Pharmacokinetics and Preclinical Safety Studies of Modified Endolysin-based Gel for Topical Application

• Published in: Journal of pharmaceutical sciences Vol. 113; no. 8; pp. 2093 - 2100
• Main Authors: Antonova, Nataliia P., Vasina, Daria V., Grigoriev, Igor V., Usachev, Evgeny V., Aleshkin, Andrey V., Vorobev, Aleksei M., Laishevtsev, Aleksei I., Kapustin, Andrey V., Savinov, Vasiliy A., Anurova, Mariia N., Zackharova, Anastasia A., Remizov, Timofey A., Makarov, Valentine V., Yudin, Sergey M., Gushchin, Vladimir A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.08.2024
• Subjects: Antiinfective; Enzyme; Pharmacokinetics; Protein formulation; Toxicology; Toxicology; Antiinfective; Protein formulation; Pharmacokinetics; Enzyme
• ISSN: 0022-3549; 1520-6017; 1520-6017
• DOI: 10.1016/j.xphs.2024.04.028

Antibacterial therapy with phage-encoded endolysins or their modified derivatives with improved antibacterial, biochemical and pharmacokinetic properties is one of the most promising strategies that can supply existing antibacterial drugs array. Gram-negative bacteria-induced infections treatment is especially challenging because of rapidly spreading bacterial resistance. We have developed modified endolysin LysECD7-SMAP with a significant antibacterial activity and broad spectra of action against gram-negative bacteria. Endolysin was formulated in a bactericidal gel for topical application with pronounced effectivity in local animal infectious models. Here we present preclinical safety studies and pharmacokinetics of LysECD7-SMAP-based gel. We have detected LysECD7-SMAP in the skin and underlying muscle at therapeutic concentrations when the gel is applied topically to intact or injured skin. Moreover, the protein does not enter the bloodstream, and has no systemic bioavailability, assuming no systemic adverse effects. In studies of general toxicology, local tolerance, and immunotoxicology it was approved that LysECD7-SMAP gel local application results in the absence of toxic effects after single and multiple administration. Thus, LysECD7-SMAP-containing gel has appropriate pharmacokinetics and can be considered as safe that supports the initiation of the phase I clinical trials of novel antibacterial drug intending to treat acute wound infections caused by resistant gram-negative bacteria. [Display omitted] •Murine pharmacokinetic study for endolysin LysECD7-SMAP gel was performed.•Therapeutic concentrations of the endolysin in healthy and wounded skin models are detected.•When applied locally LysECD7-SMAP do not reach bloodstream.•Endolysin gel is safe in general toxicology and immunotoxicology studies in rodents and rabbits.