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

• A murine pharmacokinetic study for endolysin LysECD7-SMAP lyophilizate was performed. • Therapeutic concentrations were observed in serum for 60 min after bolus i.v. administration. • Endolysin distributes in blood, degrades in blood and liver, and eliminates via kidney. • LysECD7-SMAP is safe in toxicology, immunotoxicity, and allergenicity studies in rodents. 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. [Display omitted] [ABSTRACT FROM AUTHOR]