title: Complement activation as a bioequivalence issue relevant to the development of generic liposomes and other nanoparticulate drugs.
abstract: Liposomes are known to activate the complement (C) system, which can lead in vivo to a hypersensitivity syndrome called C activation-related pseudoallergy (CARPA). CARPA has been getting increasing attention as a safety risk of i.v. therapy with liposomes, whose testing is now recommended in bioequivalence evaluations of generic liposomal drug candidates. This review highlights the adverse consequences of C activation, the unique symptoms of CARPA triggered by essentially all i.v. administered liposomal drugs, and the various features of vesicles influencing this adverse immune effect. For the case of Doxil, we also address the mechanism of C activation and the opsonization vs. long circulation (stealth) paradox. In reviewing the methods of assessing C activation and CARPA, we delineate the most sensitive porcine model and an algorithm for stepwise evaluation of the CARPA risk of i.v. liposomes, which are proposed for standardization for preclinical toxicology evaluation of liposomal and other nanoparticulate drug candidates.
authors.affiliation: Nanomedicine Research and Education Center, Semmelweis University, Budapest & SeroScience Ltd, Budapest, Hungary. Electronic address: jszebeni2@gmail.com.
authors.forename: Janos
authors.initials: J
authors.lastname: Szebeni
authors.affiliation: Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, The Netherlands.
authors.forename: Gert
authors.initials: G
authors.lastname: Storm
mesh_terms: D003167:Complement Activation / Q000187:drug effects* / Q000276:immunology*; D004342:Drug Hypersensitivity / Q000209:etiology / Q000276:immunology*; D057915:Drug Substitution / Q000009:adverse effects; D016568:Drugs, Generic / Q000009:adverse effects*; D008081:Liposomes / Q000009:adverse effects* / Q000276:immunology; D053769:Nanocapsules / Q000009:adverse effects*; D013810:Therapeutic Equivalency
chemical_list: D016568:Drugs, Generic; D008081:Liposomes; D053769:Nanocapsules
keywords: Adverse drug reactions; Anaphylatoxins; Anaphylaxis; C5a; Complement; Pigs; Pseudoallergy