Miltefosine

Identification

Summary

Miltefosine is an antileishmanial agent used to treat leishmaniasis, a group of disease caused by parasites of the Leishmania type.

Brand Names

Impavido

Generic Name

Miltefosine

DrugBank Accession Number

DB09031

Background

Miltefosine is a broad spectrum antimicrobial, anti-leishmanial, phospholipid drug that was originally developed in the 1980s as an anti-cancer agent. It is currently the only recognized oral agent used to treat visceral, cutaneous, and mucosal forms of leishmaniasis, a neglected tropical disease. It can be administered topically or orally and is only indicated in patients aged 12 years or older. The CDC has also recommended it as a first line treatment for free-living amebae (FLA) infections such as primary amebic meningoencephalitis and granulomatous amebic encephalitis.

Type

Small Molecule

Groups

Approved, Investigational

Structure

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MOLSDFPDBSMILESInChI

Similar Structures

Structure for Miltefosine (DB09031)

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Weight

Average: 407.576
Monoisotopic: 407.316445963

Chemical Formula

C₂₁H₄₆NO₄P

Synonyms

• HDPC
• hexadecyl 2-(trimethylazaniumyl)ethyl phosphate
• Hexadecylphosphocholine
• Hexadecylphosphorylcholine
• Miltefosin
• Miltefosina
• Miltéfosine
• Miltefosine
• Monohexadecylphosphocholine
• Monohexadecylphosphorylcholine

External IDs

• D 18506
• D-18506

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Pharmacology

Indication

For the treatment of mucosal (caused by Leishmania braziliensis), cutaneous (caused by L. braziliensis, L. guyanensis, and L. panamensis), and visceral leishmaniasis (caused by L. donovani). In comparing Leishmania drug susceptibility, it has been found that L. donovani is the most susceptible to miltefosine while L. major is the least susceptible. Off-label use includes treatment of free-living amebae (FLA) infections (unlabeled use; CDC, 2013).

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Associated Conditions

Indication Type	Indication	Combined Product Details	Approval Level	Age Group	Patient Characteristics	Dose Form
Treatment of	Cutaneous leishmaniasis		••••••••••••
Treatment of	Free-living amebae infection		••• •••••
Treatment of	Mucosal leishmaniasis		••••••••••••
Treatment of	Visceral leishmaniasis		••••••••••••

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Pharmacodynamics

Little is known about the clinical pharmacodynamics of miltefosine and other antileishmanial drugs.

Mechanism of action

Miltefosine has demonstrated activity against Leishmania parasites and neoplastic cells primarily due to its effects on apoptosis and disturbance of lipid-dependent cell signalling pathways. Several potential antileishmanial mechanisms of action have been proposed, however no mechanism has been identified definitely. Within the mitochondria, miltefosine inhibits cytochrome-c oxidase leading to mitochondrial dysfunction and apoptosis-like cell death. Antineoplastic mechanisms of action are related to antileishmanial targets and include inhibition of phosphatidylcholine biosynthesis and inhibition of Akt (also known as protein kinase B), which is a crucial protein within the PI3K/Akt/mTOR intracellular signalling pathway involved in regulating the cell cycle. Animal studies also suggest it may be effective against Trypanosome cruzi (the organism responsible for Chagas' disease), metronidazole-resistant strains of Trichonomas vaginalis, and it may have broad-spectrum anti-fungal activity.

Target	Actions	Organism
UP-glycoprotein 1	Not Available	Humans

Absorption

After oral administration, miltefosine is slowly absorbed from the gastrointestinal tract with an absolute bioavailability of 82% in rats and 94% in dogs. Absolute bioavailability has not been assessed in humans, however GI absorption rate in a two-compartment model is estimated to be 0.416 hr-1.

Volume of distribution

Radioactivity studies have found that miltefosine has a wide distribution with high levels in the kidney, intestinal mucosa, liver, and spleen.

Protein binding

Plasma protein binding ranges from 96% to 98%. Miltefosine binds to both serum albumin (97% bound) and low-density lipoprotein (3% bound).

Metabolism

Miltefosine is metabolized mainly by phospholipase D, releasing choline, choline-containing metabolites, and hexadecanol, which are likely to enter the intermediary metabolism. The metabolites produced by this reaction are all endogenous and are likely used for bio-synthesis of acetylcholine, cell membranes, and long-chain fatty acids.

Hover over products below to view reaction partners

• Miltefosine
  • Choline

Route of elimination

Miltefosine is almost completely eliminated by degradation via phospholipase D. Drug keeps accumulating until the end of treatment due to the extremely slow elimination, as seen by the long elimination half lives.

Half-life

The primary elimination half life is 7.05 days (range: 5.45-9.10 days) and the terminal half-life is 30.9 days (range: 30.8-31.2 days).

Clearance

Plasma clearance is very low and the terminal elimination half life was found to be 84 and 159 hours in rats and dogs respectively.

Adverse Effects

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Toxicity

Preclinical reproductive toxicity studies in animals showed fetal death and teratogenicity at doses lower than the recommended human dose. Use of miltefosine during pregnancy is therefore strictly contraindicated, and contraceptive use is mandatory for females of child-bearing age during therapy and for 5 months afterwards. Preclinical studies additionally showed impaired female and male fertility in animals. Stevens-Johnson syndrome has been reported, therefore therapy should be discontinued if an exfoliative or bullous rash occurs during treatment.

Pathways

Not Available

Pharmacogenomic Effects/ADRs Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">

Not Available

Interactions

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This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
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Acenocoumarol	The therapeutic efficacy of Acenocoumarol can be increased when used in combination with Miltefosine.
Ambroxol	The risk or severity of methemoglobinemia can be increased when Miltefosine is combined with Ambroxol.
Articaine	The risk or severity of methemoglobinemia can be increased when Miltefosine is combined with Articaine.
Benzocaine	The risk or severity of methemoglobinemia can be increased when Miltefosine is combined with Benzocaine.
Benzyl alcohol	The risk or severity of methemoglobinemia can be increased when Miltefosine is combined with Benzyl alcohol.

Food Interactions

• Drink plenty of fluids. Preventing dehydration is important to prevent kidney injury.
• Take with food. Food reduces gastric irritation.

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International/Other Brands

Miltex (Baxter)

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Impavido	Capsule	50 mg/1	Oral	Profounda, Inc.	2015-10-29	Not applicable
Impavido	Capsule	50 mg/1	Oral	Paladin Therapeutics Inc.	2014-09-19	2018-01-22

Categories

ATC Codes

P01CX04 — Miltefosine

• P01CX — Other agents against leishmaniasis and trypanosomiasis
• P01C — AGENTS AGAINST LEISHMANIASIS AND TRYPANOSOMIASIS
• P01 — ANTIPROTOZOALS
• P — ANTIPARASITIC PRODUCTS, INSECTICIDES AND REPELLENTS

Drug Categories

• Agents Against Leishmaniasis and Trypanosomiasis
• Amines
• Anti-Infective Agents
• Antifungal Agents
• Antileishmanial
• Antineoplastic Agents
• Antiparasitic Agents
• Antiparasitic Products, Insecticides and Repellents
• Antiprotozoals
• Onium Compounds
• Quaternary Ammonium Compounds
• Trimethyl Ammonium Compounds

Chemical TaxonomyProvided by Classyfire

Description

This compound belongs to the class of organic compounds known as phosphocholines. These are compounds containing a [2-(trimethylazaniumyl)ethoxy]phosphonic acid or derivative.

Kingdom

Organic compounds

Super Class

Organic nitrogen compounds

Class

Organonitrogen compounds

Sub Class

Quaternary ammonium salts

Direct Parent

Phosphocholines

Alternative Parents

Dialkyl phosphates / Tetraalkylammonium salts / Organopnictogen compounds / Organooxygen compounds / Organic salts / Organic oxides / Hydrocarbon derivatives / Amines

Substituents

Aliphatic acyclic compound / Alkyl phosphate / Amine / Dialkyl phosphate / Hydrocarbon derivative / Organic oxide / Organic oxygen compound / Organic phosphoric acid derivative / Organic salt / Organooxygen compound

Molecular Framework

Aliphatic acyclic compounds

External Descriptors

phosphocholines, phospholipid (CHEBI:75283)

Affected organisms

Not Available

Chemical Identifiers

UNII

53EY29W7EC

CAS number

58066-85-6

InChI Key

PQLXHQMOHUQAKB-UHFFFAOYSA-N

InChI

InChI=1S/C21H46NO4P/c1-5-6-7-8-9-10-11-12-13-14-15-16-17-18-20-25-27(23,24)26-21-19-22(2,3)4/h5-21H2,1-4H3

IUPAC Name

hexadecyl 2-(trimethylazaniumyl)ethyl phosphate

SMILES

CCCCCCCCCCCCCCCCOP([O-])(=O)OCC[N+](C)(C)C

References

Synthesis Reference

Eibl H, Engel J: Synthesis of hexadecylphosphocholine (miltefosine). Prog Exp Tumor Res. 1992;34:1-5. Pubmed

General References

1. Monge-Maillo B, Lopez-Velez R: Miltefosine for visceral and cutaneous leishmaniasis: drug characteristics and evidence-based treatment recommendations. Clin Infect Dis. 2015 May 1;60(9):1398-404. doi: 10.1093/cid/civ004. Epub 2015 Jan 18. [Article]
2. Dorlo TP, van Thiel PP, Huitema AD, Keizer RJ, de Vries HJ, Beijnen JH, de Vries PJ: Pharmacokinetics of miltefosine in Old World cutaneous leishmaniasis patients. Antimicrob Agents Chemother. 2008 Aug;52(8):2855-60. doi: 10.1128/AAC.00014-08. Epub 2008 Jun 2. [Article]
3. Dorlo TP, Balasegaram M, Beijnen JH, de Vries PJ: Miltefosine: a review of its pharmacology and therapeutic efficacy in the treatment of leishmaniasis. J Antimicrob Chemother. 2012 Nov;67(11):2576-97. doi: 10.1093/jac/dks275. Epub 2012 Jul 24. [Article]
4. Sindermann H, Engel J: Development of miltefosine as an oral treatment for leishmaniasis. Trans R Soc Trop Med Hyg. 2006 Dec;100 Suppl 1:S17-20. Epub 2006 May 26. [Article]
5. Saraiva VB, Gibaldi D, Previato JO, Mendonca-Previato L, Bozza MT, Freire-De-Lima CG, Heise N: Proinflammatory and cytotoxic effects of hexadecylphosphocholine (miltefosine) against drug-resistant strains of Trypanosoma cruzi. Antimicrob Agents Chemother. 2002 Nov;46(11):3472-7. [Article]
6. Blaha C, Duchene M, Aspock H, Walochnik J: In vitro activity of hexadecylphosphocholine (miltefosine) against metronidazole-resistant and -susceptible strains of Trichomonas vaginalis. J Antimicrob Chemother. 2006 Feb;57(2):273-8. Epub 2005 Dec 12. [Article]
7. Widmer F, Wright LC, Obando D, Handke R, Ganendren R, Ellis DH, Sorrell TC: Hexadecylphosphocholine (miltefosine) has broad-spectrum fungicidal activity and is efficacious in a mouse model of cryptococcosis. Antimicrob Agents Chemother. 2006 Feb;50(2):414-21. [Article]
8. FDA Approved Drug Products: IMPAVIDO (miltefosine) capsules [Link]

External Links

KEGG Drug

D02494

PubChem Compound

3599

PubChem Substance

310264984

ChemSpider

3473

BindingDB

50034220

RxNav

1494066

ChEBI

75283

ChEMBL

CHEMBL125

RxList

RxList Drug Page

Drugs.com

Drugs.com Drug Page

Wikipedia

Miltefosine

FDA label

Download (389 KB)

MSDS

Download (83.3 KB)

Clinical Trials

Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">

Phase	Status	Purpose	Conditions	Count
4	Completed	Treatment	Cutaneous Leishmaniasis	1
4	Completed	Treatment	Post Kala Azar Dermal Leishmaniasis	1
3	Active Not Recruiting	Treatment	Cutaneous Leishmaniases	1
3	Completed	Treatment	Cutaneous Leishmaniasis	2
3	Completed	Treatment	Post Kala Azar Dermal Leishmaniasis	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Capsule, coated	Oral	50 mg
Capsule	Oral	50 mg/1
Solution	Topical
Solution	Oral	6 g

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
US1999037289	No	1998-01-22	2018-01-22

Properties

State

Solid

Experimental Properties

Property	Value	Source
pKa	~2	Not Available

Predicted Properties

Property	Value	Source
Water Solubility	0.00022 mg/mL	ALOGPS
logP	2.68	ALOGPS
logP	2.25	Chemaxon
logS	-6.3	ALOGPS
pKa (Strongest Acidic)	1.88	Chemaxon
Physiological Charge	0	Chemaxon
Hydrogen Acceptor Count	2	Chemaxon
Hydrogen Donor Count	0	Chemaxon
Polar Surface Area	58.59 Å2	Chemaxon
Rotatable Bond Count	20	Chemaxon
Refractivity	125.51 m3·mol-1	Chemaxon
Polarizability	50.59 Å3	Chemaxon
Number of Rings	0	Chemaxon
Bioavailability	1	Chemaxon
Rule of Five	Yes	Chemaxon
Ghose Filter	No	Chemaxon
Veber's Rule	No	Chemaxon
MDDR-like Rule	No	Chemaxon

Predicted ADMET Features

Not Available

Spectra

Mass Spec (NIST)

Download (55 KB)

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted GC-MS Spectrum - GC-MS	Predicted GC-MS	splash10-00dj-9432000000-642b57f37f036f7f50c3
Predicted 1H NMR Spectrum	1D NMR	Not Applicable
Predicted 13C NMR Spectrum	1D NMR	Not Applicable

Chromatographic Properties

Collision Cross Sections (CCS)

Adduct	CCS Value (Å2)	Source type	Source
[M-H]-	231.5410613	predicted	DarkChem Lite v0.1.0
[M-H]-	201.31877	predicted	DeepCCS 1.0 (2019)
[M+H]+	204.91995	predicted	DeepCCS 1.0 (2019)
[M+Na]+	213.735	predicted	DeepCCS 1.0 (2019)

Targets

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Details1. P-glycoprotein 1

Kind

Protein

Organism

Humans

Pharmacological action

Unknown

General Function

Xenobiotic-transporting atpase activity

Specific Function

Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.

Gene Name

ABCB1

Uniprot ID

P08183

Uniprot Name

Multidrug resistance protein 1

Molecular Weight

141477.255 Da

References

1. Rybczynska M, Liu R, Lu P, Sharom FJ, Steinfels E, Pietro AD, Spitaler M, Grunicke H, Hofmann J: MDR1 causes resistance to the antitumour drug miltefosine. Br J Cancer. 2001 May 18;84(10):1405-11. [Article]

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Drug created at February 17, 2015 22:46 / Updated at August 19, 2021 10:27