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Doxebo (doxorubicin-free Doxil-like liposomes) is safe to use as a pre-treatment to prevent infusion reactions to PEGylated nanodrugs

Author:
Bavli, Yaelle, Winkler, Ilan, Chen, Bing Mae, Roffler, Steve, Cohen, Rivka, Szebeni, Janos, Barenholz, Yechezkel
Source:
Journal of controlled release 2019 v.306 pp. 138-148
ISSN:
0168-3659
Subject:
adverse effects, antihistamines, antineoplastic activity, blood, complement, humans, hypersensitivity, intravenous injection, mice, models, nanomaterials, neoplasms, pharmacokinetics, rats, steroids, swine, toxicity
Abstract:
The increasing use in the last decade of PEGylated nanodrugs such as Doxil® has seen a rise in the number of associated occurrences of hypersensitivity reactions (HSRs). These reactions (also called infusion reactions or IR), can range from harmless symptoms to life-threatening reactions. Current means to prevent IR include the prophylactic use of antihistamines and steroids, but they cannot ensure total prevention. We previously showed that an intravenous injection of doxorubicin-free Doxil-like PEGylated nano-liposomes (Doxebo) prior to Doxil treatment suppresses Doxil-induced complement activation-related pseudoallergy (CARPA) in pigs, a model of human hypersensitivity reactions to Doxil. However, in order to use Doxebo to prevent Doxil-induced IR, we have to prove its safety and that it does not affect Doxil's performance. Here we show that Doxebo itself does not have toxic effects on the host or tumor, and it does not interfere with Doxil's antitumor activity in mice. Blood, microscopic and macroscopic organ evaluation of rats after repeated administration confirm the lack of intrinsic adverse effect of Doxebo. Likewise, the repeated injection of Doxebo before Doxil did not impact Doxil's pharmacokinetics in plasma and therefore does not cause accelerated blood clearance (ABC). Taken together with our previous publications, these data suggest that the injection of Doxebo prior to Doxil administration can help protect against Doxil-induced IR without adversely affecting treatment efficacy and safety.
Agid:
6466282