Toxicological profile of IQG-607 after single and repeated oral administration in minipigs: An essential step towards phase I clinical trial

摘要

Abstract IQG-607 is an anti-tuberculosis drug candidate, with a promising safety and efficacy profile in models of tuberculosis infection both in?vitro and in?vivo . Here, we evaluated the safety and the possible toxic effects of IQG-607 after acute and 90-day repeated administrations in minipigs. Single oral administration of IQG-607 (220?mg/kg) to female and male minipigs did not result in any morbidity or mortality. No gross lesions were observed in the minipigs at necropsy. Repeated administration of IQG 607 (65, 30, or 15?mg/kg), given orally, for 90 days, in both male and female animals did not cause any mortality and no significant body mass alteration. Diarrhea and alopecia were the clinical signs observed in animals dosed with IQG-607 for 90 days. Long-term treatment with IQG-607 did not induce evident alterations of blood cell counts or any hematological parameters. Importantly, the repeated schedule of administration of IQG-607 resulted in increased cholesterol levels, increased glucose levels, decrease in the globulin levels, and increased creatinine levels over the time. Most necropsy and histopathological alterations of the organs from IQG-607-treated groups were also observed for the untreated group. In addition, pharmacokinetic parameters were evaluated. IQG-607 represents a potential candidate molecule for anti-tuberculosis drug development programs. Its promising in?vivo activity and mild to moderate toxic events detected in this study suggest that IQG-607 represents a candidate for clinical development. Highlights ? Unique and repeated doses of IQG-607 did not result in mortality in minipigs. ? Few adverse effects, diarrhea and alopecia, were observed in the repeated dose study. ? Repeated doses of IQG-607 increased cholesterol, glucose, and creatinine levels. ? Treatments did not induce significant histopathological alterations in tissues.