A 14-day repeat dose oral gavage range-finding study of a first-in-class CDI investigational antibiotic, in rats

Abstract

Drug resistant bacteria are winning the fight over antibiotics with some bacteria not responding to any antibiotics, threatening modern medicine as we know it. The development of new, effective and safe antibiotics is critical for addressing this issue. Ramizol, a first-in-class styrylbenzene based antibiotic, is an investigational drug indicated for Clostridium difficile infections (CDI). The objective of this range-finding study was to evaluate the potential general toxicity (based on toxicological endpoints selected) and toxicokinetics of Ramizol in male and female rats that may arise from repeated exposure via oral gavage over a test period of at least 14 days at doses of 50 mg/kg, 500 mg/kg and 1500 mg/kg. There were no mortalities in this study and no Ramizol-related clinical observations. Additionally, there were no changes in mean body weight, body weight gain, food consumption or food efficiency for male and female rats attributable to Ramizol administration. The observed pharmacokinetic behavior showed the presence of Ramizol in plasma at 24 hours post-dosing combined with increasing AUC(0–24) values during the course of this study in groups administered 1500 mg/kg/day, which suggests that at least some dosing groups will show accumulation of compound during repeated dose studies. These toxicology results have shown Ramizol is well-tolerated at very high concentrations in rats and support the further drug development of Ramizol as a first-in-class antibiotic for the treatment of CDI.

Assessing the Safety of MA-[D-Leu-4]-OB3, a Synthetic Peptide Leptin Mimetic: Two Pre-Clinical Toxicity Studies in Male and Female C57BL/6 Mice

“…Short-term acute toxicity study: A time-line describing this protocol based on Sibley et al 23 is shown in Figure 1.…”

<p>Investigational Treatment Agents for Recurrent <em>Clostridioides difficile</em> Infection (rCDI)</p>

“…70 A 14-day study was conducted in rats to determine possible toxicity from ramizol administered via oral gavage at repeat dosing that ranged from 50 mg/ kg, 500 mg/kg and 1500 mg/kg. 71 It was observed that high doses of ramizol at 1500 mg/kg/day were well tolerated. Phase I studies will be required to assess the safety of ramizol in healthy volunteers.…”

Polyphenol and Tannin Nutraceuticals and Their Metabolites: How the Human Gut Microbiota Influences Their Properties

“…It is also worth noting that several stilbene-based engineered drugs have been approved by the U.S. Food and Drug Administration agency (FDA) and the European Medicines Agency (EMA) and are effectively in use for estrogen-receptor modulating therapies such as raloxifene (osteoporosis in women), toremifene and tamoxifen (both in use for hormone receptor-positive breast cancer) [ 117 ]. Another stilbene derivate, Ramizol, is currently under preclinical investigation for the treatment of Clostridioides difficile infections [ 118 , 119 ].…”