PKPD modeling and simulation of an inhaled antibiotic targeting Gram-negative bacteria, using a bacteriophage-derived endolysin.

Patients with pneumonia frequently experience a high prevalence of respiratory tract infections. The increasing global prevalence of multidrug-resistant Gram-negative bacteria urgently necessitates the development of new antimicrobial agents for the treatment of infections caused by Gram-negative bacteria. Bacteriophage endolysins, bacteriophage-encoded enzymes, are potentially significant for the treatment of multidrug-resistant bacterial infections. Its mechanism involves the targeted hydrolysis of the bacterial cell wall, leading to rapid eradication of Gram-negative bacteria.In non-clinical experiments, we have demonstrated that bacteriophage endolysins exhibit promising antimicrobial efficacy against pneumococcus, the causative agent of pneumonia in humans. We examined the in vitro antibacterial efficacy of endolysin and observed its highly effective reduction of colony-forming units (CFU) across a range of Gram-negative bacteria. Additionally, we validated its antibacterial activity against the colistin-resistant E. coli mcr-1-positive FORC81 strain, confirming that LNT103 is also active against colistin-resistant bacteria.In a mouse model of pneumonia caused by Acinetobacter baumannii and treated with endolysin, resulted in 100% mortality in the control group by day 1. In contrast, approximately 50% of the mice treated with LNT103 survived until day 7, indicating a significant increase in survival compared with the control group. Additionally, improved survival rates were observed in the antibiotic-treated groups.To predict human pharmacokinetic (PK) parameters, we have calculated in three species (mouse, rat, and dog). In mice, intravenous (IV) administration of a 30 mg/kg dose resulted in a mean bioavailability in plasma of 15.5%, with a PK profile characterized by area under the curve (AUC) 33,184.78 ng·hr/mL, half-life (t1/2) 1.99 hr, clearance (CL) 901.25 mL/hr/kg, and steady-state volume of distribution (Vdss) 129.18 mL/kg.In rats, IV administration of a 25 mg/kg dose resulted in PK parameters of AUC 35,413.45 ng·hr/mL, t1/2 0.28 hr, CL 705.67 mL/hr/kg, and Vdss 71.56 mL/kg.In dogs, IV administration of a 25 mg/kg dose resulted in PK parameters of AUC 90,968.04 ng·hr/mL, t1/2 0.3 hr, CL 282.69 mL/hr/kg, and Vdss 86.75 mL/kg.Based on these studies, we aim to conduct PK/PD modeling and simulation of inhaled endolysin using non-clinical data to predict its pharmacokinetics in humans, thereby identifying the optimal exposure or dose.Citations: [1]Secher et al., Correlation and clinical relevance of animal models for inhaled pharmaceuticals and biopharmaceuticals, Adv. Drug Delivery Rev (2020)[2]Borghardt et al.,Pharmacometric Models for Characterizing the Pharmacokinetics of Orally Inhaled Drugs, AAPS J 17(4):853-70. (2015)