Is Pegylation of Drugs Associated to Hypersensitivity Reactions? An Analysis of The Italian National Spontaneous Adverse Drug Reaction Reporting System

• Published in: Drug safety Vol. 45; no. 10; p. 1316
• Main Authors: Crisafulli, S, Cutroneo, P M, Luxi, N, Fontana, A, Ferrajolo, C, Marchione, P, Sottosanti, L, Zanoni, G, Moretti, U, Franzè, S, Minghetti, P, Trifirò, G
• Format: Journal Article
• Language: English
• Published: Auckland Springer Nature B.V 01.10.2022
• Subjects: Comparators; Drugs; Hypersensitivity; Immunoglobulins; Interferon; Liposomes; Mathematical analysis; Patients; Pharmacovigilance
• ISSN: 0114-5916; 1179-1942

Introduction: Increasing evidence highlights the allergenic potential of pegylated drugs as a result of the production of anti-PEG immunoglobulins [1-3]. Objective: To investigate the risk of hypersensitivity reactions of pegylated drugs using the Italian spontaneous adverse drug reaction (ADR) reporting system database (SRS). Methods: We selected ADR reports attributed to medicinal products containing pegylated active substances and/or pegylated liposomes from the Italian SRS in the period between its inception and March 2021. As comparators, we extracted ADR reports of medicinal products containing the same non-pegylated active substances and/or non-pegylated liposomes (if not available, compounds belonging to the same mechanistic class). A descriptive analysis of all ADR reports, and of hypersensitivity reactions specifically, was carried out. Reporting rates and time to onset of hypersensitivity reactions for each medicinal product were also calculated. As a measure of hypersensitivity reactions reporting disproportionality, we also calculated the reporting odds ratio. Furthermore, the relationship between the proportion of hypersensitivity reactions for the study drugs and their PEG size was assessed. Results: Overall, 3,865 ADR reports were related to pegylated medicinal products and 11,961 to their non-pegylated comparators. Concerning both overall ADRs and hypersensitivity reactions reports, around two-thirds of patients were females and they mostly concerned patients aged between 46 and 64 years. The frequency of hypersensitivity reactions reporting was higher among pegylated vs. nonpegylated medicinal products (11.7% vs. 9.4%, p < 0.0001) and the proportion of serious hypersensitivity reactions was two times higher for pegylated vs. non-pegylated medicinal products (33.0% vs. 16.3%; p < 0.0001). The hypersensitivity reaction reporting rates were always higher for pegylated vs. non-pegylated medicinal products, with reporting rate ratios ranging from 1.4 (95% CI 0.8-2.5) for pegfilgrastim vs. filgrastim to 20.0 (95% CI 2.8-143.5) for peginterferon alpha-2a vs. interferon alpha-2a. The median time to onset of hypersensitivity reactions ranged from < 1 day and 69 days for pegylated medicinal products, and from < 1 day and 345 days for non-pegylated comparators. Disproportionality analysis showed that both pegylated and non-pegylated medicinal products were not associated with an increased reporting trend of hypersensitivity reactions. Moreover, higher PEG molecular weights were not statistically associated with an increased risk of hypersensitivity reaction reporting. Conclusion: Although disproportionality analysis showed that neither pegylated nor non-pegylated medicinal products were associated with an increased hypersensitivity reactions reporting trend, findings of this study suggest a potential involvement for pegylation in triggering drug-related hypersensitivity reactions, especially clinically relevant ones. However, further clinical assessment is required to validate pharmacovigilance data.