Evaluation of VT-1161 for Treatment of Coccidioidomycosis in Murine Infection Models

Shubitz, Lisa F.; Trinh, Hien T.; Galgiani, John N.; Lewis, Maria L.; Fothergill, Annette W.; Wiederhold, Nathan P.; Barker, Bridget M.; Lewis, Eric R. G.; Doyle, Adina; Hoekstra, William J.; Schotzinger, Robert J.; Garvey, Edward P.

doi:10.1128/aac.00593-15

Cited by 51 publications

(33 citation statements)

References 27 publications

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“…Time-weighted average plasma concentrations of VT-1161 showed that all the dogs had levels much greater than the MIC 90 for Coccidioides spp. (2 g/ml for 52 isolates) (13) and that there was no difference in clinical responses for dogs with a mean plasma TWA of 39 g/ml (high dose) and those with a mean plasma TWA of 19 g/ml (low dose). In addition, there was no significant relationship between the plasma level and the percent reduction in disease score, most likely because all plasma concentrations were well above the MIC for Coccidioides spp.…”

Section: Discussionmentioning

confidence: 87%

“…These results show that the plasma concentration was dose dependent but not linearly proportionate. Plasma concentrations from both groups were well above the MIC 90 for Coccidioides strains (13). To determine if a relationship existed between the plasma concentration of VT-1161 and the clinical response, the percent change in disease score at enrollment and exit was calculated for each dog, and linear regression was performed.…”

Section: Resultsmentioning

confidence: 99%

“…Although VT-1161 penetrates CNS tissues and has shown efficacy for treatment of CNS coccidioidomycosis in a murine infection model (13), only pulmonary cases were selected for assessment of VT-1161 in naturally infected dogs because of the ease of enrollment and monitoring and the ability to assess responses in a short time period (60 days). Pulmonary coccidioidomycosis is common, while CNS manifestations in dogs are infrequent, similar to those in humans, and quantitative assessment would require serial imaging performed under anesthesia, as well as a long enrollment period to collect sufficient cases.…”

Section: Discussionmentioning

confidence: 99%

“…VT-1161 has a favorable toxicity profile with minimal predicted drug-drug interactions and minimal toxicity in preclinical and clinical studies to date. We recently showed that it is efficacious in reducing brain and lung fungal burdens in murine models of central nervous system (CNS) and respiratory coccidioidomycosis, respectively, and significantly extends survival in both models (13).…”

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confidence: 99%

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Efficacy of the Investigational Antifungal VT-1161 in Treating Naturally Occurring Coccidioidomycosis in Dogs

Shubitz

Roy²,

Trinh

et al. 2017

Antimicrob Agents Chemother

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Coccidioidomycosis can be a chronic, systemic fungal infection requiring long-term to lifetime medication. Thus, there is a need for improved antifungal agents with greater efficacy and reduced toxicity. VT-1161 has a low affinity for mammalian cytochromes and potently inhibits fungal CYP51 with proven efficacy in murine models of central nervous system (CNS) and respiratory coccidioidomycosis. Dogs experience coccidioidomycosis similar to humans and are a useful preclinical model for naturally occurring disease. Twenty-four client-owned dogs diagnosed with respiratory coccidioidomycosis based on radiography, serology, clinical signs, and clinicopathologic abnormalities were treated with a loading dose of VT-1161 for 14 days, followed by 46 days of a lower maintenance dose. Twelve dogs received a high dose (29 mg/kg loading, 6 mg/kg maintenance) and 12 received a low dose (10 mg/kg loading, 1.6 mg/kg maintenance). Response to treatment was assessed by calculating the reduction in disease scores at exit compared to disease scores at enrollment. Overall, 20 of 24 (83%) dogs had Ն50% reduction in enrollment disease scores at exit (P Ͻ 0.001), with no difference between the high-and low-dose groups (P ϭ 0.66). Time-weighted average plasma concentrations for the high-and low-dose groups were 39 Ϯ 5 g/ml and 19 Ϯ 2 g/ml, respectively. In this openlabel study, VT-1161 was efficacious for the treatment of respiratory coccidioidomycosis in naturally infected dogs. Combined with previously reported murine data, this finding supports the further development of VT-1161 for the treatment of coccidioidomycosis in humans.

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Section: Discussionmentioning

confidence: 87%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Efficacy of the Investigational Antifungal VT-1161 in Treating Naturally Occurring Coccidioidomycosis in Dogs

Shubitz

Roy²,

Trinh

et al. 2017

Antimicrob Agents Chemother

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“…The initial antifungal program focused on Candida yeasts and dermatophytes, ultimately resulting in the selection of VT-1161 for clinical phase 1 pharmacokinetic studies and phase 2a efficacy studies. The safety and pharmacokinetics in humans have mirrored the data from preclinical studies with animals, insofar as VT-1161 appeared to raise no safety concerns and achieved an excellent pharmacokinetic profile when administered orally, exhibiting an extended half-life (23)(24)(25). All data obtained to date support the potential for VT-1161 to be a best-in-class CYP51 antifungal, overcoming the side effect profiles of the currently marketed fungal CYP51 inhibitors (26), which offer limited dosing options.…”

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confidence: 80%

Clinical Candidate VT-1161's Antiparasitic Effect In Vitro , Activity in a Murine Model of Chagas Disease, and Structural Characterization in Complex with the Target Enzyme CYP51 from Trypanosoma cruzi

Hoekstra

Hargrove

Wawrzak

et al. 2016

Antimicrob Agents Chemother

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Antifungal Agents

Lockhart,

Berkow

2023

ClinMicroNow

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This chapter summarizes the comparative activities of the major systemic antifungal agents against important groups of fungi. It discusses the characteristics of the several other agents that can be used for the oral or parenteral treatment of superficial, subcutaneous, or systemic fungal infections. The allylamines are a group of synthetic antifungal compounds effective in the topical and oral treatment of dermatophytoses. Terbinafine is a lipophilic drug that is available for oral or topical administration. With the exception of fluconazole and isavuconazole, food has a significant effect on the absorption of azole antifungals. Itraconazole is a lipophilic triazole drug available for oral or parenteral administration. Ketoconazole is a lipophilic drug formulated for oral or topical use. The echinocandins are semisynthetic lipopeptide antifungal agents that target the fungal cell wall. Micafungin is a water‐soluble antifungal agent, derived from a fermentation product of Coleophoma empetri .

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Evaluation of VT-1161 for Treatment of Coccidioidomycosis in Murine Infection Models

Cited by 51 publications

References 27 publications

Efficacy of the Investigational Antifungal VT-1161 in Treating Naturally Occurring Coccidioidomycosis in Dogs

Efficacy of the Investigational Antifungal VT-1161 in Treating Naturally Occurring Coccidioidomycosis in Dogs

Clinical Candidate VT-1161's Antiparasitic Effect In Vitro , Activity in a Murine Model of Chagas Disease, and Structural Characterization in Complex with the Target Enzyme CYP51 from Trypanosoma cruzi

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