Pharmacokinetic and preclinical safety studies of endolysin-based therapeutic for intravenous administration.

Pharmacokinetics and safety studies of innovative drugs is an essential part of drug development process. Previously we have developed a novel drug for intravenous administration (lyophilizate) containing modified endolysin LysECD7-SMAP that showed notable antibacterial effect in different animal models of systemic infections. Here we present data on pharmacokinetics of endolysin in mice after single and multiple injections. Time-concentration curves were obtained, and pharmacokinetic parameters for preparation (C ₀ , k _el t _1/2 , AUC _0-∞ , MRT, Cl _T , V _ss ) were calculated. It was shown that although endolysin is rather short-lived in blood serum (t _1/2 = 12.5 min), the therapeutic concentrations of LysECD7-SMAP (in degraded and non-degraded form) were detected for 60 minutes after injection that is sufficient for antibacterial effect. Based on the obtained data, it was proposed that endolysin distributes presumably in murine blood, degrades in blood and liver, and is eliminated via glomerular filtration. Safety profile of the preparation relating to general toxicity, immunotoxicity and allergenicity was assessed in rodents. It was demonstrated that LysECD7-SMAP in potential therapeutic (12.5 mg/kg), 10-fold (125 mg/kg) and 40-fold (500 mg/kg) doses showed no signs of intoxication and significant abnormalities after single and repeated i.v. administrations, preparation was non-immunogenic and induced minor and reversible allergic reaction in animals.
Competing Interests: Declaration Funding: This work was supported by the Centre for Strategic Planning of FMBA of Russia (State Contract n. 0373100122120000008). Competing interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: VDV, NPA, VVM, SMY and VAG are listed as the inventors in patent (RU2792679C1) on LysECD7-SMAP dosage form for parenteral use. VVM and SMY are the current employees of Centre for Strategic Planning and Management of Biomedical Health Risks of the Federal Medical Biological Agency. All other authors declare no competing interests. Authorship contributions: Nataliia P. Antonova: Methodology, Investigation, Formal analysis, Visualization, Writing–original draft. Daria V. Vasina: Conceptualization, Methodology, Data curation, Visualization, Writing–review & editing. Igor V. Grigoriev: Methodology, Investigation, Formal analysis. Aleksei I. Laishevtsev: Methodology, Investigation. Andrey V. Kapustin: Investigation. Vasiliy A. Savinov: Investigation. Andrey V. Aleshkin: Formal analysis, Data curation. Aleksei M. Vorobev: Investigation. Anastasia A. Zackharova: Project administration, Resources. Timofey A. Remizov: Project administration, Resources. Valentine V. Makarov: Funding acquisition. Sergey M. Yudin: Funding acquisition. Vladimir A. Gushchin: Conceptualization, Supervision, Writing–review & editing.
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