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Published on: May 2, 2018
Pharmacodynamic evaluation of the neutralization of endotoxin by PMX622 in mice
Philip Lake1, Jeffrey DeLeo, Franklin Cerasoli
1Novartis Institute for Biomedical Research, East Hanover, New Jersey 07901, USA.
Abstract:
Polymyxin B (PMB) binds to and neutralizes endotoxin, but its systemic clinical utility is limited by neuro- and nephrotoxicity. PMX622 is a covalent conjugate of PMB and Dextran-70 designed to retain the ability of PMB to neutralize endotoxin and to retain the favorable colloidal, pharmacokinetic, and metabolic properties of Dextran-70. PMX622 has demonstrated efficacy in a number of animal models and effectively neutralized endotoxin in phase I clinical trials. Here, we systematically evaluated the pharmacodynamic properties of PMX622 in a murine model of endotoxin-induced lethality in galactosamine-sensitized mice. PMX622 completely and dose dependently inhibited lethality in this model. A stoichiometric relationship was found between the endotoxin challenge dose and the dose of PMX622 needed for protection. PMX622 neutralized endotoxin from four different genera of gram-negative bacteria but not Neisseria meningitidis. PMX622 was significantly less toxic than PMB in the mouse, suggesting that PMX622 has a better margin of safety than PMB. The timing of PMX622 administration relative to endotoxin was crucial. PMX622 was active for several hours prior to the endotoxin challenge; however, PMX622 did not protect mice if administered >/=15 min after endotoxin challenge. This suggests that PMX622 would best be clinically used prophylactically rather than therapeutically. These studies will be crucial in designing and interpreting human clinical trials assessing PMX622 efficacy.
Insights
PMX622, a novel conjugate, effectively neutralizes endotoxin and prevents death in mice. Its prophylactic use is key, as it shows reduced toxicity compared to Polymyxin B.
Area of Science:
- Pharmacology
- Toxicology
- Microbiology
Background:
- Polymyxin B (PMB) neutralizes endotoxin but has dose-limiting neurotoxicity and nephrotoxicity.
- PMX622 is a conjugate of PMB and Dextran-70, designed to mitigate PMB toxicity while retaining endotoxin-neutralizing capacity.
- PMX622 has shown promise in preclinical models and Phase I clinical trials.
Purpose of the Study:
- To evaluate the pharmacodynamic properties of PMX622 in a murine model of endotoxin-induced lethality.
- To determine the dose-response relationship, spectrum of activity, toxicity profile, and optimal administration timing of PMX622.
Main Methods:
- A murine model of galactosamine-sensitized, endotoxin-induced lethality was used.
- PMX622 was administered at various doses and time points relative to endotoxin challenge.
- Endotoxin neutralization by PMX622 was tested against bacteria from different genera.
Main Results:
- PMX622 demonstrated dose-dependent protection against endotoxin-induced lethality.
- A stoichiometric relationship was observed between endotoxin dose and PMX622 required for protection.
- PMX622 neutralized endotoxin from most Gram-negative bacteria tested but not Neisseria meningitidis.
- PMX622 exhibited significantly lower toxicity than PMB in mice.
- Efficacy was dependent on timely administration; PMX622 was ineffective if given after endotoxin challenge.
Conclusions:
- PMX622 is a potent endotoxin neutralizer with a potentially improved safety profile compared to PMB.
- The prophylactic administration of PMX622 is crucial for its efficacy.
- These findings support the clinical development of PMX622, particularly for preventative strategies.
