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Leishmaniasis pharmacotherapy: New and old treatments for New and Old World disease
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The Leishmania genus of parasites is transmitted through bites of sand flies, and infection can manifest in three different disease presentations: cutaneous leishmaniasis, visceral leishmaniasis or mucosal leishmaniasis. Leishmaniasis is a tropical disease primarily found in South and Central America, India and Africa. Distribution of disease differs depending on both Leishmania spp. and clinical presentation. For example, L. donovani and L. infantum commonly cause visceral leishmaniasis in East Africa, and L. braziliensis and L. panamensis are frequently implicated in cutaneous leishmaniasis in South and Central America. Causative species and geographic location are used to further classify cutaneous leishmaniasis as Old World or New World. The Eastern Hemisphere is considered the Old World, where common pathogens include, among those listed above, L. tropica, L. major, and L. aethiopica. In the Western Hemisphere, New World cutaneous leishmaniasis is more commonly caused by the L. mexicana complex or the Viannia subspecies, which include L. braziliensis and L. panamensis.
Disease presentation and severity ranges widely from mild and spontaneously resolving cutaneous leishmaniasis (CL) lesions to invasive and potentially fatal visceral leishmaniasis (VL), with differing degrees of infection in between. Given the variability of disease presentation and causative species with a paucity of clinical trials, standardized guidelines do not exist. As leishmaniasis can be progressive and potentially disfiguring, treatment is often pursued with a small variety of available agents.
Existing treatment options
The pentavalent antimony (SbV) complexes meglumine antimoniate (Glucantime, Aventis Pharma) and sodium stibogluconate (Pentostam, GlaxoSmithKline) have historically served as mainstays of therapy and continue to be first-line options in several treatment settings. The mechanisms by which the antimony agents function remain unclear, but they appear to impede cellular active transport and disrupt membrane permeability. Treatment with SbV is given either intramuscularly or intravenously, with the additional option for local intralesional injection in the setting of a mild, isolated CL lesion. Side effects, including liver enzyme elevations, injection-related discomfort and myelosuppression, are typically minor and reversible, though treatment-related deaths from arrhythmias and pancreatitis have been rarely described. Other limitations of SbV include development of resistance among selected Leishmania spp. and a lower response rate in children, possibly owing to its more rapid rate of elimination compared with adults.
Before 2014, liposomal amphotericin B (AmBisome, Astellas) had long been the only drug licensed for VL treatment in the United States, at a dose of 3 mg/kg once daily. This regimen has been used effectively in other countries as well, though cost has been identified as a limiting factor.
A variety of other agents have been studied with varied success in the treatment of different forms of leishmaniasis, including paromomycin, ketoconazole, pentamidine, interferon and allopurinol; however these are not routinely recommended.
Miltefosine
The newest antileishmanial miltefosine (Impavido, Knight Therapeutics) exerts antiparasitic activity through incompletely understood mechanisms thought to involve disruption of cellular lipids and mitochondrial function to induce cell death. It was approved by the FDA in March 2014 at a dose of one 50-mg capsule given twice daily for patients weighing 30 kg to 44 kg, and three times daily for patients 45 kg and heavier. Dosing for smaller patients has been studied using 10-mg capsules to attain doses between 1.5 mg/kg/day to 2.5 mg/kg/day divided in two or three daily doses. Co-administration with food is recommended to avoid gastrointestinal effects described in about one-third of patients, as is regular monitoring of renal and hepatic function owing to elevations in serum creatinine and liver function tests observed in a phase 3 trial. Thrombocytopenia and Stevens-Johnson syndrome also were observed. Miltefosine is Pregnancy Category D and should not be given to pregnant women. In a 2012 study comparing miltefosine with meglumine antimoniate for children with CL, miltefosine was deemed noninferior, with a treatment failure rate 15% less than that of meglumine antimoniate. Additionally, miltefosine was significantly more effective than meglumine antimoniate among children aged younger than 7 years.
Leah Molloy
Access to therapy
Liposomal amphotericin B continues to be the only leishmaniasis treatment readily available in the US; however, a US commercialization plan for the more recently approved miltefosine is currently under development. At this time, miltefosine access in the US still requires an investigational new drug (IND) request to be filed through the FDA, after which the manufacturer may ship the drug to the treating facility. Similarly, sodium stibogluconate access in the US also requires an IND, as well as adherence to a treatment protocol developed by the CDC. Direct communication with the CDC for assistance with treatment selection and access should be considered.
Priority review voucher
The Neglected Tropical Disease Priority Review Voucher Program was developed by the FDA to grant expedited review of an eligible new drug application (NDA) or biologic license application (BLA). An expedited review decreases the typically targeted time to FDA review of an NDA or BLA from 10 months down to 6 months. The voucher program was created as a means to encourage development of new therapeutics for neglected tropical diseases such as leishmaniasis by providing the incentive of quicker FDA review. Priority review vouchers are transferable between companies, which recently happened in November 2014. Knight Therapeutics, the current manufacturer of miltefosine, sold its priority review voucher to Gilead Sciences, possibly signaling increased interest and commitment to the treatment of neglected tropical diseases.
References:
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Knight Therapeutics. Knight sells priority review voucher to Gilead. http://www.gud-knight.com/en/knight-sells-priority-review-voucher-to-gilead. Accessed Dec. 18, 2014.
CDC. Leishmaniasis — Resources for Health Professionals. http://www.cdc.gov/parasites/leishmaniasis/health_professionals/index.html#tx. Accessed Dec. 18, 2014.
Rubiano LC. J Infect Dis. 2012;205:684-692.
Sundar S. Curr Opin Infect Dis. 2002;15:593-598.
Magill AJ. Leishmania species: visceral (kala-azar), cutaneous, and mucosal leishmaniasis. In: MJ Blaser (Ed.), Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases. Philadelphia: Saunders/Elsevier; 2015:3091-3107.
For more information:
Leah Molloy, PharmD, is a clinical pharmacist, specialist in infectious diseases, at Children’s Hospital of Michigan, Detroit. She can be reached at Children’s Hospital of Michigan, Department of Pharmacy Services, 3901 Beaubien St., Detroit, MI 48201; email: lmolloy@dmc.org.
Disclosure: Molloy reports no relevant financial disclosures.