Safety evaluations of a synthetic antimicrobial peptide administered intravenously in rats and dogs

Abstract

The antimicrobial peptide SET-M33 is under study for the development of a new antibiotic against major Gram-negative pathogens. Here we report the toxicological evaluation of SET-M33 administered intravenously to rats and dogs. Dose range finding experiments determined the doses to use in toxicokinetic evaluation, clinical biochemistry analysis, necroscopy and in neurological and respiratory measurements. Clinical laboratory investigations in dogs and rats showed a dose-related increase in creatinine and urea levels, indicating that the kidneys are the target organ. This was also confirmed by necroscopy studies of animal tissues, where signs of degeneration and regeneration were found in kidney when SET-M33 was administered at the highest doses in the two animal species. Neurological toxicity measurements by the Irwin method and respiratory function evaluation in rats did not reveal any toxic effect even at the highest dose. Finally, repeated administration of SET-M33 by short infusion in dogs revealed a no-observed-adverse-effect-level of 0.5 mg/kg/day.

In Vivo Efficacy and Toxicity of an Antimicrobial Peptide in a Model of Endotoxin-Induced Pulmonary Inflammation

“…The data reported in this article, added to that previously published for different animal models [28,29,36,37] complete the experimentation of the SET-M33 peptide. SET-M33 has now concluded all preclinical stages of development, including safety evaluations and toxicokinetic parameters, for administration by intravenous bolus or infusion [36] and inhalation.…”

“…Data on analogous forms of the peptide produced with D-amino-acids [32], in dimeric form [33], in a pegylated version [34], encapsulated in dextran nanoparticles [35] and in poly(lactide-coglycolide) nanoparticles [36] are already reported in the literature. The peptide SET-M33 has completed preclinical development with toxicity results for intravenous administration in rats and dogs, two animal species recommended as rodent and non-rodent test systems, respectively, by international guidelines [37].…”

Inhalable Polymeric Nanoparticles for Pulmonary Delivery of Antimicrobial Peptide SET-M33: Antibacterial Activity and Toxicity In Vitro and In Vivo

“…A preclinical stage in the development of SET-M33, including toxicity and pharmacological safety assessments of the free peptide when administered by intravenous short infusion, has been concluded [ 40 ]. The toxicity results and efficacy data already reported [ 5 , 10 , 40 ] showed a satisfactory therapeutic index, even with the narrow range of doses used.…”

“…A preclinical stage in the development of SET-M33, including toxicity and pharmacological safety assessments of the free peptide when administered by intravenous short infusion, has been concluded [ 40 ]. The toxicity results and efficacy data already reported [ 5 , 10 , 40 ] showed a satisfactory therapeutic index, even with the narrow range of doses used. Likewise, preliminary experiments with free SET-M33 administered intratracheally by nebulization systems gave promising results in terms of efficacy and toxicity, indicating a preliminary NOAEL in mice of about 4 mg/Kg/day.…”

Antimicrobial Peptides towards Clinical Application—A Long History to Be Concluded

“…Studies conducted in cell lines and preclinical models in vivo show that AMPs may generally be toxic to renal tubule cells. The cell mechanisms involved include oxidative stress, apoptosis (via mitochondrial, death receptor, and endoplasmic reticulum pathways), cell cycle arrest, and autophagy [122][123][124][125]. Many AMPs in clinical and preclinical development have safety pharmacology data that demonstrate a certain level of nephrotoxicity in different animal models.…”