Intravenous administration of liposomal drugs can entail infusion reactions, also
known as hypersensitivity reactions (HSRs), that can be severe and sometimes life-threatening
in a small portion of patients. One empirical approach to prevent these reactions
consists of lowering the infusion speed and extending the infusion time of the drug.
However, different liposomal drugs have different levels of reactogenicity, which
means that the optimal protocol for each liposomal drug may differ and should be identified
and evaluated to make the treatment as safe and convenient as possible. The goal of
the present study was to explore the use of pigs for that purpose, using PEGylated
liposomal prednisolone (PLP) as a model drug. We compared the reactogenicities of
bolus versus infusion protocols involving 2-, 3- and 4-step dose escalations for a
clinically relevant total dose, also varying the duration of infusions. The strength
of the reaction was measured via continuous recording of hemodynamic parameters and
blood thromboxane B2 levels. We showed that bolus administration or rapid infusion
of PLP caused transient changes in systemic and pulmonary blood pressure and heart
rate, most notably pulmonary hypertension with paralleling rises in plasma thromboxane
B2. These adverse responses could be significantly reduced or eliminated by slow infusion
of PLP, with the 3-h 3-step dose escalation protocol being the least reactogenic.
These data suggest that the pig model enables the development of safe infusion protocols
for reactogenic nanomedicines.
