Magistral preparation of fumagillin for the treatment of Enterocytozoon bieneusi microsporidiosis: between active pharmaceutical ingredient shortage and major therapeutic need.

S. Filali1, C. Dupuis1, A. Louguet1, M. Rabodonirina2, N. Laverdure3, Ph. Poirier4, A. Von Kanel1, B. Lapras1, C. Pivot1, C. Paillet1, C. Merienne1, F. Pirot1
1 Preparation and Control of Medicines Unit, FRIPHARM platform, Pharmacy, Edouard Herriot Hospital - Hospices Civils de Lyon.
2 Parasitology and Medical Mycology Department, Croix-Rousse Hospital - Hospices Civils de Lyon.
3 Pediatric gastroenterology, hepatology and nutrition department, Femme Mère Enfant Hospital - Hospices Civils de Lyon.
4 Parasitology and mycology department, Clermont-Ferrand University Hospital - Gabriel Montpied Hospital.

Background and objectives
Fumagillin is a hematotoxic antimicrobial used to treat intestinal E. bieneusi microsporidiosis, which is responsible for severe and potentially fatal diarrhea in immunocompromised patients [1]. Discontinuation of the only commercial product proven to be effective requires the use of a magistral preparation (MP) in a context of shortage of chemically unstable active pharmaceutical ingredient (API). We report a translational approach that made available a treatment for E. bieneusi microsporidiosis (EBM) in immunocompromised patients.

Materials and methods
A request for fumagillin sample, addressed to the former marketing authorization holder with information to ANSM, was granted with a transfer of API (-80°C). Upon receipt, analyses of the API by infrared, UV spectrometry and high performance liquid chromatography coupled to mass spectrometry (HPLC-MS) were performed by our control laboratory. The formulation of a suspension of fumagillin (20 mg/ml) in an oily excipient of propylene glycol dicaprylate/dicaprate (e.g., excipient reported in the former summary of product characteristics) was performed by dispersion of the powder in the excipient and then distributed in hermetically sealed capsules. The fumagillin content of the capsules was determined by UV spectrometry and HPLC-MS, and a request for a waiver to treat two patients with EBM was submitted to the Commission du Médicament et des Dispositifs Médicaux Stériles (COMEDIMS).

Results and discussion
Analyses of API and fumagillin content of the MP were conforms to physicochemical specifications in respect of storage conditions limiting hydrolysis and photodegradation of the active pharmaceutical ingredient. The waiver request was granted by COMEDIMS.

Conclusion
Despite context of API shortage, we developed a fumagillin MP, which highlights the importance of developing a network of national and European API providers. Developing this fumagillin MP is a concrete and translational pharmaceutical solution to a major therapeutic need.

1. E.S. Didier, L. M. Weiss. Microsporidiosis: not just in AIDS patients. Curr Opin Infect Dis. 2011 Oct;24(5):490-5.

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