Toxicological Research

Korean Society of Toxicology & Korea Environmental Mutagen Society (한국독성학회)
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Toxicity of a novel antifungal agent (ATB1651 gel) in Yucatan minipigs (Sus scrofa) following 4 weeks of daily dermal administration

  • Hyung-Sun Kim (Animal Model Research Group, Jeonbuk Branch Institute, Korea Institute of Toxicology) ;
  • Goo-Hwa Kang (Animal Model Research Group, Jeonbuk Branch Institute, Korea Institute of Toxicology) ;
  • Mi-Jin Yang (Jeonbuk Pathology Research Group, Jeonbuk Branch Institute, Korea Institute of Toxicology) ;
  • Yun-Jeong Joo (Jeonbuk Quality Assurance Unit, Jeonbuk Branch Institute, Korea Institute of Toxicology) ;
  • Dong-Gi Lee (AmtixBio Co., Ltd.) ;
  • Han-Seung Lee (AmtixBio Co., Ltd.) ;
  • Jong-Seung Lee (AmtixBio Co., Ltd.) ;
  • Jeong Ho Hwang (Animal Model Research Group, Jeonbuk Branch Institute, Korea Institute of Toxicology)
  • Received : 2023.08.09
  • Accepted : 2023.12.11
  • Published : 2024.04.15
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Abstract

ATB1651 gel is an antifungal drug candidate that enhances antifungal activity through substitution of several aryl rings, alkyl chains, and methyl groups. To ensure safety of use of ATB1651 gel, assessment of its potentially toxic side effects is necessary. In this study, we examined the repeated-dose toxicity of ATB1651 gel to Yucatan minipigs (Sus scrofa) in accordance with the Good Laboratory Practice guidelines. Five doses of ATB1651 gel (0%, 0.2%, 0.5%, 1.0%, 3.0%) were administered dermally to the left and right flanks of 38 minipigs daily for 4 weeks. Mortality, clinical symptoms, dermal scores, body weights, and physiological, biochemical, pathological, and toxicokinetic analyses were performed after the treatment period. No systemic toxicological damage was observed in either male or female minipigs regardless of dose; however, dermal application of ATB1651 gel caused some skin alterations at the application sites. Specifically, erythema and eschar formation, edema, and scabs or raise spots were observed at the application site(s) in males in the 3.0% ATB1651 gel treatment group and in females at ATB1651 gel concentrations ≥ 1.0%, with dermal scores ranging from grade 1 to 2. Additionally, histopathological assay indicated infiltration of different types of inflammatory cells and the presence of pustule/crust at the application site(s) in both males and females at ATB1651 gel concentrations ≥ 0.5%. However, these changes were reversible after a 2-week recovery period and were considered a local irritation effect of ATB1651 gel. The no-observed-adverse-effect level of ATB1651 gel was 3.0% with regard to topical and systemic toxicity in both male and female minipigs. Collectively, our results imply that ATB1651 gel is a safe candidate for clinical development as an antifungal drug with a wide therapeutic window.

Keywords

Acknowledgement

We would like to thank the Jeonbuk Branch Institute of the Korea Toxicology Institute for technical support regarding data acquisition and AmtixBio Co., Ltd. for financial support.

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