Miltefosine

證據等級: L5

預測適應症: 10 個

Miltefosine: From Visceral Leishmaniasis to Diffuse Cutaneous Leishmaniasis

One-Sentence Summary

Miltefosine (Impavido®) is an oral alkylphosphocholine antiprotozoal agent primarily approved for visceral leishmaniasis, with additional documented use for skin metastases in breast cancer and an EU orphan designation for cutaneous T-cell lymphoma. The TxGNN model predicts it may be effective for Leishmaniasis, Diffuse Cutaneous (DCL) — a severe, treatment-refractory form caused by species such as Leishmania amazonensis and L. aethiopica. With 0 registered clinical trials but 20 publications currently supporting this direction, the evidence base rests largely on case series and systematic reviews, with a highly promising 2026 case report documenting the first complete remission using a prolonged 180-day regimen.

Quick Overview

Item	Content
Original Indication	Visceral leishmaniasis (oral); topical use for breast cancer skin metastases
Predicted New Indication	Leishmaniasis, diffuse cutaneous (DCL)
TxGNN Prediction Score	99.72%
Evidence Level	L3
India Market Status	Not marketed
Number of Registrations	0
Recommended Decision	Proceed with Guardrails

Why is This Prediction Reasonable?

Detailed mechanism of action (MOA) data is not available in this Evidence Pack. Based on known pharmacological information, miltefosine (hexadecylphosphocholine) is a synthetic phosphocholine analogue originally developed in the 1980s as an anticancer agent. It disrupts Leishmania phosphatidylcholine (PC) biosynthesis and induces apoptosis-like cell death in the parasite. Its known molecular target includes AKT serine/threonine kinase 1 (AKT1), suggesting additional effects on host intracellular signalling pathways that may modulate both parasitic survival and the host immune microenvironment.

Visceral leishmaniasis (VL) and diffuse cutaneous leishmaniasis (DCL) share a critical pathological feature: both involve heavy parasite burdens coupled with suppressed cell-mediated immunity (CMI) against Leishmania. DCL is caused primarily by L. amazonensis in South America and L. aethiopica in Ethiopia, and is characterised by host T-cell anergy — making it profoundly refractory to antimonial-based standard treatments. Because miltefosine’s antiparasitic mechanism is effective against VL through the same phospholipid disruption pathway, extension to DCL is biologically plausible, and in vitro studies confirm its activity against L. amazonensis (PMID 25033218).

The central challenge for DCL, however, is not parasitic resistance but host immune failure: clinical case series (PMID 17441955, PMID 16796642) consistently show that patients achieve initial responses on miltefosine, but relapse shortly after cessation because the immunologically anergic host cannot maintain parasite suppression independently. A 2026 case report (PMID 41666471) provides a critical signal — complete disease remission was achieved after a 180-day extended miltefosine course in a patient with a 22-year treatment history of over 60 failed regimens — suggesting that prolonged treatment may overcome the relapse barrier by enabling gradual immune reconstitution.

Clinical Trial Evidence

Currently no related clinical trials registered for miltefosine in diffuse cutaneous leishmaniasis.

Literature Evidence

PMID	Year	Type	Journal	Key Findings
32853410	2020	Cochrane Systematic Review	Cochrane Database Syst Rev	Reviews interventions for American CL/MCL; pentavalent antimonials remain first-line but miltefosine is evaluated as a meaningful alternative with documented efficacy
26568336	2015	Review	J Am Acad Dermatol	Comprehensive review of diagnosis and management of cutaneous and mucocutaneous leishmaniasis; species-specific treatment considerations discussed
22050890	2011	Clinical Guideline	JDDG	German multisociety guideline for CL/MCL; includes miltefosine within evidence-based recommendations for cases with limited alternative options
34048461	2021	Pilot Study (Prospective)	PLoS Negl Trop Dis	Miltefosine for L. aethiopica CL in Ethiopia; the only oral anti-leishmanial agent, with a more favourable side-effect profile than standard sodium stibogluconate (SSG)
28712122	2017	Retrospective Cohort	Trop Med Int Health	Treatment outcomes for CL in NW Ethiopia including severe DCL; highlights treatment challenges and outcomes with available agents
40845055	2025	Observational Study	PLoS Negl Trop Dis	Classification ambiguities across LCL/MCL/DCL subtypes at two Ethiopian treatment sites; calls for standardised definitions to improve comparability of treatment studies
17441955	2007	Case Series	Br J Dermatol	DCL responds to miltefosine but consistently relapses after cessation — landmark evidence defining the core treatment challenge specific to DCL
25033218	2014	In Vitro / Animal Study	PLoS Negl Trop Dis	Confirms miltefosine susceptibility of L. amazonensis (the primary DCL agent in Brazil) both in vitro and in a mouse model
41666471	2026	Case Report	Am J Trop Med Hyg	First documented complete remission of DCL after 180-day miltefosine course; patient had failed >60 prior regimens over 22 years — strongest clinical signal for extended regimen strategy
16796642	2006	Case Report	Int J Dermatol	Early case of DCL treated with miltefosine; documented initial clinical and parasitological response, establishing proof-of-concept

India Market Information

Miltefosine is currently not marketed in India. No regulatory licenses are on record. The drug is marketed internationally under the brand names Impavido® (Profounda Inc., USA — FDA approved 2014 for VL/CL) and Miltex® (topical, EU). Any future commercialisation in India would require de novo regulatory submission.

Cytotoxicity

Miltefosine was originally developed as an antineoplastic agent (alkylphosphocholine class) and retains EU orphan drug designation for cutaneous T-cell lymphoma (CTCL). It may also be used topically to treat skin metastases in breast cancer. The cytotoxicity profile is therefore relevant.

Item	Content
Cytotoxicity Classification	Conventional cytotoxic (Alkylphosphocholine / lipid analogue class)
Myelosuppression Risk	Low to moderate — less haematotoxic than classical cytotoxics; not a primary safety concern at anti-leishmanial doses
Emetogenicity Classification	Moderate — nausea and vomiting are among the most common adverse effects reported
Monitoring Items	Renal function (nephrotoxicity risk), hepatic enzymes (LFTs), complete blood count; pregnancy test mandatory prior to initiation
Handling Protection	Exercise standard precautions; full cytotoxic handling protocols apply if used at oncological doses — refer to local pharmacy guidelines

Safety Considerations

Drug Interactions (Moderate — Source: DDInter)

Miltefosine has documented moderate interactions with multiple hormonal contraceptive components. Given that miltefosine is also known to be embryotoxic and teratogenic, the co-prescription of hormonal contraceptives is clinically significant and patients of reproductive potential must receive thorough counselling.

Interacting Drug	Level	Drug Class
Levonorgestrel	Moderate	Progestogen
Norethisterone	Moderate	Progestogen
Desogestrel	Moderate	Progestogen
Ethinylestradiol	Moderate	Estrogen
Drospirenone	Moderate	Progestogen
Norgestrel	Moderate	Progestogen
Dienogest	Moderate	Progestogen
Norgestimate	Moderate	Progestogen
Idelalisib	Moderate	PI3Kδ inhibitor (oncology)

Formal warnings and contraindications data were not available in this Evidence Pack. Please refer to the Impavido® package insert for complete safety information, including teratogenicity (Pregnancy Category D / contraindicated in pregnancy), mandatory contraception requirements, and renal/hepatic monitoring protocols.

Conclusion and Next Steps

Decision: Proceed with Guardrails

Rationale: A Cochrane systematic review, multiple clinical guidelines, prospective pilot studies, and a pivotal 2026 case report collectively demonstrate that miltefosine has meaningful antiparasitic activity in diffuse cutaneous leishmaniasis. However, the absence of registered clinical trials, a consistent pattern of post-treatment relapse in published cases, and the lack of an optimised dosing protocol represent significant guardrails that must be addressed before broader use or regulatory pursuit.

To proceed, the following is needed:

Safety data gap closure: Obtain and review the complete Impavido® package insert (TFDA/FDA) to document teratogenicity warnings, contraindications, and mandatory monitoring requirements
MOA documentation: Query the DrugBank API (DB09031) to complete the mechanism of action record and support mechanistic link analysis
Prospective clinical trial design: A Phase 2 trial evaluating extended miltefosine regimens (≥90–180 days) for DCL, incorporating immunological endpoints (CMI/T-cell response restoration) alongside standard parasitological cure criteria
Relapse prevention strategy: Investigate combination therapy (e.g., miltefosine + immunomodulatory agents) or maintenance dosing protocols to address host T-cell anergy — the root cause of relapse
Species-stratified analysis: Clinical outcomes differ significantly by Leishmania species; any trial must stratify by L. amazonensis vs L. aethiopica to identify which populations benefit most
India regulatory pathway: As the drug is not currently marketed in India, assess whether DCL qualifies for orphan drug or rare disease designation to facilitate a streamlined regulatory pathway
Disclaimer

This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.