Abstract C079: H. pylori eradication for mitigating gastro-duodenal cancers: Modeling pharmacokinetics of levofloxacin niosomes in Sprague-Dawley rats

Abstract

Abstract Eradication of Helicobacter pylori (H. pylori) and, hence, control of its associated conditions (peptic ulcer, gastric cancer, and lymphoma) still constitute major challenge to therapeutics. H. pylori has been implicated in 60% of gastric and 90 % of duodenal ulcers and has been classified as a Class 1 carcinogen in human by the International Agency for Research on Cancer and the World health Organization (Enerson et al, 2016; Vogiatzi et al, 2007; WHO). It affects 4million people world-wide of which 0.5million is from the US and 70% are of 25-64 y/o (Chung & Shelat, 2017). Presently, gastric cancer is the second leading cause of neoplastic mortality globally (Contreras et al, 2014; Owen et al, 2018). The efficacy of currently used antibiotics (erythromycin, clarithromycin, levofloxacin, and azithromycin) in triple or quadruple combinations with proton pump inhibitor (PPI) is decreasing due to resistance development via lipopolysaccharide modification, increased drug efflux, and reduced porin pathway. Adaptive response by bacteria to specific signal due to antibacterial presence in its environment, leading to up-regulation of the efflux system (MexXY/OprM), and down-regulation of porin pathway (OprD) has been recognized as key factor in the resistance manifestation. In an earlier study, we reported that encapsulation of an anti-H. pylori drug (levofloxacin) molecules in niosomes (nano-size lipid vesicles) improved its molecular assimilation by drug-resistant E. coli and Ps. aeruginosa and produced approximately 50 % reduction in their minimum inhibitory concentrations (MIC) (Jankie et al, 2012). In this study, we investigated the in vivo bioavailability of levofloxacin niosomes administered intraperitoneally to Sprague Dawley rats. Plasma data modelling in Gastroplus PKTM for non-compartmental through 3-compartmental models, using Hooke & Jeeves pattern search, indicated that pure levofloxacin obeyed two-compartment kinetic model, while levofloxacin niosomes demonstrated one-compartmental model. In addition, niosome encapsulation increased drug exposure (AUC) about 5 folds and duration of action (mean residence time, MRT) about 1.6 folds. Thus, niosome encapsulation changed distribution pattern and the values of PK parameter supported 2-compartmental and 1-compartmental models for levofloxacin and its niosomes respectively. The knowledge of in vivo rodent PK generated in this study is vital for the determination of test doses in a higher animal species and, subsequent, for the calculation of thee first in human dose of levofloxacin using allometric equations. Generally, the potential is quite high for niosomes encapsulation to enhance the efficacy of other anti-H. pylori drugs against drug-resistant bacterial strains and needs to be investigated. Citation Format: Amusa S. Adebayo, Satish Jankie. H. pylori eradication for mitigating gastro-duodenal cancers: Modeling pharmacokinetics of levofloxacin niosomes in Sprague-Dawley rats [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr C079.