APX001 Is Effective in the Treatment of Murine Invasive Pulmonary Aspergillosis
| Autor: | Abdullah Alqarihi, Mili Kapoor, Ashraf S. Ibrahim, Sondus Alkhazraji, Teclegiorgis Gebremariam, Yiyou Gu, Heewon H. Jeon, Karen J Shaw |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Male
Posaconazole Antifungal Agents Aminopyridines Pharmacology Aspergillosis Aspergillus fumigatus Mice Medicine Pharmacology (medical) skin and connective tissue diseases infection model Lung Invasive Pulmonary Aspergillosis 0303 health sciences Mice Inbred ICR Gwt1 biology Pharmacology and Pharmaceutical Sciences Inbred ICR Infectious Diseases medicine.anatomical_structure Aspergillus Medical Microbiology Infection medicine.drug APX001 Microbial Sensitivity Tests Microbiology 1-aminobenzotriazole Fungal Proteins 03 medical and health sciences Immunocompromised Host Rare Diseases Pharmacotherapy Pharmacokinetics In vivo Animals Experimental Therapeutics 030304 developmental biology Animal 030306 microbiology business.industry APX001A Isoxazoles Triazoles biology.organism_classification medicine.disease bacterial infections and mycoses Disease Models Animal Emerging Infectious Diseases Orphan Drug IPA Disease Models business antifungal |
| Zdroj: | Antimicrobial Agents and Chemotherapy Antimicrobial agents and chemotherapy, vol 63, iss 2 |
| ISSN: | 1098-6596 0066-4804 |
| Popis: | Invasive pulmonary aspergillosis (IPA) due to Aspergillus fumigatus is a serious fungal infection in the immunosuppressed patient population. Despite the introduction of new antifungal agents, mortality rates remain high, and new treatments are needed. Invasive pulmonary aspergillosis (IPA) due to Aspergillus fumigatus is a serious fungal infection in the immunosuppressed patient population. Despite the introduction of new antifungal agents, mortality rates remain high, and new treatments are needed. The novel antifungal APX001A targets the conserved Gwt1 enzyme required for the localization of glycosylphosphatidylinositol-anchored mannoproteins in fungi. We evaluated the in vitro activity of APX001A against A. fumigatus and the in vivo activity of its prodrug APX001 in an immunosuppressed mouse model of IPA. APX001A inhibited the growth of A. fumigatus with a minimum effective concentration of 0.03 μg/ml. The use of 50 mg/kg 1-aminobenzotriazole (ABT), a suicide inhibitor of cytochrome P450 enzymes, enhanced APX001A exposures (area under the time-concentration curve [AUC]) 16- to 18-fold and enhanced serum half-life from ∼1 to 9 h, more closely mimicking human pharmacokinetics. We evaluated the efficacy of APX001 (with ABT) in treating murine IPA compared to posaconazole treatment. Treatment of mice with 78 mg/kg once daily (QD), 78 mg/kg twice daily, or 104 mg/kg QD APX001 significantly enhanced the median survival time and prolonged day 21 postinfection overall survival compared to the placebo. Furthermore, administration of APX001 resulted in a significant reduction in lung fungal burden (4.2 to 7.6 log10 conidial equivalents/g of tissue) versus the untreated control and resolved the infection, as judged by histopathological examination. The observed survival and tissue clearance were comparable to a clinically relevant posaconazole dose. These results warrant the continued development of APX001 as a broad-spectrum, first-in-class treatment of invasive fungal infections. |
| Databáze: | OpenAIRE |
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