Different liposomal amphotericin B formulations for visceral leishmaniasis–Author's reply
Authors: Nilima Kshirsagar
Journal: The Lancet Global Health (2014)

Control 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 amphotericin manufactured by Gilead—is better tolerated and is effective as a single dose. However, its limited production is inadequate for all cases of visceral leishmaniasis, and its cost needs further reduction.1Gaspani S Milani B Access to liposomal generic formulations: beyond AmBisome and Doxil/Caelyx.Generics Biosimilars Initiative J. 2013; 2: 60-62Crossref Google Scholar The liposomal or lipid-associated amphotericin products Amphotec, Abelcet, and Ambisome have different 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 Ambisome and Anfogen (a liposomal amphotericin by Genpharma, Argentina, withdrawn for further development) have the same composition but are manufactured differently and have different particle sizes, toxic effects, and efficacy in the aspergillosis mouse model.2Olson JA Adler-Moore JP Jensen GM Schwartz J Dignani MC Proffitt RT Comparison of the physicochemical, antifugal and toxic properties of two liposomal amphotericin B products.Antimicrob Agents Chemother. 2008; 52: 259-268Crossref PubMed Scopus (59) Google Scholar The liposomal amphotericin Fungisome, developed by academic institutions3Kshirsagar NA Kirodian GB Liposomal drug delivery system from laboratory to patients: our experience.Proc Indian Natl Sci Acad. 2002; 68: 333-348Google Scholar and marketed in India, is indeed not a generic of Ambisome: it contains different lipids (soy phosphadidylcholine and cholesterol), and has a different vesicle size, formulation, and pharmacokinetics in preclinical and clinical phase 1 studies. It is safe and effective in animal models of mouse aspergillosis and visceral leishmaniasis; in phases 2, 3, and 4 of systemic mycosis; in a phase 2 dose-finding study of visceral leishmaniasis;3Kshirsagar NA Kirodian GB Liposomal drug delivery system from laboratory to patients: our experience.Proc Indian Natl Sci Acad. 2002; 68: 333-348Google Scholar and in a single-dose study in visceral leishmaniasis (personal communication, Lifecare). WHO prequalification is useful for UN organisations to increase access and affordability, 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.4European Medicine AgencyReflection 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/Scientific_guideline/2013/03/WC500140351.pdfGoogle Scholar Indian pharmacopoeal standards have been withdrawn owing to inconsistencies with marketed products. Gaspani and Milani1Gaspani S Milani B Access to liposomal generic formulations: beyond AmBisome and Doxil/Caelyx.Generics Biosimilars Initiative J. 2013; 2: 60-62Crossref Google Scholar suggest that pharmaceutical characterisation and clinical pharmacokinetics are sufficient for a product to be designated the same as the innovator. For a product to be designated similar but not the same, preclinical animal pharmacokinetic and efficacy data are also needed. However, liposomal drug distribution is affected by disease. Targeting, dose, and clinical efficacy are different in visceral leishmaniasis and mycosis, thus necessitating specific preclinical and clinical studies for safety and efficacy. Despite preclinical and clinical studies on Fungisome,3Kshirsagar NA Kirodian GB Liposomal drug delivery system from laboratory to patients: our experience.Proc Indian Natl Sci Acad. 2002; 68: 333-348Google Scholar Thomas Dorlo and Manica Balasegaram conclude that Fungisome's testing is inadequate and that it is difficult to use. They miss the point of the need for economic alternatives to Ambisome, rational standards to ensure safety and efficacy, post-marketing monitoring, and concerted efforts 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. Single-dose liposomal amphotericin B for visceral leishmaniasisDinesh Mondal and colleagues (January, p e51)1 investigated the safety and efficacy of single-dose liposomal amphotericin B for treatment of visceral leishmaniasis (also known as kala azar) in Bangladesh. The successful administration of single-dose liposomal amphotericin B at a primary health centre is heartening. In a linked Comment, Prabhat Kumar Sinha and Sujit Bhattacharya2 discussed adverse events reported in the study. Concerns about potential risks of adverse drug reactions and resistance prompted WHO to initiate pharmacovigilance for miltefosine,3 another drug used to treat leishmaniasis, and develop an educational manual for patients and health workers. Full-Text PDF Open Access