Pharmacodynamics of the Orotomides against <italic toggle="yes">Aspergillus fumigatus</italic>: New Opportunities for Treatment of Multidrug-Resistant Fungal Disease

ABSTRACT F901318 is an antifungal agent with a novel mechanism of action and potent activity against Aspergillus spp. An understanding of the pharmacodynamics (PD) of F901318 is required for selection of effective regimens for study in phase II and III clinical trials. Neutropenic murine and rabbit...

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Autores principales:	William W. Hope, Laura McEntee, Joanne Livermore, Sarah Whalley, Adam Johnson, Nicola Farrington, Ruwanthi Kolamunnage-Dona, Julie Schwartz, Anthony Kennedy, Derek Law, Michael Birch, John H. Rex
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2017
Materias:	Aspergillus fumigatus antifungal agents antifungal resistance antifungal susceptibility testing drug discovery laboratory animals Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/ee5b4c0c99644111aad9e0e94bbbb141
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spelling	oai:doaj.org-article:ee5b4c0c99644111aad9e0e94bbbb1412021-11-15T15:51:44ZPharmacodynamics of the Orotomides against <italic toggle="yes">Aspergillus fumigatus</italic>: New Opportunities for Treatment of Multidrug-Resistant Fungal Disease10.1128/mBio.01157-172150-7511https://doaj.org/article/ee5b4c0c99644111aad9e0e94bbbb1412017-09-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01157-17https://doaj.org/toc/2150-7511ABSTRACT F901318 is an antifungal agent with a novel mechanism of action and potent activity against Aspergillus spp. An understanding of the pharmacodynamics (PD) of F901318 is required for selection of effective regimens for study in phase II and III clinical trials. Neutropenic murine and rabbit models of invasive pulmonary aspergillosis were used. The primary PD endpoint was serum galactomannan. The relationships between drug exposure and the impacts of dose fractionation on galactomannan, survival, and histopathology were determined. The results were benchmarked against a clinically relevant exposure of posaconazole. In the murine model, administration of a total daily dose of 24 mg/kg of body weight produced consistently better responses with increasingly fractionated regimens. The ratio of the minimum total plasma concentration/MIC (Cmin/MIC) was the PD index that best linked drug exposure with observed effect. An average Cmin (mg/liter) and Cmin/MIC of 0.3 and 9.1, respectively, resulted in antifungal effects equivalent to the effect of posaconazole at the upper boundary of its expected human exposures. This pattern was confirmed in a rabbit model, where Cmin and Cmin/MIC targets of 0.1 and 3.3, respectively, produced effects previously reported for expected human exposures of isavuconazole. These targets were independent of triazole susceptibility. The pattern of maximal effect evident with these drug exposure targets was also apparent when survival and histopathological clearance were used as study endpoints. F901318 exhibits time-dependent antifungal activity. The PD targets can now be used to select regimens for phase II and III clinical trials. IMPORTANCE Invasive fungal infections are common and often lethal. There are relatively few antifungal agents licensed for clinical use. Antifungal drug toxicity and the emergence of drug resistance make the treatment of these infections very challenging. F901318 is the first in a new class of antifungal agents called the orotomides. This class has a novel mechanism of action that involves the inhibition of the fungal enzyme dihydroorotate dehydrogenase. F901318 is being developed for clinical use. A deep understanding of the relationship between dosages, drug concentrations in the body, and the antifungal effect is fundamental to the identification of the regimens to administer to patients with invasive fungal infections. This study provides the necessary information to ensure that the right dose of F901318 is used the first time. Such an approach considerably reduces the risks in drug development programs and ensures that patients with few therapeutic options can receive potentially life-saving antifungal therapy at the earliest opportunity.William W. HopeLaura McEnteeJoanne LivermoreSarah WhalleyAdam JohnsonNicola FarringtonRuwanthi Kolamunnage-DonaJulie SchwartzAnthony KennedyDerek LawMichael BirchJohn H. RexAmerican Society for MicrobiologyarticleAspergillus fumigatusantifungal agentsantifungal resistanceantifungal susceptibility testingdrug discoverylaboratory animalsMicrobiologyQR1-502ENmBio, Vol 8, Iss 4 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Aspergillus fumigatus antifungal agents antifungal resistance antifungal susceptibility testing drug discovery laboratory animals Microbiology QR1-502
spellingShingle	Aspergillus fumigatus antifungal agents antifungal resistance antifungal susceptibility testing drug discovery laboratory animals Microbiology QR1-502 William W. Hope Laura McEntee Joanne Livermore Sarah Whalley Adam Johnson Nicola Farrington Ruwanthi Kolamunnage-Dona Julie Schwartz Anthony Kennedy Derek Law Michael Birch John H. Rex Pharmacodynamics of the Orotomides against <italic toggle="yes">Aspergillus fumigatus</italic>: New Opportunities for Treatment of Multidrug-Resistant Fungal Disease
description	ABSTRACT F901318 is an antifungal agent with a novel mechanism of action and potent activity against Aspergillus spp. An understanding of the pharmacodynamics (PD) of F901318 is required for selection of effective regimens for study in phase II and III clinical trials. Neutropenic murine and rabbit models of invasive pulmonary aspergillosis were used. The primary PD endpoint was serum galactomannan. The relationships between drug exposure and the impacts of dose fractionation on galactomannan, survival, and histopathology were determined. The results were benchmarked against a clinically relevant exposure of posaconazole. In the murine model, administration of a total daily dose of 24 mg/kg of body weight produced consistently better responses with increasingly fractionated regimens. The ratio of the minimum total plasma concentration/MIC (Cmin/MIC) was the PD index that best linked drug exposure with observed effect. An average Cmin (mg/liter) and Cmin/MIC of 0.3 and 9.1, respectively, resulted in antifungal effects equivalent to the effect of posaconazole at the upper boundary of its expected human exposures. This pattern was confirmed in a rabbit model, where Cmin and Cmin/MIC targets of 0.1 and 3.3, respectively, produced effects previously reported for expected human exposures of isavuconazole. These targets were independent of triazole susceptibility. The pattern of maximal effect evident with these drug exposure targets was also apparent when survival and histopathological clearance were used as study endpoints. F901318 exhibits time-dependent antifungal activity. The PD targets can now be used to select regimens for phase II and III clinical trials. IMPORTANCE Invasive fungal infections are common and often lethal. There are relatively few antifungal agents licensed for clinical use. Antifungal drug toxicity and the emergence of drug resistance make the treatment of these infections very challenging. F901318 is the first in a new class of antifungal agents called the orotomides. This class has a novel mechanism of action that involves the inhibition of the fungal enzyme dihydroorotate dehydrogenase. F901318 is being developed for clinical use. A deep understanding of the relationship between dosages, drug concentrations in the body, and the antifungal effect is fundamental to the identification of the regimens to administer to patients with invasive fungal infections. This study provides the necessary information to ensure that the right dose of F901318 is used the first time. Such an approach considerably reduces the risks in drug development programs and ensures that patients with few therapeutic options can receive potentially life-saving antifungal therapy at the earliest opportunity.
format	article
author	William W. Hope Laura McEntee Joanne Livermore Sarah Whalley Adam Johnson Nicola Farrington Ruwanthi Kolamunnage-Dona Julie Schwartz Anthony Kennedy Derek Law Michael Birch John H. Rex
author_facet	William W. Hope Laura McEntee Joanne Livermore Sarah Whalley Adam Johnson Nicola Farrington Ruwanthi Kolamunnage-Dona Julie Schwartz Anthony Kennedy Derek Law Michael Birch John H. Rex
author_sort	William W. Hope
title	Pharmacodynamics of the Orotomides against <italic toggle="yes">Aspergillus fumigatus</italic>: New Opportunities for Treatment of Multidrug-Resistant Fungal Disease
title_short	Pharmacodynamics of the Orotomides against <italic toggle="yes">Aspergillus fumigatus</italic>: New Opportunities for Treatment of Multidrug-Resistant Fungal Disease
title_full	Pharmacodynamics of the Orotomides against <italic toggle="yes">Aspergillus fumigatus</italic>: New Opportunities for Treatment of Multidrug-Resistant Fungal Disease
title_fullStr	Pharmacodynamics of the Orotomides against <italic toggle="yes">Aspergillus fumigatus</italic>: New Opportunities for Treatment of Multidrug-Resistant Fungal Disease
title_full_unstemmed	Pharmacodynamics of the Orotomides against <italic toggle="yes">Aspergillus fumigatus</italic>: New Opportunities for Treatment of Multidrug-Resistant Fungal Disease
title_sort	pharmacodynamics of the orotomides against <italic toggle="yes">aspergillus fumigatus</italic>: new opportunities for treatment of multidrug-resistant fungal disease
publisher	American Society for Microbiology
publishDate	2017
url	https://doaj.org/article/ee5b4c0c99644111aad9e0e94bbbb141
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Pharmacodynamics of the Orotomides against <italic toggle="yes">Aspergillus fumigatus</italic>: New Opportunities for Treatment of Multidrug-Resistant Fungal Disease

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