Correspondence

www.thelancet.com/lancetgh Vol 2 August 2014 e450

Diff erent liposomal amphotericin B formulations for visceral leishmaniasisAuthor’s replyControl of visceral leishmaniasis requires access to low-cost, safe, and effective treatment. Amphotericin causes infusion-related fever, rigor, and nephrotoxicity, limiting its use. Ambisome—a liposomal ampho tericin manufactured by Gilead—is better tolerated and is eff ective as a single dose. However, its limited production is inadequate for all cases of visceral leishmaniasis, and its cost needs further reduction.1

The liposomal or lipid-associated amphotericin products Amphotec, Abelcet, and Ambisome have diff erent lipids, shapes, sizes, toxic effects, pharmacokinetics, manufacturing processes, and formulations, yet similar efficacies. Ambisome and Anfogen (a liposomal amphotericin by Genpharma, Argentina, withdrawn for further development) have the same composition but are manufactured diff erently and have diff erent particle sizes, toxic eff ects, and effi cacy in the aspergillosis mouse model.2

The liposomal amphotericin Fungi some, developed by academic institutions3 and marketed in India, is indeed not a generic of Ambisome: it contains different lipids (soy phosphadidyl choline and cholesterol), and has a different vesicle size, formulation, and pharmaco kinetics in

preclinical and clinical phase 1 studies. It is safe and eff ective in animal models of mouse aspergil losis and visceral leishmaniasis; in phases 2, 3, and 4 of systemic mycosis; in a phase 2 dose-fi nding study of visceral leishmaniasis;3 and in a single-dose study in visceral leishmaniasis (personal communica-tion, Lifecare).

WHO prequalification is useful for UN organisations to increase access and aff ordability, and includes products that comply with Good Manufacturing Practice, have been studied as per Good Clinical Practice, and that meet WHO standards.

But for liposomal amphotericin there are no WHO standards. The 2002 draft of the US Food and Drug Administration guidance document is under revision. European Medicines Agency 2013 guidelines are based on innovator products as reference, the extent and complexity of non-clinical and clinical studies to be defined on a case-by-case basis.4 Indian pharmaco poeal standards have been withdrawn owing to inconsistencies with marketed products. Gaspani and Milani1 suggest that pharmaceutical characterisation and clinical pharma-cokinetics are suffi cient for a product to be designated the same as the innovator. For a product to be designated similar but not the same, preclinical animal pharmaco kinetic and effi cacy data are also needed. However, liposomal drug distribution is aff ected by disease. Targeting, dose, and clinical effi cacy are diff erent in visceral leishmaniasis and mycosis, thus

necessitating specific preclinical and clinical studies for safety and effi cacy.

Despite preclinical and clinical studies on Fungisome,3 Thomas Dorlo and Manica Balasegaram conclude that Fungisome’s testing is inadequate and that it is diffi cult to use. They miss the point of the need for economic alternatives to Ambisome, rational standards to ensure safety and effi cacy, post-marketing monitor ing, and concerted eff orts by all to control this neglected disease.I declare no competing interests. Development of liposomal amphotericin was funded by the Government of India at G S Medical College, KEM Hospital, where I worked until 2007.

Copyright © Kshirsagar. Open Access article distributed under the terms of CC BY-NC-ND.

Nilima Kshirsagarkshirsagarna@yahoo.in

Indian Council of Medical Research, Government of India, Mumbai, India; and Post Graduate Institute of Medical Science and Research, Mahatama Gandhi Memorial Hospital, Parel, Mumbai, India

1 Gaspani S, Milani B. Access to liposomal generic formulations: beyond AmBisome and Doxil/Caelyx. Generics Biosimilars Initiative J 2013; 2: 60–62.

2 Olson JA, Adler-Moore JP, Jensen GM, Schwartz J, Dignani MC, Proffi tt RT. Comparison of the physicochemical, antifugal and toxic properties of two liposomal amphotericin B products. Antimicrob Agents Chemother 2008; 52: 259–68.

3 Kshirsagar NA, Kirodian GB. Liposomal drug delivery system from laboratory to patients: our experience. Proc Indian Natl Sci Acad 2002; 68: 333–48.

4 European Medicine Agency. Refl ection paper on data requirement for intravenous liposomal products developed with reference to an innovator liposomal product. http://www.ema.europa.eu/docs/en_GB/document_library/Scientifi c_guideline/2013/03/WC500140351.pdf (accessed July 3, 2014).