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Identification
NameMiltefosine
Accession NumberDB09031
TypeSmall Molecule
GroupsApproved
DescriptionMiltefosine 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.
Structure
Thumb
Synonyms
HDPC
hexadecyl 2-(trimethylazaniumyl)ethyl phosphate
Hexadecylphosphocholine
Hexadecylphosphorylcholine
Miltefosin
Miltefosina
Miltefosina
Miltéfosine
Miltefosine
Monohexadecylphosphocholine
Monohexadecylphosphorylcholine
External Identifiers
  • D-18506
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
ImpavidoCapsule50 mg/1OralPaladin Therapeutics Inc.2014-09-19Not applicableUs
ImpavidoCapsule50 mg/1OralProfounda, Inc.2015-10-29Not applicableUs
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International Brands
NameCompany
MiltexBaxter
Brand mixturesNot Available
SaltsNot Available
Categories
UNII53EY29W7EC
CAS number58066-85-6
WeightAverage: 407.576
Monoisotopic: 407.316445963
Chemical FormulaC21H46NO4P
InChI KeyPQLXHQMOHUQAKB-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
Pharmacology
IndicationFor 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).
Structured Indications
PharmacodynamicsLittle is known about the clinical pharmacodynamics of miltefosine and other antileishmanial drugs.
Mechanism of actionMiltefosine 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.
Related Articles
AbsorptionAfter 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 bindingPlasma 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.

SubstrateEnzymesProduct
Miltefosine
CholineDetails
Route of eliminationMiltefosine 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 lifeThe 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.

ToxicityPreclinical 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 organismsNot Available
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
Interactions
Drug Interactions
DrugInteractionDrug group
AcetyldigitoxinAcetyldigitoxin may decrease the cardiotoxic activities of Miltefosine.Approved
AmlodipineThe risk or severity of adverse effects can be increased when Miltefosine is combined with Amlodipine.Approved
Amphotericin BThe therapeutic efficacy of Amphotericin B can be decreased when used in combination with Miltefosine.Approved, Investigational
AmrinoneThe risk or severity of adverse effects can be increased when Miltefosine is combined with Amrinone.Approved
AnvirzelAnvirzel may decrease the cardiotoxic activities of Miltefosine.Investigational
AzelnidipineThe risk or severity of adverse effects can be increased when Miltefosine is combined with Azelnidipine.Approved
AzimilideThe risk or severity of adverse effects can be increased when Miltefosine is combined with Azimilide.Investigational
BarnidipineThe risk or severity of adverse effects can be increased when Miltefosine is combined with Barnidipine.Approved
BenidipineThe risk or severity of adverse effects can be increased when Miltefosine is combined with Benidipine.Approved
BepridilThe risk or severity of adverse effects can be increased when Miltefosine is combined with Bepridil.Approved, Withdrawn
BevacizumabBevacizumab may increase the cardiotoxic activities of Miltefosine.Approved, Investigational
BuspironeThe metabolism of Buspirone can be decreased when combined with Miltefosine.Approved, Investigational
BusulfanThe serum concentration of Busulfan can be increased when it is combined with Miltefosine.Approved, Investigational
CabazitaxelThe risk or severity of adverse effects can be increased when Cabazitaxel is combined with Miltefosine.Approved
CaiThe risk or severity of adverse effects can be increased when Miltefosine is combined with Cai.Investigational
CilnidipineThe risk or severity of adverse effects can be increased when Miltefosine is combined with Cilnidipine.Approved
CinnarizineThe risk or severity of adverse effects can be increased when Miltefosine is combined with Cinnarizine.Approved
CisaprideThe serum concentration of Cisapride can be increased when it is combined with Miltefosine.Approved, Investigational, Withdrawn
ClevidipineThe risk or severity of adverse effects can be increased when Miltefosine is combined with Clevidipine.Approved
ConivaptanThe metabolism of Conivaptan can be decreased when combined with Miltefosine.Approved, Investigational
CyclophosphamideCyclophosphamide may increase the cardiotoxic activities of Miltefosine.Approved, Investigational
CyclosporineThe metabolism of Cyclosporine can be decreased when combined with Miltefosine.Approved, Investigational, Vet Approved
DarodipineThe risk or severity of adverse effects can be increased when Miltefosine is combined with Darodipine.Experimental
DeslanosideDeslanoside may decrease the cardiotoxic activities of Miltefosine.Approved
DidanosineDidanosine can cause a decrease in the absorption of Miltefosine resulting in a reduced serum concentration and potentially a decrease in efficacy.Approved
DigitoxinDigitoxin may decrease the cardiotoxic activities of Miltefosine.Approved
DigoxinDigoxin may decrease the cardiotoxic activities of Miltefosine.Approved
DiltiazemThe risk or severity of adverse effects can be increased when Miltefosine is combined with Diltiazem.Approved
DocetaxelThe metabolism of Docetaxel can be decreased when combined with Miltefosine.Approved, Investigational
DofetilideThe metabolism of Dofetilide can be decreased when combined with Miltefosine.Approved
DotarizineThe risk or severity of adverse effects can be increased when Miltefosine is combined with Dotarizine.Investigational
EfonidipineThe risk or severity of adverse effects can be increased when Miltefosine is combined with Efonidipine.Approved
EperisoneThe risk or severity of adverse effects can be increased when Miltefosine is combined with Eperisone.Approved, Investigational
EtravirineThe serum concentration of Etravirine can be increased when it is combined with Miltefosine.Approved
FelodipineThe risk or severity of adverse effects can be increased when Miltefosine is combined with Felodipine.Approved, Investigational
FendilineThe risk or severity of adverse effects can be increased when Miltefosine is combined with Fendiline.Withdrawn
FlunarizineThe risk or severity of adverse effects can be increased when Miltefosine is combined with Flunarizine.Approved
FosphenytoinThe serum concentration of Miltefosine can be decreased when it is combined with Fosphenytoin.Approved
GabapentinThe risk or severity of adverse effects can be increased when Miltefosine is combined with Gabapentin.Approved, Investigational
GallopamilThe risk or severity of adverse effects can be increased when Miltefosine is combined with Gallopamil.Investigational
IsradipineThe risk or severity of adverse effects can be increased when Miltefosine is combined with Isradipine.Approved
LacidipineThe risk or severity of adverse effects can be increased when Miltefosine is combined with Lacidipine.Approved
LamotrigineThe risk or severity of adverse effects can be increased when Miltefosine is combined with Lamotrigine.Approved, Investigational
LercanidipineThe risk or severity of adverse effects can be increased when Miltefosine is combined with Lercanidipine.Approved, Investigational
LosartanThe metabolism of Losartan can be decreased when combined with Miltefosine.Approved
Magnesium SulfateThe risk or severity of adverse effects can be increased when Miltefosine is combined with Magnesium Sulfate.Approved, Vet Approved
ManidipineThe risk or severity of adverse effects can be increased when Miltefosine is combined with Manidipine.Approved
MibefradilThe risk or severity of adverse effects can be increased when Miltefosine is combined with Mibefradil.Withdrawn
NaftopidilThe risk or severity of adverse effects can be increased when Miltefosine is combined with Naftopidil.Investigational
NicardipineThe risk or severity of adverse effects can be increased when Miltefosine is combined with Nicardipine.Approved
NifedipineThe risk or severity of adverse effects can be increased when Miltefosine is combined with Nifedipine.Approved
NiguldipineThe risk or severity of adverse effects can be increased when Miltefosine is combined with Niguldipine.Experimental
NiludipineThe risk or severity of adverse effects can be increased when Miltefosine is combined with Niludipine.Experimental
NilvadipineThe risk or severity of adverse effects can be increased when Miltefosine is combined with Nilvadipine.Approved
NimesulideThe risk or severity of adverse effects can be increased when Miltefosine is combined with Nimesulide.Approved, Withdrawn
NimodipineThe risk or severity of adverse effects can be increased when Miltefosine is combined with Nimodipine.Approved
NisoldipineThe risk or severity of adverse effects can be increased when Miltefosine is combined with Nisoldipine.Approved
NitrendipineThe risk or severity of adverse effects can be increased when Miltefosine is combined with Nitrendipine.Approved
OuabainOuabain may decrease the cardiotoxic activities of Miltefosine.Approved
PaclitaxelThe risk or severity of adverse effects can be increased when Paclitaxel is combined with Miltefosine.Approved, Vet Approved
PerhexilineThe risk or severity of adverse effects can be increased when Miltefosine is combined with Perhexiline.Approved
PhenytoinThe serum concentration of Phenytoin can be increased when it is combined with Miltefosine.Approved, Vet Approved
PimozideMiltefosine may increase the arrhythmogenic activities of Pimozide.Approved
PinaveriumThe risk or severity of adverse effects can be increased when Miltefosine is combined with Pinaverium.Approved
PregabalinThe risk or severity of adverse effects can be increased when Miltefosine is combined with Pregabalin.Approved, Illicit, Investigational
PrenylamineThe risk or severity of adverse effects can be increased when Miltefosine is combined with Prenylamine.Withdrawn
ProgesteroneThe therapeutic efficacy of Progesterone can be decreased when used in combination with Miltefosine.Approved, Vet Approved
QuinidineThe metabolism of Quinidine can be decreased when combined with Miltefosine.Approved
RanolazineThe metabolism of Ranolazine can be decreased when combined with Miltefosine.Approved, Investigational
RifabutinThe serum concentration of Rifabutin can be increased when it is combined with Miltefosine.Approved
RifampicinThe serum concentration of Rifampicin can be increased when it is combined with Miltefosine.Approved
RifapentineThe serum concentration of Rifapentine can be increased when it is combined with Miltefosine.Approved
RisedronateThe risk or severity of adverse effects can be increased when Miltefosine is combined with Risedronate.Approved, Investigational
SolifenacinThe metabolism of Solifenacin can be decreased when combined with Miltefosine.Approved
SucralfateSucralfate can cause a decrease in the absorption of Miltefosine resulting in a reduced serum concentration and potentially a decrease in efficacy.Approved
SunitinibThe metabolism of Sunitinib can be decreased when combined with Miltefosine.Approved, Investigational
TacrolimusThe metabolism of Tacrolimus can be decreased when combined with Miltefosine.Approved, Investigational
Tolfenamic AcidThe risk or severity of adverse effects can be increased when Miltefosine is combined with Tolfenamic Acid.Approved
TranilastThe risk or severity of adverse effects can be increased when Miltefosine is combined with Tranilast.Approved, Investigational
TrastuzumabTrastuzumab may increase the cardiotoxic activities of Miltefosine.Approved, Investigational
VerapamilThe risk or severity of adverse effects can be increased when Miltefosine is combined with Verapamil.Approved
VinpocetineThe risk or severity of adverse effects can be increased when Miltefosine is combined with Vinpocetine.Investigational
XylometazolineThe risk or severity of adverse effects can be increased when Miltefosine is combined with Xylometazoline.Approved
ZiconotideThe risk or severity of adverse effects can be increased when Miltefosine is combined with Ziconotide.Approved
ZolpidemThe serum concentration of Zolpidem can be increased when it is combined with Miltefosine.Approved
Food InteractionsNot Available
References
Synthesis Reference
  1. 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 ]
External Links
ATC CodesL01XX09
AHFS Codes
  • 8:30.92
PDB EntriesNot Available
FDA labelDownload (389 KB)
MSDSDownload (83.3 KB)
ADMET
Predicted ADMET featuresNot Available
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage forms
FormRouteStrength
CapsuleOral50 mg/1
PricesNot Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US1999037289 No1998-01-222018-01-22Us
Properties
StateSolid
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
Polarizability50.58 Å3ChemAxon
Number of Rings0ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Download (55 KB)
SpectraNot Available
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as phosphocholines. These are compounds containing a [2-(trimethylazaniumyl)ethoxy]phosphonic acid or derivative.
KingdomOrganic compounds
Super ClassOrganonitrogen compounds
ClassQuaternary ammonium salts
Sub ClassCholines
Direct ParentPhosphocholines
Alternative Parents
Substituents
  • Phosphocholine
  • Dialkyl phosphate
  • Alkyl phosphate
  • Phosphoric acid ester
  • Organic phosphoric acid derivative
  • Organic phosphate
  • Hydrocarbon derivative
  • Organic salt
  • Organooxygen compound
  • Amine
  • Organic zwitterion
  • Aliphatic acyclic compound
Molecular FrameworkAliphatic acyclic compounds
External Descriptors

Enzymes

Kind
Protein
Organism
Human
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 intravesicular membrane traffic (By similarity).
Gene Name:
PLD1
Uniprot ID:
Q13393
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 ]
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Drug created on February 17, 2015 15:46 / Updated on August 17, 2016 12:24