Pharmacodynamics of Flubendazole for Cryptococcal Meningoencephalitis: Repurposing and Reformulation of an Anti- Parasitic Agent for a Neglected Fungal Disease

Nixon, Gemma, McEntee, Laura, Johnson, Adam, Farrington, Nikki, Whalley, Sarah, Livermore, Joanne, Natal, Christien, Washbourn, Gina, Bibby, Jaclyn, Berry, Neil, Lestner, Jodi, Truong, Megan, Owen, Andrew, Lalloo, David ORCID: https://orcid.org/0000-0001-7680-2200, Charles, Ian and Hope, William (2018) 'Pharmacodynamics of Flubendazole for Cryptococcal Meningoencephalitis: Repurposing and Reformulation of an Anti- Parasitic Agent for a Neglected Fungal Disease'. Antimicrobial Agents and Chemotherapy, Vol 62, Issue 4, e01909-17.

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Abstract

Current therapeutic options for cryptococcal meningitis are limited by toxicity, global supply and emergence of resistance. There is an urgent need to develop additional antifungal agents that are fungicidal within the central nervous system and preferably orally bioavailable. The
benzimidazoles have broad-spectrum anti-parasitic activity, but also have in vitro antifungal activity that includes Cryptococcus neoformans. Flubendazole (a benzimidazole) has been reformulated by Janssen Pharmaceutica as an amorphous solid drug nanodispersion to develop an orally bioavailable medicine for the treatment of neglected tropical diseases such as onchocerciasis. We investigated the in vitro activity, the structure-activity-relationships and both in vitro and in vivo pharmacodynamics of flubendazole for cryptococcal meningitis. Flubendazole has potent in vitro activity against Cryptococcus neoformans with a modal MIC of 0.125 mg/L using European Committee for Antimicrobial Susceptibility Testing (EUCAST) methodology. Computer models provided an insight into the residues responsible for the binding of flubendazole to cryptococcal ß-tubulin. Rapid fungicidal activity was evident in a hollow fiber infection model of cryptococcal meningitis. The solid drug nanodispersion was orally
bioavailable in mice with higher drug exposure in the cerebrum. The maximal dose of flubendazole (12 mg/kg/day) orally resulted in a ~2 log10CFU/g reduction in fungal burden compared with vehicle-treated controls. Flubendazole was orally bioavailable in rabbits, but there were no quantifiable drug concentrations in the CSF or cerebrum and no antifungal activity was demonstrated in either CSF or cerebrum. These studies provide evidence for the further study and development of the benzimidazole scaffold for the treatment of cryptococcal
meningitis.

Item Type:	Article
Subjects:	QV Pharmacology > Anti-Inflammatory Agents. Anti-Infective Agents. Antineoplastic Agents > QV 253 Anthelmintics WC Communicable Diseases > Mycoses > WC 450 Mycoses (General or not elsewhere classified) WC Communicable Diseases > Tropical and Parasitic Diseases > WC 850 Nematode infections (General) WL Nervous System > WL 300 General works (Include works on brain alone)
Faculty: Department:	Clinical Sciences & International Health > Clinical Sciences Department
Digital Object Identifer (DOI):	https://doi.org/10.1128/AAC.01909-17
Depositing User:	Stacy Murtagh
Date Deposited:	22 Jan 2018 16:44
Last Modified:	12 Apr 2018 13:25
URI:	https://archive.lstmed.ac.uk/id/eprint/8106

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