Identification

Name
Miltefosine
Accession Number
DB09031
Description

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
Thumb
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

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).

Associated Conditions
Contraindications & Blackbox Warnings
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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.

TargetActionsOrganism
UP-glycoprotein 1Not AvailableHumans
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.

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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.

Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
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.
DrugInteraction
AcenocoumarolThe therapeutic efficacy of Acenocoumarol can be increased when used in combination with Miltefosine.
Darbepoetin alfaThe risk or severity of Thrombosis can be increased when Darbepoetin alfa is combined with Miltefosine.
DicoumarolThe therapeutic efficacy of Dicoumarol can be increased when used in combination with Miltefosine.
ErythropoietinThe risk or severity of Thrombosis can be increased when Erythropoietin is combined with Miltefosine.
FluindioneThe therapeutic efficacy of Fluindione can be increased when used in combination with Miltefosine.
Methoxy polyethylene glycol-epoetin betaThe risk or severity of Thrombosis can be increased when Methoxy polyethylene glycol-epoetin beta is combined with Miltefosine.
PeginesatideThe risk or severity of Thrombosis can be increased when Peginesatide is combined with Miltefosine.
PhenindioneThe therapeutic efficacy of Phenindione can be increased when used in combination with Miltefosine.
PhenprocoumonThe therapeutic efficacy of Phenprocoumon can be increased when used in combination with Miltefosine.
WarfarinThe therapeutic efficacy of Warfarin can be increased when used in combination with Miltefosine.
Additional Data Available
  • Extended Description
    Extended Description

    Extended description of the mechanism of action and particular properties of each drug interaction.

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  • Severity
    Severity

    A severity rating for each drug interaction, from minor to major.

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  • Evidence Level
    Evidence Level

    A rating for the strength of the evidence supporting each drug interaction.

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  • Action
    Action

    An effect category for each drug interaction. Know how this interaction affects the subject drug.

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

Products

International/Other Brands
Miltex (Baxter)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
ImpavidoCapsule50 mg/1OralPaladin Therapeutics Inc.2014-09-192018-01-22US flag
ImpavidoCapsule50 mg/1OralProfounda, Inc.2015-10-29Not applicableUS flag
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Categories

ATC Codes
P01CX04 — Miltefosine
Drug Categories
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)

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. [PubMed:25601455]
  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. [PubMed:18519729]
  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. [PubMed:22833634]
  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. [PubMed:16730362]
  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. [PubMed:12384352]
  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. [PubMed:16344287]
  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. [PubMed:16436691]
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
PhaseStatusPurposeConditionsCount
4CompletedTreatmentLeishmaniasis, Cutaneous1
4CompletedTreatmentPost-kala-azar Dermal Leishmaniasis1
3Active Not RecruitingTreatmentVisceral Leishmaniasis1
3CompletedTreatmentLeishmaniasis, Cutaneous2
3CompletedTreatmentPost Kala Azar Dermal Leishmaniasis1
3CompletedTreatmentVisceral Leishmaniasis4
3Not Yet RecruitingTreatmentCutaneous Leishmaniases1
3Not Yet RecruitingTreatmentOld World Cutaneous Leishmaniasis1
3Unknown StatusTreatmentLeishmaniasis, Cutaneous1
2CompletedTreatmentLeishmaniasis, Cutaneous4

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Capsule, coatedOral50 mg
CapsuleOral50 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US1999037289No1998-01-222018-01-22US flag
Additional Data Available
  • Filed On
    Filed On

    The date on which a patent was filed with the relevant government.

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Properties

State
Solid
Experimental Properties
PropertyValueSource
pKa~2Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.00022 mg/mLALOGPS
logP2.68ALOGPS
logP2.25ChemAxon
logS-6.3ALOGPS
pKa (Strongest Acidic)1.88ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area58.59 Å2ChemAxon
Rotatable Bond Count20ChemAxon
Refractivity125.51 m3·mol-1ChemAxon
Polarizability50.59 Å3ChemAxon
Number of Rings0ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Download (55 KB)
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available

Targets

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. [PubMed:11355955]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Phospholipase d activity
Specific Function
Implicated as a critical step in numerous cellular pathways, including signal transduction, membrane trafficking, and the regulation of mitosis. May be involved in the regulation of perinuclear int...
Gene Name
PLD1
Uniprot ID
Q13393
Uniprot Name
Phospholipase D1
Molecular Weight
124183.135 Da
References
  1. 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. [PubMed:16730362]

Drug created on February 17, 2015 15:46 / Updated on June 12, 2020 10:52

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