VT-1161 Dosed Once Daily or Once Weekly Exhibits Potent Efficacy in Treatment of Dermatophytosis in a Guinea Pig Model
| Autor: | William R. Moore, Lisa Long, Edward P. Garvey, R. J. Schotzinger, W. J. Hoekstra, Mahmoud A. Ghannoum |
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| Rok vydání: | 2015 |
| Předmět: |
Male
Antifungal Agents Pyridines Itraconazole Guinea Pigs Tetrazoles Microbial Sensitivity Tests Pharmacology Guinea pig Tinea Trichophyton Pharmacokinetics In vivo medicine Animals Experimental Therapeutics Tissue Distribution Pharmacology (medical) Dosing Skin Dose-Response Relationship Drug business.industry Dose–response relationship Regimen Infectious Diseases Terbinafine business medicine.drug |
| Zdroj: | Antimicrobial Agents and Chemotherapy. 59:1992-1997 |
| ISSN: | 1098-6596 0066-4804 |
| DOI: | 10.1128/aac.04902-14 |
| Popis: | Current therapies used to treat dermatophytoses such as onychomycosis are effective but display room for improvement in efficacy, safety, and convenience of dosing. We report here that the investigational agent VT-1161 displays potent in vitro antifungal activity against dermatophytes, with MIC values in the range of ≤0.016 to 0.5 μg/ml. In pharmacokinetic studies supporting testing in a guinea pig model of dermatophytosis, VT-1161 plasma concentrations following single oral doses were dose proportional and persisted at or above the MIC values for at least 48 h, indicating potential in vivo efficacy with once-daily and possibly once-weekly dosing. Subsequently, in a guinea pig dermatophytosis model utilizing Trichophyton mentagrophytes and at oral doses of 5, 10, or 25 mg/kg of body weight once daily or 70 mg/kg once weekly, VT-1161 was statistically superior to untreated controls in fungal burden reduction ( P < 0.001) and improvement in clinical scores ( P < 0.001). The efficacy profile of VT-1161 was equivalent to those for doses and regimens of itraconazole and terbinafine except that VT-1161 was superior to itraconazole when each drug was dosed once weekly ( P < 0.05). VT-1161 was distributed into skin and hair, with plasma and tissue concentrations in all treatment and regimen groups ranging from 0.8 to 40 μg/ml (or μg/g), at or above the MIC against the isolate used in the model (0.5 μg/ml). These data strongly support the clinical development of VT-1161 for the oral treatment of onychomycosis using either once-daily or once-weekly dosing regimens. |
| Databáze: | OpenAIRE |
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