safety [Drug Saf]
Volume Number	46
DOI	10.1007/s40264-023-01277-5
PubMed Central reference number	PMC9930046
Issue Number	4
PubMed reference number	36790561
e-ISSN	11791942
Language	English
Publisher	Springer International Publishing
Publisher Date	2023-02-15
Publisher Place	Gewerbestrasse 11, Cham, Ch 6330, Switzerland
Access Restriction	Open
Rights License	Open AccessThis article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/. © The Author(s) 2023
Content Type	Text
Resource Type	Article
Subject	Toxicology Pharmacology Pharmacology (medical)