Miltefosine: a review of its pharmacology and therapeutic efficacy in

22 Pages·2012·1 MB·English

J Antimicrob Chemother 2012; 67: 2576–2597
doi:10.1093/jac/dks275 Advance Access publication 24 July 2012
Miltefosine: a review of its pharmacology and therapeutic
efficacy in the treatment of leishmaniasis
ThomasP. C.Dorlo1,2*, Manica Balasegaram3, JosH. Beijnen2 andPeter J. de Vries1†
1CenterforTropicalMedicineandTravelMedicine,DivisionofInfectiousDiseases,AcademicMedicalCenter,UniversityofAmsterdam,
Amsterdam,TheNetherlands; 2Departmentof PharmacyandPharmacology,SlotervaartHospital/The NetherlandsCancer Institute, D
Amsterdam,TheNetherlands; 3Drugs forNeglected Diseases initiative(DNDi), Geneva,Switzerland ow
n
lo
a
*Correspondingauthor.DivisionofInfectiousDiseases,RoomF4–217,AcademicMedicalCenter,Meibergdreef9,1105AZ,Amsterdam, d
e
TheNetherlands.Tel:[phone];Fax:[phone];E-mail:[email protected] d
†Presentaddress:DivisionofInternalMedicine,Tergooiziekenhuizen,Hilversum,TheNetherlands. fro
m
h
Miltefosine is an alkylphosphocholine drug with demonstrated activity against various parasite species and ttp
s
cancercellsas wellassome pathogenic bacteriaand fungi. For 10years it has been licensed inIndiafor the ://a
treatment of visceral leishmaniasis (VL), a fatal neglected parasitic disease. It is the first and still the only ca
d
oral drug that can be used to treat VL and cutaneous leishmaniasis (CL). The standard 28day miltefosine e
m
monotherapy regimen is well tolerated, except for mild gastrointestinal side effects, although its teratogenic ic
.o
potential severely hampers its general use in the clinic and roll-out in national elimination programmes. The u
p
pharmacokinetics of miltefosine are mainly characterized by its long residence time in the body, resulting .c
o
in extensive drug accumulation during treatment and long elimination half-lives. At the moment, different m
combination therapy strategies encompassing miltefosine are being tested in multiple controlled clinical /jac
ttrhiaelsmionstvasraiolieunstgperoeg-cralinpihciaclalanadreaclsinoicfalepnhdaemrmicaictyo,lobgoictahl ianspSeocuttshoAfsmiailtaenfodsinEaes,titsAfmriceac.hWaneismheroef raecvtiieown /article
against Leishmania parasites and other pathogens, and provide a systematic overview of the efficacy and -a
b
safetydatafromallclinicaltrialsofmiltefosine,eitheraloneorincombination,inthetreatmentofVLandCL. stra
c
t/6
Keywords: clinicalpharmacology,pre-clinical pharmacology,alkylphosphocholine, cutaneous leishmaniasis, visceral leishmaniasis, 7
mechanism ofaction, pharmacokinetics, pharmacodynamics,antiparasiticagents, antiprotozoalagents, Leishmania /11
/2
5
7
6
/7
0
9
Overview of treatment options for Treatment of VL and CL is complicated by intrinsic species- 24
leishmaniasis specificdifferencesindrugsusceptibility,4andalsobydifferences 9 b
y
in the apparent efficacy of the drugs between geographical g
Leishmaniasis is an infection caused by obligate intracellular areas,5whichimpliesthateachnewtreatmentandcombination ue
s
protozoan Leishmania parasites transmitted by the bite of has to be reassessed in every distinct geographical location t o
certainsandflyspecies.1,2AmultitudeofLeishmaniaspeciesspe- whereVLor CL isendemic. n 1
cific to various geographical areas are able to cause disease in Sincetheirdiscoveryinthe1940s,thetoxicparenteralpenta- 5 A
hVuismcearanlslaeinsdhmcaanniraessiuslt(VinLoservkearlaal-daizvaerr,swehcilcinhicmalemanasnibfelasctkatfieovnesr. tvraelaetnmteannttimfoornye(itShbeVr) ctoympepooufndlseihshamveanbeiaesnis,thmeomstainnsotataybolyf pril 2
0
in Hindi), the most severe form of leishmaniasis, is typically intravenous- or intramuscular-injected sodium stibogluconate 1
9
causedbytheLeishmaniadonovanispeciescomplex.Itischarac- (Pentostamw, GlaxoSmithKline, UK, or the generic product from
terizedbydisseminatedvisceralinfectionofthereticuloendothe- Albert David, India) and meglumine antimoniate (Glucantimew,
lialsystemandisinevitablyfatalifleftuntreated.3Theulcerated Aventis, France).6 Despite the apparent, sometimes life-
skin lesions typical for cutaneous leishmaniasis (CL) are mainly threatening, toxicity of these compounds, antimonials are still
caused by Leishmania major and Leishmania tropica in the Old first-line treatment for both VL and CL in most areas. Only in
World (Europe, Africa, Central Asia and the Middle East) and by Biharstate,theareawhereVLismostendemicinIndia,hasin-
the Leishmania braziliensis, Leishmania guyanensis and Leish- creasingnon-susceptibilityoftheparasitestoantimonialsledto
mania mexicana species complexes in the New World (Latin widespreadtreatmentfailureandashifttoconventionalampho-
America), of which the former two species complexes can dis- tericin B.7,8 Currently, liposomal amphotericin B (AmBisomew,
seminate to the nasopharyngeal tissues and evolve into a GileadSciences,CA,USA)ispreferredoverconventionalampho-
moredestructivemucosalform(mucocutaneousleishmaniasis). tericin B because of its milder toxicity profile, although its use
#TheAuthor2012.PublishedbyOxfordUniversityPressonbehalfoftheBritishSocietyforAntimicrobialChemotherapy.Allrightsreserved.
ForPermissions,pleasee-mail:[email protected]
2576
JAC
Review
remainsverylimitedinresource-poorsettingsduetoitsveryhigh Medica (later Zentaris GmbH), the WHO Special Programme for
costs.9 Recent studies have shown the efficacyof a single-dose ResearchandTraininginTropicalDiseases,andtheGovernment
treatmentofliposomalamphotericinBforVLinIndia,although ofIndia.32Eventually,severalsuccessfulPhaseIIandIIItrialson
itisstillunclearwhetherthisisapplicabletoothergeographical VLinIndialedtotheapprovalofmiltefosinein2002asthefirst
areas as well.10,11 Paromomycin (aminosidine, Gland Pharma, andstilltheonlyoraldrugforthetreatmentofVL.33Since2008,
India), an aminoglycoside antibiotic, was rediscovered as an PaladinLabs(Montreal,Canada)isthelicenceholderfororalmil-
antileishmanialagentinthe1980sandhasbeenusedsuccess- tefosine for the indication leishmaniasis (for more information,
fullyasaparenteralagentinthetreatmentofVLand,withmore see the Pharmaceutical products, drug licensing and availability
variable success, as a topical agent for CL as well.12–15Several section). The clinical development and licensing of the com-
treatment combinations using paromomycin and, generally, pound, either as monotherapy or as part of a combination
sodium stibogluconate were evaluated both in India and East therapy for VL, is still ongoing in various VL-endemic countries
D
Africa.5,16–20 Another historic agent still being used mainly in in collaboration with, amongst others, national governments, o
w
the treatment of New World CL is pentamidine (Pentamw, Me´decins Sans Frontie`res and the Drugs for Neglected Diseases n
lo
Abbott,IL,USA),21whichhasgainedrenewedinterestforitspos- initiative(DNDi). a
d
sible use as secondary prophylaxis in HIV-coinfected VL ed
patients.21–23 All these available agents, of which most have Methods from
already been in use for multiple decades, have to be adminis-
h
tered parenterally. The need for a safe oral agent that does For systematic identification of published clinical trials of miltefosine in ttp
notrequirehospitalizationwasthereforegreat.Sinceitsregistra- the treatment of leishmaniasis, the literature database PubMed was s://a
tion in 2002, miltefosine isthe first and still the onlyoral agent searchedwiththefollowingterms:(miltefosine)AND[(visceralleishman- c
a
that is used forthe treatment of alltypes ofleishmaniasis. iasis) OR (cutaneous leishmaniasis) OR (mucocutaneous leishmaniasis)], d
e
with the restricting limits ‘Article type’ set to all clinical study or trial- m
ic
related publications and ‘Species’ set to ‘Humans’; there were no .o
Historical perspective fFuorrthtehrereostthreicrtiosnesctifoonrs‘Piunbltichaistiornevdieawte,sn’,o‘Asgyesst’e,m‘Laatnicguaapgperso’aocrh‘Sweax’s. up.co
m
appliedtoidentifypublications.
The simultaneous but independent discovery of the antipro- /ja
tozoal and antineoplastic activities of miltefosine and related c/a
alkylphosphocholinedrugsoccurredintheearly1980s.24Coinci- Pharmacological class rtic
dentally, the compound was synthesized by two different re- le
search groups who were screening platelet-aggregating-factor Miltefosine belongs to the class of alkylphosphocholine drugs, -ab
s
analogues for their anti-inflammatory properties in the UK and whicharephosphocholineestersofaliphaticlong-chainalcohols. tra
similarlyfortheirantitumouractivityinGermany.Despitetheex- These alkylphosphocholine compounds are structurally related ct/6
cellent activity profile of miltefosine against trypanosomatid tothegroupofalkyl-lysophospholipids,whicharesyntheticana- 7/1
parasites, priority was given to the development of the com- loguesoflysophosphatidylcholinesorlysolecithins,butlacktheir 1/2
pound as a local treatment for cutaneous metastases of glycerolbackbone.Fromafunctionalpointofview,miltefosineis 57
breastcancerandeventuallyledtotheapprovalofatopicalfor- consideredaninhibitorofAkt[otherwiseknownasproteinkinase 6/7
mulationofmiltefosine(Miltexw,Baxter,UK).25Theapplicationof B (PKB)]. Akt/PKB is a crucial protein within the phos- 09
miltefosine in an oral formulation in the treatment of solid phatidylinositol 3-kinase/Akt/mammalian target of rapamycin 24
9
tumourswasalsoevaluatedinseveralPhaseIIstudieswithdif- (PI3K/Akt/mTOR) intracellular signalling pathway, which is b
ferent tumour types,26–28but was eventually discontinued due involvedincellsurvival.34 y g
u
to dose-limiting gastrointestinal side effects in these cancer es
patients.29IncitedbyencouraginginvitrofindingsonLeishmania Physicochemical properties t on
parasites, apparent high bioavailability in previous pre-clinical 1
5
studies and a clear need for an easy-to-administer oral treat- The chemical name of miltefosine is hexadecyl 2-(trimethyl- A
p
mentfor VL, subsequent evaluation oforalmiltefosine for VL in azaniumyl)ethyl phosphate, also known as hexadecylphospho- ril 2
a mouse model demonstrated superior activity of oral miltefo- choline (Figure 1). The empiricalformula is C21H46NO4P, yielding 01
sine over standard intravenous sodium stibogluconate.30 The a molecular weight of 407.57g/mol. Otheralkylphosphocholine 9
first Phase II study of oral miltefosine in the treatment of compounds that were tested for their antileishmanial or anti-
human VL was conducted in India with very promising cancer activity differ from miltefosine both in alkyl chain
results.31 These observations led to the development of a length and/or backbone, and distances between P and N.35
unique public–private partnership collaboration between ASTA Another closely related group of tested compounds are the
O– H C
H C O 3 CH
3 3
P N
O (cid:129)
O CH
3
Figure1. Structuralformulaofmiltefosine.
2577
Review
alkylglycerophosphocholines, also known as ether lipids, which Drug dosage, costs and cost-effectiveness
have only small structural modifications compared with
miltefosine.36 For example, edelfosine contains an ether-linked The currently recommended dose for miltefosine as monother-
2-methyl-glycerol backbone and has an octadecyl alkyl apy for either CL or VL is 2.5mg/kg/day for a total of 28days.
chain, while ilmofosine additionally contains a thioether However, due to regular unavailability of the 10mg capsule in
group.37,38 Perifosine, another structurally related compound clinical practice, other dosages are being administered. For
that has received considerable clinical attention, has an example,theIndiangovernmentrecommends100mg/daymil-
octadecyl alkyl chain and a piperidine head group instead of a tefosine for patients with a body weight ≥25kg (corresponding
choline headgroup.39 to (cid:2)1.7–4mg/kg/day) and 50mg/day for body weights
Miltefosine is an amphiphilic and zwitterionic compound due ,25kg (corresponding to (cid:2)2–5.5mg/kg/day). Recently, Dorlo
tothepositivelychargedquaternaryaminegroup(permanently etal.48demonstratedthatchildrenwererelativelyunderexposed
charged) and negatively charged phosphoryl group (pKa: (cid:2)2). to miltefosine compared with adults when given the same Do
w
The crystalline compound is a white to off-white hygroscopic mg/kgdosage.Anewoptimalmiltefosinedosagewassuggested n
powderandreadilydissolvableinbothaqueousandorganicsol- that would leadto similardrug exposure. loa
d
vents.ThesolubilityinethanolandDMSOis1.25and0.8mg/mL, For public use and control programmes in resource-poor ed
respectively,whileinphosphatebuffersolution(pH7.2)orwater countries‘wherepatientsarebeingtreatedfreeofcharge’,33mil- fro
thisis ≥2.5mg/mL. tefosine isavailable at apreferentialWHO-negotiated price, but m
othnelyoprderer2,0p0ri0ce0s0mcaapysuvlaerybabtecthwoeerdnerE:4d5e.p2e8nadnindgEo5n4t.h9e2sfiozre5o6f https
capsules containing 50mg of miltefosine, and between E34.36 ://a
c
Pharmaceutical products, drug licensing and and E39.30 for 56 capsules containing 10mg of miltefosine. ad
e
For a typical male VL patient from Bihar, India, weighing m
availability 39kg,49thismeansthatthedrugcostforastandardmonother- ic.o
The following proprietary miltefosine products are available apymiltefosineregimen(28days)hasdroppedonaveragefrom up
on the market: Impavidow (oral solid human pharmaceutical an initial US$20046 to a current cost of E50. For resource-rich .co
m
panrodduMcitlt),efMorilatenxww(o(troaplicliaqlulidiquviedtehruinmaraynpphhaarrmmaacceeuutticicaallpprroodduucctt)). creoguinmterines(1t5h0emavge/rdaagyefodrru2g8cdoasyts)focarnonaemcooumntpuleptetomEil3te0f0o0s.ine /jac/a
Impavidow, the product that is licensed for the treatment of The cost-effectiveness of miltefosine, either alone or as part rtic
hThuimsafonrmVLu,laistioanvaciolanbtlaeinass, b1e0siadneds m50iltmefgosminielt,ehfoigshinlyedciasppseursleesd. oVfLainctohmeIbnindaiatnionsu,bhcaosntbineeennt.inOvfetshtiegactoemdpfaorredthmeotnreoatthmereanpteuo-f le-ab
s
silicon dioxide, microcrystalline cellulose, lactose monohydrate, tic options, miltefosine appeared to be the most cost-effective tra
toaxlicd,emanadgnpeusriiufimed swtaeaterar.t4e0,IngeIlnadtiinae,,atgiteanneiurimc ordailoxmidilet,efofesrinriec otipmtioonnyincoamrepaosuwndhse.r5e0tWhehreeniscaomknpoawrinngnomno-snuostcheeprtaibpiileitsywtoithana- ct/67/1
product for the treatment of VL has been added to the list of combination therapy of liposomal amphotericin B (single dose) 1/2
registereddrugsforhumanuse.41Alocallyprocuredpoor-quality and miltefosine (various durations) in the Indian context, the 57
genericoralmiltefosineproductwasfoundinBangladesh,which combination therapy is more cost-effective than most mono- 6/7
containednoactivepharmaceuticalingredientatall.42,43Miltefo- therapies, with US$124–160 per averted death.51 In the case 09
sine (Impavidow) has been approved for the treatment of VL in that also indirect costs (i.e. loss of productivity) are taken into 24
9
Nepal,andbothVLandCLinArgentina,Bangladesh,Bolivia,Co- account, the combination of miltefosine plus paromomycin b
y
lombia,Ecuador,Germany,Guatemala,Honduras,India,Mexico, was the most cost-effective, with US$97 per averted death, al- g
u
Pakistan, Paraguay and Peru.33 Furthermore, miltefosine was though strategies employing liposomal amphotericin B were es
designatedasanorphandrugproductforthetreatmentof(vis- overallfound to be the mosteffective.52 t o
n
ceral) leishmaniasis by both the European Medicines Agency in 1
5
2002 and by the US Food and Drug Administration (FDA) in Analytical assay A
p
2M0o0d6e.l RLeisctenotfly,EstsheentdiarlugMehdaiscinaelsso.44beOernalamddiletedfotsoinethecaWn HbOe The structure of miltefosine lacks any chromophores, which ril 20
1
obtainedin the USAfrom themanufacturer throughan Investi- makesultraviolet or fluorescence detectionverydifficult. Onlya 9
gational New Drug application to the FDA in conjunction with single validated and sensitive bioanalytical method to quantify
local institutional review board (IRB) approval,45 whereas miltefosine in human matrices has been reported hitherto.53
in European countries the drug can be imported from Germany The method employed reversed-phase liquid chromatography
on a named patient basis or through compassionate use pro- coupled to tandem mass spectrometry to detect miltefosine in
grammes, depending on national legislation. In India, serious human EDTA plasma with pre-treatment bysolid-phase extrac-
concerns have been raised about the unrestricted over-the- tion and had a lower limit of quantification of 4ng/mL using a
counteravailabilityofmiltefosineintheprivatesectorinrelation 250mLaliquotofplasma,whichwassensitiveenoughtodeter-
tonon-compliance.46,47Stricterregulation,free-of-chargesuper- minemiltefosine concentrations upto 5months aftercessation
vised public distribution and directly observed therapy have of treatment (with a 28day regimen).54 Chromatography was
therefore been advocated and implemented in the context of performed on an alkaline-resistant C column under isocratic
18
the national elimination programmes for VL in the Indian sub- and alkaline conditions. Several other methods have been
continent; nevertheless, this drug availability issue remains of reported for the bioanalysis of the structurally related com-
pivotalimportancefor the lifespan ofmiltefosine. pounds perifosine,55,56 edelfosine,57 erucylphosphocholine58
2578
JAC
Review
and CLR1401.59 Recently, a platform of analytical techniques unlabelled miltefosine dose was administered, which demon-
waspresentedforthedeterminationandidentificationofmilte- strated highest drug concentrations in the adrenal glands,
fosineinpharmaceuticalformulations,whichcanbeusedtodis- kidneys, spleen and skin.67 Steady-state concentrations could
tinguish poor-quality miltefosine-containing pharmaceutical be achieved in all investigated organs and serum, except for
products.42 Mostnotably, a simple and inexpensive colorimetric thekidneysandbrain.Itremainsunknowntowhatextentmilte-
method was presented that can be used for the identification fosinepenetratesthehumanbrain;however,substantialmiltefo-
andsemi-quantificationofmiltefosineinpharmaceuticalformu- sineconcentrationscouldbedemonstratedintheCSFofpatients
lations in thefield.42 treatedforBalamuthiaandNaegleriainfections,althoughitwas
unclear how intact their blood–brain barrier was (T. P. C. Dorlo
and G. S. Visvesvara, unpublished data). Placental distribution
Pharmacokinetics
and transfer through the umbilical cord have not been investi-
D
The pre-clinical pharmacokinetics of miltefosine, investigated gated,butshouldbeassumedgiventheresultsfromreproductive o
w
duringthedevelopmentofthedrug,aresummarizedbySinder- toxicity studies in animals.29 Plasma protein binding ranges nlo
mann and Engel.29 Little research was done on the clinical between 96% and 98%, with no concentration dependence ad
pharmacokinetics of miltefosine before the drug was available beingobserved.Miltefosinebindstobothserumalbuminandlipo- ed
onthemarket.Scantypharmacokineticdataonoralmiltefosine proteins, with a preference for albumin (97% of the fraction fro
inIndianVLpatientsareprovidedbythemanufacturerandcan bound)overlow-densitylipoprotein(3%ofthefractionbound).62 m h
betracedinregistrationdocuments.40Aftertheapprovalofmil- ttp
s
tDeufotcshines,oaldnieersxtetrnesaivteedphwairtmhamcoilkteinfeotsiicnestufodryCwLa.5s4pCeurfrorermntelyd,ina Metabolism ://ac
a
pharmacokinetic studyis ongoing aspart of arandomized con- Inpre-clinicalinvitrostudies,nooxidativemetabolismbyanyof de
trolledclinicaltrialontheevaluationofmiltefosineandcombin- the investigated reconstituted cytochrome P450 (CYP) isoen- mic
ationtherapystrategiesforVLinEastAfrica.60Anotherstudyhas zymes was observed.29 The investigated isoenzymes included .o
u
recentlybeeninitiatedaspartoftheevaluationofmiltefosinein 1A1, 1A2, 1B1, 2A6, 2B6, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, 3A4, p.c
paediatric and adult CLpatientsin Colombia.61 3A5,3A7and4A1.Moreover,noinductionofCYP3Aisoenzymes om
bymiltefosine could be demonstrated in bothmale and female /ja
rats.29 Metabolic drug–drug interactions at the CYP level are c/a
Absorption thereforenotexpected,althoughevidencefromhumansubjects rtic
Afteroral administration, miltefosine showed a slow absorption on thistopicis currentlynot available. le-a
process, with an absolute bioavailability of 82% in rats and The main, and possibly only, metabolic pathway of miltefo- bs
94%indogs,withthetimetoreachthemaximalconcentration sine appears to be mediated by phospholipases. In vitro data tra
c
(Tmax) between4 and 48h.29 In humans, the absolute bioavail- suggested that miltefosine was a substrate only for reconsti- t/6
ability has never been assessed due to possible haemolysis tuted phospholipase D and not for phospholipase A, B or C.29 7/1
after intravenous administration,62 but the gastrointestinal ab- However,otherstudiesshowedthatbothphospholipaseC(Bacil- 1/2
sorptionrate(half-life)estimatedinatwo-compartmentpopula- luscereus)andphospholipaseD(partiallypurifiedfromcabbage) 57
tion pharmacokinetic model was 0.416h21 (1.67h).48 The were able to hydrolyse miltefosine.42,66 Probably, the original 6/7
0
mechanism of absorption was investigated in more depth by sourceofthephospholipaseenzymesfromwhichtheywerepuri- 9
2
Me´nez et al.63,64using in vitro permeability testing with Caco-2 fied determines the substrate specificity and can explain these 49
cells. Below 50mM (20.4mg/mL), membrane translocation different observations. The importance of the phospholipase- b
y
appeared to be mediated mainly through a non-saturable mediated metabolism was confirmed in mice in which the gu
passive paracellular diffusion that was pH independent, while metabolic fate of 3H-radiolabelled miltefosine in the liver was es
above this concentration the transport mechanism was found examined after intravenous administration.66 After 24h, the t o
n
tobesaturableandwasprobablyanactivecarrier-mediatedcel- mainstay of the radioactivity could be characterized as un- 1
5
lulartransport.63,64Mostlikely,boththesetransportmechanisms changed miltefosine (63%), while radiolabelled choline (32%), A
p
playaroleinthegastrointestinalabsorptionofmiltefosine.Indir- phosphocholine (3%) and diacyllecithin (2%) were identified as ril 2
ect evidence suggested possible inhibition of the ATP-binding metabolites of miltefosine in the liverof these mice. After 72h, 0
1
cassette (ABC) transporter P-glycoprotein in a Caco-2 cell line, a decreased relative amount of radiolabelled miltefosine (37%) 9
whichcould imply possibledrug–drug interactions.65 and more choline (53%) could be detected. In vitro studies
with human hepatocytes showed consistentlya slowrelease of
choline after incubation with miltefosine. Phospholipase D
Distribution
enzymes generally cleave phosphocholines just after the phos-
Distributionstudiesinratsfollowingsingleoraladministrationof phate before the choline group, resulting in the release of
14C-radiolabelled miltefosine, and in mice following single oral choline;phospholipaseCenzymeshaveapreferenceforcleavage
and intravenous administration 3H-radiolabelled miltefosine just before the phosphate group at the side of the alkyl chain,
(25mgtotaldose)indicatedawidegeneraldistributionofmilte- resulting in the release of an alcohol.68 Both enzymes may
fosine.29,66Thesestudiesdemonstratedthattheuptakeofradio- playaroleinthemetaboliccleavageofmiltefosine.Thedegrad-
labelled miltefosine in rats and mice was extensive and in a ation products of miltefosine are endogenous compounds with
range of tissues, with the highest accumulation of radioactivity physiological purposes and are therefore difficult to recover.
in the liver, lungs, kidneys and spleen. This was confirmed in a Choline, the main metabolite found in animal studies and the
subsequent study in rats in which a repeated steady-state oral product of phospholipase D cleavage, is likely used in the
2579
Review
physiologicalbiosynthesisofcellmembranesorasanimportant 70mg/mL at day 23 of treatment and indicated an elimination
sourceforthesynthesisofe.g.acetylcholineorlecithin.Thelong- half-life of between 150 and 200h ((cid:2)7days). For Indian chil-
chainalcoholthatresultsfromthephospholipaseCcleavageof dren, treated with 2.5mg/kg, the reported mean pre-dose con-
miltefosine can be oxidized into palmitic acid and subsequently centration between days 23 and 28 of treatment was 24mg/
used for the biosynthesisof otherlong-chain fattyacids. mL, withan elimination half-life of180h.
Afterclinicaldevelopmentandmarketingofthedrug,several
case reports describing miltefosine plasma concentrations in
Excretion
patients with CL70 and with VL,71,72 and one larger and more
Miltefosine is almost completely eliminated by the metabolic detailedpopulationpharmacokineticstudyinCLpatients54were
mechanisms described above. Excretion in the urine appeared published,whichallowedamoreextensiveevaluationofitsclinical
to be ,0.2% of the administrated dose at day 23 of a 28day pharmacokinetics.Absorptionofmiltefosineisslow,withanab-
D
treatment regimen.40 Faecal excretion of miltefosine was not sorption rate of 0.36h21 in these CL patients.54 Drug clearance o
w
investigated clinically in humans, but is not expected based on and the volumeof distribution areratherconstant, asindicated n
lo
its extremely long elimination half-life and high accumulation bytheestimatedbetween-subjectvariation.Miltefosinekeepsac- a
d
duringtreatment.However,inBeagledogs,aslowfaecalexcre- cumulatinguntiltheendoftreatment(day28)and,dependingon ed
tion was recently shown, where faecal clearance amounted to the exact daily dosage and the individual’s body weight, fro
10% (+4.86%) of the total miltefosine clearance.69 Excretion steady-state is reached in a subset of patients in the last week m
h
into breast milk was not investigated due to the teratogenic oftreatment(seeFigure2).Theextremelysloweliminationofmil- ttp
potentialof miltefosine, butmustbeexpected.29 tefosineismanifestedbythelongeliminationhalf-livesestimated s://a
fromatwo-compartmentpharmacokineticmodel,withaprimary c
a
elimination half-life of 7.05days (range: 5.45–9.10days) and a d
Clinical pharmacokinetics terminalhalf-lifeof30.9days(range:30.8–31.2days).54Various em
ic
During the clinical development of oral miltefosine in general, reportedmaximalorsteady-statemiltefosineconcentrations,all .o
u
little attention was paid to the clinical pharmacokinetics of this taken around the last week of treatment, recorded 14.6– p
.c
drug. No pharmacokinetic evaluation was performed in healthy 15.6mg/mL (100mg/day, n¼1),71,73 11.9mg/mL (150mg/day, o
m
individuals.Dose-findingstudieswereperformedwithoutexten- n¼1),72 29–38mg/mL (150mg/day, n¼2)70 and a median /ja
sivepharmacokinetic evaluations and only verysparse pharma- 30.8mg/mL (IQR: 25.2–33.4mg/mL; 150mg/day, n¼22).54,74 c/a
cokinetic data from these studies, which were never published Monitoringsteady-stateconcentrationsinthelastweekoftreat- rtic
originally, can be traced in registration documents.40 These ment could be considered to assess treatment adherence, al- le-a
data,obtainedfromIndianadultstreatedwith100mgofmilte- thoughthiswillonlyrevealindividualswhomissedasubstantial b
s
fosine for 28days, showed a median maximal concentration of partoftheirregimen. tra
c
t/6
7
/1
1
/2
End of treatment 5
7
6
100000.0 /7
0
9
2
90% Prediction interval 4
9
mL) 10000.0 Median predicted concentration by
g/ gu
n e
on ( st o
ati 1000.0 n 1
centr 5 Ap
a con 100.0 ril 201
m 9
s
a
pl 10.0
e
n
si
o
ef
Milt 1.0
0.1
0 50 100 150 200
Time (days)
Figure 2. Visualpredictivecheckofpopulationpharmacokineticmodelformiltefosine.Opencirclesrepresentobserveddata(n¼382)from31CL
(L. major) patients. All patients were treated with 150mg/day miltefosine for 28days. The grey area shows the 90% interval of the model
predictions;thebrokenlinedisplaysthemedianpredictedconcentrations.FromDorloetal.,54withpermission.
2580
JAC
Review
Population pharmacokinetic modelling of the pooled original equallysusceptibletomiltefosine,andvariouspitfallscomplicate
pharmacokinetic data collected during the paediatric Indian the interpretation and comparison of in vitro results for the
Phase II/III trial,75 the adult Indian Phase II trial76 and the screeningofantileishmanialdrugactivity.Thereisageneralcon-
adult European CL study,54 yielding a pharmacokinetic dataset sensus that the most appropriate in vitro test model for Leish-
fromawiderangeofbodyweights,revealedthatdrugclearance mania is the intracellular amastigote model.79 However,
formiltefosineisbestscaledbyallometricthree-quartersscaling interpretation of the results is complicated by variability in the
and not linear scaling, based on fat-free mass instead of total (rate of) infectivity of the promastigotes for the macrophage
body weight.77 The estimates of normalized pharmacokinetic host cells,80 in drug activity dependent on the type of macro-
parameters and variabilities from that pooled analysis can be phage host cell used,81 but also in the intrinsic susceptibility of
found inTable1. laboratory strains and clinical isolates.82 More standardization
of Leishmania drug susceptibility testing is therefore needed. In
D
a comparison between intracellular amastigotes of L. donovani, o
Clinical pharmacodynamics w
Leishmania aethiopica, L. tropica, Leishmania panamensis, n
lo
Besides the clinically observed effects of miltefosine, little is L. mexicana and L. major laboratory strains, L. donovani was a
d
konthoewrnaanbtioleuisthtmheancilainlicdarlugpshainrmgaecnoedryanl,ammiacisnloyfbtehcisaudsreuggaonodd 3th.3e–4m.6omstMs(ucsocrerepstpibolenditnog mtoilt1e.f3o–s1in.e9,mgw/imthL),ECw5h0ilevaLl.uemsajoorf ed fro
m
quantitative markers of parasite load and treatment response was the least susceptible, with EC values of 31.6–37.2mM
50 h
remain lacking for leishmaniasis. A recent study looking at the (corresponding to 12.9–15.2mg/mL).83 In general, intracellular ttp
preaarla-stiimteebiRoTm–aPsCsRintasrkginetbiniogpsthieesoLefiCshLmleasnioians1u8sSinrgRNquAagnetintaotmivee LBei(s(cid:2)hm10a-nfoialda),mbausttigloetsesssaursecemptoibrelesutoscespotdibiulemtostaibmogplhuoctoenriactine s://ac
estimated a parasite clearance rate for miltefosine of (cid:2)1log/ ((cid:2)0.1–0.3-fold) when compared with miltefosine. Interestingly, ad
e
week foran L. major infection.70 A similar rateof decline of the substantial intrinsic variability was found between clinical iso- m
ic
parasiteloadwasobservedinbloodofaVLpatient(Leishmania lates. In a study by Yardley et al., all L. donovani isolates from .o
u
infantum) treated with miltefosine (150mg/day).72 Currently, Nepal were very susceptible to miltefosine, with an EC of p
50 .c
trials are ongoing to evaluate the effect of different miltefosine 0.04–8.7mg/mL, while the isolates from Peru showed remark- o
m
regimens and combination therapies on the parasite biomass able variability, with EC50 values between 8.4 and .30mg/mL /ja
inperipheral bloodusing the same quantitativeapproach.60 for L. braziliensis and L. mexicana (n¼9) and between 1.9 and c/a
3.4mg/mL for Leishmania lainsoni (n¼4).82 For comparison, a rtic
Activity and mechanism of action median miltefosine plasma concentration of 30.8mg/mL in le-a
patientstreatedwith150mg/dayfor28dayswasonlyachieved b
s
Miltefosine has demonstrated activity against Leishmania para- inthelastweekoftreatment(seealsotheClinicalpharmacokin- tra
sites and neoplastic cells. Remarkably, very similar molecular eticssection).54Thereisthusagreatnaturalvariabilityofsuscep- ct/6
modes of action of miltefosine were identified against both tibilitytomiltefosineamongthevariousLeishmania(sub)species, 7/1
Leishmaniaparasitesandhumancancercells,linkingitsactivity certainly between the causative species of CL. This correlates 1/2
mainlyto(i)apoptosisand(ii)disturbanceoflipid-dependentcell with variability in the clinical response and is unrelated to the 57
6
signallingpathways. emergence ofresistance (seethe Clinical efficacysection). /7
0
Several potential hypotheses for the antileishmanial 9
2
mechanism of action of miltefosine have emerged over recent 4
Antileishmanial activity and mechanism of action years and are schematically depicted in Figure 3; however, no 9 b
y
The in vitro and in vivo antileishmanial activity of miltefosine mechanism has been identified definitely. The multitude of g
u
wasfirstdescribedbyCroftetal.78Theseresultswerereplicated proposed potential mechanisms and contradictory studies may es
with the oral administration of miltefosine in experimentally indicate that miltefosine has more than one molecular site of t o
n
VL-infected BALB/c mice.30 Not all Leishmania species are action. 1
5
A
p
Table1. Populationpharmacokineticestimatesandderivedparametersfromamodellingstudyincorporatingmiltefosinepharmacokineticdata ril 2
fromIndianVLpatientsandEuropeanCLpatientsexhibitingawiderangeofbodyweights;fromDorloetal.,48,77withpermission 0
1
9
Parameter Estimate[relativeSE(%)] Between-subjectvariability[relativeSE(%)]
Absorptionrate(k )(h21) 0.416(11.5) 18.2%(115.5)
a
Clearance(CL/F)(L/day) 3.99(3.5)a,b 32.1%(18.4)
Volumeofcentralcompartment(V /F)(L) 40.1(4.5)a,b 34.1%(27.3)
2
Intercompartmentalclearance(Q/F)(L/day) 0.0347(18.3) notestimated
Volumeofperipheralcompartment(V /F)(L) 1.75(8.2) notestimated
3
Initialeliminationhalf-life(t1a)(days) 6.13(4.35–9.55)c notestimated
2
Terminaleliminationhalf-life(t1b)(days) 35.6(35.2–36.6)c notestimated
2
aEstimatesarenormalizedtoafat-freemassof53kgandscaledallometricallywithapowerof0.75forCL/Fand1forV /F.
2
bBetween-subjectvariabilitiesinCL/FandV /Fcorrelatedwithacorrelationcoefficientof0.92.
2
cRange.
2581
Review
Protein-bound miltefosine Free miltefosine
(96–98%) (2–4%)
Albumin
D
o
Passive or active passage through w
n
macrophage lipid bilayer? lo
a
Macrophage d
Host cell & immuno- e
d
modulatory effects fro
m
h
IFN - gg receptors & ttp
LdM Ilinpwida trrda ntrsaloncsapsoerts through responsiveness s://ac
T a
/LdR Restoring Th1 / Th2 balance dem
o ic
s3 Leishmania Th1 Th2 .ou
p
.c
o
Lipid metabolism & m
membrane composition: /ja
c
PE & PC due to /a
intracellular choline PI3K-Akt Apoptosis rticle
Apoptosis: -a
b
MCityotocchhornodmriea :c oxidase DNA fragmentation Influencing susceptibility to stra
infection & host cell survival? c
t/6
7
/1
1
/2
5
7
6
/7
Figure3. Antileishmanialmechanismofactionofmiltefosine.Thevariousproposedmechanismsofactionofmiltefosineagainstthe(intracellular) 0
9
Leishmaniaparasiteandthemacrophagehostcellduringleishmaniasisinfection.PC,phosphatidylcholine.Thisfigureappearsincolourintheonline 2
4
versionofJACandinblackandwhiteintheprintversionofJAC. 9
b
y
g
u
e
s
Lipid metabolism as well as a reduction in ergosterol levels, indicating that t o
Preliminarystudies in miltefosine-treatedL. mexicana promasti- fatty-acidandsterolmetabolismareprobablytargetsformilte- n 1
gotesshowedanassociationbetweentheefficacyofmiltefosine fosine.87 Interestingly, transient treatment with miltefosine 5 A
led to moderate effects on phospholipid metabolism and the p
andperturbationofether-phospholipidmetabolism(majorcom- parasite’s membrane composition: a decrease in phosphati- ril 2
ponents in the membrane), glycosylphosphatidylinositol (GPI) 0
dylcholine by inhibiting its synthesis through the cytidine 1
anchorbiosynthesis(importantparasitesurfacemoleculesimpli- 9
5′-diphosphocholine pathway, but an increase in phosphotidy-
cated in virulence) and, more generally, signal transduction
lethanolamine (PE) by stimulation of cytidine triphosphate:PE
within the parasite.84 However, the role of GPIs and phospholi-
cytidylyltransferase activity and/or inhibition of PE-N-methyl-
pids in the survival of Leishmania amastigotes was seriously
transferase activity.88 This observation might be related to the
questioned by the viability of an L. major knockout model
miltefosine-mediated inhibition of the inward transport of ex-
overall lacking ether phospholipids and specific GPIs,85 which
ogenous choline intothe parasite.89
makes this a less likely target for miltefosine. Later, the
miltefosine-induced perturbation of ether phospholipid meta-
bolism was specified to the inhibition of the glycosomal
Apoptosis-like cell death
alkyl-specific acyl-CoA acyltransferase,86 but this pathway also
is probably not the primary target due to the high IC value Apoptosis-likecelldeathcomparabletometazoanapoptosishas
50
(50mM) needed to inhibit this enzyme.35 Nevertheless, promas- been demonstrated in Leishmania promastigotes following
tigotes of a miltefosine-resistant strain of L. donovani showed exposure to reactive oxygen species, resulting in e.g. nuclear
changes in the length and level of unsaturation of fatty acids, condensation, DNA fragmentation and loss of cell volume.90
2582
JAC
Review
Miltefosineisabletoinducethisprogrammedapoptosis-likecell induction of apoptosis by inhibition of the PI3K/Akt/PKB
death at its IC in promastigotes91 and intra-/extracellular pathway.34,113 All these mechanisms lead to reduced cell sur-
50
amastigotes of L. donovani,92 and in Leishmania amazonensis vival or increased apoptosis, mediated either through inducing
and L. infantum promastigotes.93,94This is corroborated by the intracellular stress (reactive oxygen species), by blocking essen-
recentfindingthattoleranceofprogrammedcelldeathinLeish- tialsurvivalsignalsorbyinducingvariouspro-apoptoticcellsig-
maniaislinkedtoemergingmultidrugresistancewithinthepara- nalling pathways.109
site invitro.95
Other actions and activities of miltefosine
Mitochondrial effects
BesidesitspotentactivityagainstLeishmaniaparasites,miltefo-
The involvement of mitochondrial dysfunction has also been sine has activityagainst other trypanosomatid parasites (Trypa-
D
investigated. In L. panamensis promastigotes, the mitochon- nosoma sp.), Entamoeba sp., Acanthamoeba sp., Schistosoma o
w
drialmembranepotentialwassubstantiallyreducedafterexperi- worms, pathogenicbacteria andvariousfungi. n
lo
mental treatment with miltefosine.96 Within the mitochondria, a
d
cytochrome-c oxidase was inhibited by miltefosine in a dose- ed
dependent matter and appeared a likely target for miltefosine Antitrypanosomal activity fro
in Leishmania promastigotes.97 Recently, the inhibition of AfricanTrypanosomaparasitesarelesssusceptibletoalkylphos- m
h
cytochromecoxidasebymiltefosinewaslinkedtotheapoptosis- phocholinesthanotherkinetoplastidparasites.BothTrypanosoma ttp
likecelldeathinducedintheyeastSaccharomycescerevisiae.98 brucei brucei and T. b. rhodesiense, which cause sleeping s://a
sickness in animals or humans, demonstrated moderate EC50 ca
values of miltefosine of 35.5mM (14.5mg/mL) and 47.0mM d
Immunomodulatory effects (19.2mg/mL),respectively,114whichwascorroboratedbylimited em
ic
Miltefosine’simmunomodulatorypropertieshavebeenproposed life extensioninvivoininfectedmice.115Againstallphenotypes .o
u
as an additional contributory factor to its antileishmanial activ- ofTrypanosomacruzi,theSouthAmericanTrypanosomaspecies p
.c
ity,99,100 despite the fact that miltefosine retains its activity andtheaetiologicalagentofChagas’disease,thereportedEC , o
50 m
against Leishmania infections in severe combined immunodefi- IC50/72h and IC50/120h values of miltefosine were 0.5mM /ja
cient mice.101 The immunostimulatory properties of miltefosine (0.2mg/mL),0.7mM(0.3mg/mL)and1mM(0.4mg/mL),respect- c/a
were alreadyshown in other pre-clinical models in which milte- ively.114,116,117Highervalueswerereportedunderdifferentcondi- rtic
fosine induced cytokine release.39,99,102,103 In Leishmania, the tions.118SuppressionofT.cruziinfectioninmicewasonlynoted le-a
intracellular antileishmanial activity of miltefosine was severely after five administrations of 30mg/kg114 and 100% survival of b
s
compromised in interferon-g-deficient L. donovani-infected infectedBALB/cmicewasachievedwithadoseof25mg/kg/day tra
c
macrophages. Moreover, miltefosine enhanced interferon-g for 20days, comparable to benznidazole, the current drug of t/6
receptorsandtherebyrestoredboththeinterferon-gresponsive- choiceforChagas’disease.116Themechanismofactionofmilte- 7/1
ness in infected macrophages and the Th1/Th2 balance in fosineinT.cruziseemstobespecificallyrelatedtotheinhibition 1/2
infected macrophages by promoting the interleukin-12- ofdenovophosphatidylcholinebiosynthesisandphospholipidsig- 57
dependent Th1 response.100 However, the immunostimulatory nallingpathwaysthroughtheinhibitionofphospholipaseC.117,119 6/7
0
contribution to miltefosine’s antileishmanial activity is not 9
2
without controversy. A recent study showed that miltefosine 4
did not up-regulate major histocompatibility complex II or any Other antiprotozoal activity 9 b
y
costimulatory molecules that influence the maturation of den- Miltefosine possesses activity against various other protozoan g
u
dritic cells, nor did it alter the release of the cytokines parasitesaswell.AlthoughlesspotentthanagainstLeishmania, es
interleukin-10, interleukin-12 or tumour necrosis factor-a.104 activity was demonstrated against Entamoeba histolytica, a t o
n
Relatedtothis,miltefosineinhibitsboththereleaseofmediators protozoan parasite causing amoebic dysentery and liver 1
5
frommastcellsaswellastherelatedmastcellactivation.105In abscesses. Forexample, the median EC after 48h was 53mM A
50 p
thisrole,theapplicationoftopicalmiltefosineforthetreatment (range 28–99mM) [corresponding to 22mg/mL (11–40mg/mL)] ril 2
of skin lesions in mastocytosis patients is currently being for the most susceptible Entamoeba strain, which was compar- 0
1
investigated.106 able to that of metronidazole.120 Comparable amoebistatic ac- 9
Recently,itwasshownthathostcellswerelesssusceptibleto tivity was shown against free-living amoebae of the
infection by CL-causing parasite species after the inhibition of Acanthamoeba genus, causative species for both keratitis and
two PI3Ks (PI3K-g and -d).107,108This supports that miltefosine, granulomatous amoebic encephalitis, with complete cell death
asaknownhumanPI3K/Aktinhibitor,mayinfluencethesuscep- at 40mM (16mg/mL).121 The amoeba species displayed
tibilityof host cellinfectionalso through thispathway. miltefosine-induced alterations of the membrane architec-
ture.120,121 The anti-acanthamoebic activity of miltefosine was
confirmed in an Acanthamoeba keratitis Syrian hamster model
Anticancer action
in which topically applied miltefosine [160mM (65mg/mL),
The antineoplastic mechanisms of action of alkylphosphocho- 28days] resulted in complete cure of the infection in 85% of
lines were recently reviewed by van Blitterswijk and Verheij.109 thehamsters.122Also,againstTrichomonasvaginalis,thecausa-
Themostprominentmoleculartargetsformiltefosine’santican- tive agent of trichomoniasis, miltefosine showed modest activ-
ceractivityarerelatedtotheantileishmanialtargets,andinclude ities, most notably also against metronidazole-resistant
theinhibitionofphosphatidylcholinebiosynthesis110–112andthe strains, with EC values between 8 and 40mM (3.3 and
50
2583
Review
16.3mg/mL).123 Miltefosine is therefore also a potential new Antiviral activity
treatmentforthiscommonsexuallytransmitteddisease.Theac-
Recently, it was shown that the host PI3K/Akt pathway is
tivityofmiltefosineagainstCryptosporidiumparvumwasdemon-
exploited by the HIV-1 virus to establish a cytoprotective
stratedinvitro,124butitsclinicalapplicationseemstobelimited
effect, which prolongs the lifespan of HIV-1-infected macro-
inHIV-infected immunocompromisedhosts.125
phages,therebycreatinganimportantvirusreservoir.134Miltefo-
sinereversesthis:itpreventsactivationofthePI3K/Aktpathways
in HIV-1-infected macrophages and specifically inhibits Akt
Antischistosomal activity
kinase.135 Moreover, the drug induces cell death of HIV-1-
Recent pre-clinical studies have shown activity of miltefosine infected macrophages upon exposure to stress and ultimately
against Schistosoma mansoni, the major cause of intestinal eventerminatesthe production ofviralparticles.134
schistosomiasis. Its activity in Schistosoma seems to be related D
o
to both apoptosis and damaging of the tegumental outer w
surface and lipid bilayers of this flatworm.126,127Eissa et al.126 Resistance in leishmaniasis nlo
a
showed that administration of a high dosage (20mg/kg/day) d
onfeeodreadl mtoiltinedfouscineeafosirgn5ifidcaaynsttroedSu.ctmioannsoofntih-ienfwecotremd bmuircdeenis, Mreillatetifvoesliyneearseislyistbaencine,duocredratihnevritdroru,galtnhoonu-gsuhscitephtaibsilintyo,tcboeueldn ed fro
m
characterized in vivo yet. L. donovani promastigote clones that
hepaticgranulomatasizeandameliorationofhepaticpathology h
fordifferent developmental stages ofS. mansoni. are resistant up to 40mM (16.3mg/mL) miltefosine have ttp
aaplrpeaeadryedbe1e5n-foglednelerastsedsusincepthtieblelabtooramtoilrtye.f1o3s6inTeh.1e3s7eBcoltohneas s://ac
a
Antibacterial activity defect in drug internalization into the parasite and increased de
drug efflux from the parasite were incriminated as possible m
Miltefosinehasdemonstratedsignificantbacteriocidalactivityin mechanisms ofresistance. ic.o
vitro against pneumococcal bacteria. The determined MIC Thetransportofmiltefosineovertheparasitecellmembrane up
rangedbetween5and6.25mM(2–2.5mg/mL)forStreptococcus isthoughttobefacilitatedbyaputativeL.donovanimiltefosine .co
m
opntheeurmpoantiaheogsetnraicinss,treapntdocforoccmi.12180Atgoai2n0stmMme(t4h–ic8illming-/rmesLis)tafnotr transporter (LdMT) and the protein LdRos3. It was shown that /jac
decreasedmiltefosineaccumulationanddefectiveinwardtrans- /a
Staphylococcusaureus,alowerMICwasdemonstratedcompared location was the major determinant of decreased susceptibil- rtic
wmiLth),suresscpeepcttibivleelSy..1a2u9reMusil:t2ef2omsiMne(9amlsgo/mhLa)dvermsuosd4e4ramteM(a1c8tivmigty/ iintya,1c3t7ivawtiohnichofwLdaMsTdaenmdonLsdtRroatse3d(Ftigourbee3)m.13e8d–i1a4t0edLdMthTroiusgha le-ab
s
against vancomycin-resistant Enterococcus [MIC: 44mM (18mg/ novel inward-directed lipid translocase that belongs to the P4 tra
mL)].129 In a murine peritonitis/sepsis model, this activity could subfamily of P-type ATPases and LdRos3 is a non-catalytic ct/6
cnseioeetsm.b13se0troeApgblaeicianlitsmetditGeirnda,mvsiiv-nonc,eegpnarootibvaaecbtlbiyvaidtcyuteecroiatuo,ldemxbipelteeorfibomsseeinrnevte’asdl aiinncttrviivictiatroy- swpuhhboiucshpnhitotooligfpeitdthhiasesrmympelmmaybertaraynneoifpmrtophtoeeritnpaanrretalasritoteeldemtionemthmberaaCinndetca.51in401infgLadmMtihlTye-, 7/11/257
onbothEscherichiacoliandPseudomonasaeruginosa.128 6
associated miltefosine resistance could be transferred to the /7
0
amastigote stage, with no apparent loss of infectivity, and 9
2
even persists in vivo.142 In clinical isolates, low expression of 4
Antifungal activity the LdMT-LdRos3 complex was correlated to the natural non- 9 b
y
Miltefosine exhibits broad-spectrum antifungal activity. IC susceptibility to miltefosine ofL.braziliensis strains.140 g
90 u
values against Candida albicans, Candida glabrata, Candida Increased efflux of miltefosine (and other endogenous es
krusei, Cryptococcus neoformans, Cryptococcus gattii, Aspergillus phospholipid analogues) has also been implicated in miltefosine t o
n
fumigatus,Fusariumsolani,Scedosporiumprolificans,Scedospor- resistance, mediated through theoverexpression of an ABCtrans- 1
5
ium apiospermum, Candida tropicalis, Aspergillus terreus and porter: the Leishmania P-glycoprotein-like transporter (Leishmania A
p
Candida parapsilosis were 2–8mg/mL.131,132 Another study ABCB1 or LtrMDR1).143,144 Probably, there are more Leishmania- ril 2
showed MICs of miltefosine against C. neoformans and C. albi- specific ABC transporters implicated in phospholipid trafficking 0
1
cans of 2.75 and 5.5mM (1.12 and 2.2mg/mL), respectively.129 and reduction in miltefosine accumulation. The overexpression of 9
FungicidalactivityagainstC.neoformanswasconfirmedinadis- two Leishmania-specific ABC subfamily G-like transporters
seminated mouse model.132 In an in vitro test panel of 77 der- (LiABCG6 and LiABCG4 half-transporters) conferred resistance to
matophytes, including several Microsporum and Trichophyton notonlymiltefosineinvitro,butalsotoaminoquinolines.145,146
species, miltefosine showed better activity (geometric mean Whole genome sequencing recently revealed that miltefosine
MIC of 0.67mg/mL) and broader specificity when compared resistanceinL.majormutantscanbebothgeneticallyandpheno-
withthe standarddrug itraconazole.133 typically highly heterogeneous.147 Two of the three identified
Aproposedmechanismoffungicidalactionisrelatedtomiltefo- markers of miltefosine resistance in this study were implicated
sine’s similarity to natural substrates (lysophospholipids) of in drug susceptibility: the previously described P-type ATPase
phospholipase B, which is a major fungal virulence factor.129,132 and pyridoxal kinase.147 Pyridoxal kinase plays a vital role in the
However, high concentrations of miltefosine [e.g. 250mM formationofpyridoxal-5′-phosphate(activevitaminB6).
(102mg/mL)]wereneededtoestablishonlyminimalinhibitionof Aclinicaldecreaseinthesusceptibilityofparasitestomiltefo-
phospholipase B and therefore it is unlikely that this isthe main sine in vivo, a precursor of the emergence of drug resistance,
antifungaltargetofmiltefosineorotheralkylphosphocholines.129 has not yet been formally described, although several relapse
2584
JAC
Review
cases after initial successful primary miltefosine treatment in females of child-bearing potential during and after miltefosine
immunocompetent patients have been reported for both CL treatment. A recent study indicates that, based on translational
and VL.148–150A recent evaluation of miltefosine for Indian VL, animal-to-human pharmacokinetic modelling, 4months of
after a decade of availability of the drug in India, showed a contraceptivecoveraftertheendoftreatmentmightbeadequate
90.3% final cure rate at 6month follow-up.151 This cure rate forthestandard28daymiltefosineregimen,whileforallshorter
had decreased from the 94% final cure rate that was achieved regimens (5, 7 or 10days) 2months may be considered ad-
in Indian Phase III trials a decade earlier (Table 2), but was equate.77Basedonthephysicochemicalpropertiesofmiltefosine,
stillhigherthanthemostrecentreportedcurerateinneighbour- itmaybeassumedthatmiltefosineistransferredintobreastmilk.
ingBangladesh, wheremiltefosinewasonlyrecentlyintroduced
(Table2).Theinvitrosusceptibilitiesofclinicalisolatesfromthis
Male reproduction
recentIndianstudyremaintobereported.Anotherrecentstudy
D
reportedthatagradualdecreaseofthemiltefosinesusceptibility Preclinical animal studies additionally showed (reversible) tes- o
w
ofL.infantumisolatesfromanon-responsiveHIV/VLpatientwas ticular atrophy and impaired fertility in male rats at a dose of nlo
associated with the occurrence of a single nucleotide poly- 8.25mg/kg.29 Spermiogram analyses in Colombian male ad
morphism in the Ldmt gene, L832F, which reverted back to the patientsaswellaslimitedretrospectiveanalysesofreproductive ed
wild-type allele3years afterwithdrawalfrom miltefosine.152 performanceinIndianmalepatientssuggestedanabsenceofa fro
m
clinically relevant effect on male fertility.153,154 Conversely, re- h
Safety cently it was shown in a retrospective, observational study that ttp
s
a large proportion of miltefosine-treated males (1.3–2.1mg/ ://a
The main safety concerns for miltefosine relate to its effect on kg/day,28days)experiencedasubstantialtreatment-relatedre- c
a
themucosaofthegastrointestinaltractanditspotentialterato- versible reduction of ejaculate.74 Although nothing is known de
m
genicity, as shown in pre-clinical reproductive toxicity studies in about sperm count and quality in these patients, this finding ic
animals. The gastrointestinal side effects of miltefosine were does clearly point at effects of miltefosine on the male repro- .o
u
already demonstrated in early studies in cancer patients, in ductivesystem. p.c
which loss of appetite, nausea and vomiting were found to be om
dose-limiting side effects.26–28Vomiting and/or diarrhoea were /ja
Drug–drug interactions c
observedineveryclinicaltrialperformedwithmiltefosine(sum- /a
marizedinTables2and3),andwerealsotheprimaryobserved Basedonmiltefosine’srouteofmetabolism,nodrug–druginter- rtic
andmostseveresideeffectsinthelargePhaseIVtrialinIndian actionsaretobeexpectedatthelevelofCYPisoenzymes.Never- le-a
VL patients (n¼1119), especially in the first week of treatment theless, other interactions can be hypothesized, corresponding bs
(8.2% experienced one or more episodes).153 During treatment, with e.g. its very high serum protein binding and its presumed tra
c
the severity of these effects decreased (3.2% in the last week (moderate) substrate affinity for the multidrug transporter P- t/6
oftreatment).153Thegastrointestinalsideeffectsaremostprob- glycoprotein.155,156 Theoretical relevant drug–drug interactions 7/1
1
ably directly related to the oral intake of the drug and the of miltefosine might therefore e.g. include ritonavir-boosted /2
detergent-likepropertiesofmiltefosineaffectingthegastrointes- highly active antiretroviral treatment in VL patients coinfected 57
6
tinallining.Intakeof(fatty)foodtogetherorjustbeforemiltefo- with HIV, possibly resulting in a decreased miltefosine bio- /7
0
sine intake drastically reduces the gastrointestinal side availability and/or intracellular accumulation. Clinical evidence 92
effects70,74and probably has no effecton bioavailability. pointing at either the presence or absence of these theoretical 49
Other frequently observed miltefosine-related toxicities are drug–drug interactions is still not available. by
mainlyassociatedwiththekidneysandliver.Elevatedserumcre- gu
e
atininelevelsduringtreatmentarefrequentlyobserved(Tables2 s
and 3), possibly related to occasional dehydration by severe Clinical efficacy t on
vomiting/diarrhoea;29 severe nephrotoxicity caused by miltefo- 1
sine is, however, rare. Serum levels ofboth alanine aminotrans- VL 5 A
p
ferase (ALT) and aspartate aminotransferase (AST) tend to Severalclinicalstudieshavebeenconductedofmiltefosine,both ril 2
increase mildly in the first week of miltefosine treatment in VL alone and in combination with other therapies, in the treatment 0
1
patients, possibly due to immediate necrosis of pre-damaged of VL. The efficacy and toxicity data from these trials are sum- 9
hepatocytes.29 This generally normalizes in the subsequent marized in Table 2. The role of miltefosine in the treatment of
weekstogetherwiththeresolvinginfection.Ophthalmologicreti- VL has been well established, however, it should be noted that
notoxicsideeffectshavebeenreportedinpre-clinicalstudies,but almostallclinicaltrialsofmiltefosineforVLhavebeenperformed
havesofar not been observedin anyVLor CLpatients.29 inasingleareaofVLendemicity,namelytheIndiansubcontinent,
and from this region all studies except one originate from the
state of Bihar, India (Table 2). The other important VL foci, in
Pregnancy
South America (Brazil), East Africa (Sudan, Ethiopia, Kenya and
Preclinical reproductive toxicity studies in animals showed both Uganda) and other South Asian countries (Nepal and Bangla-
embryo- and fetotoxicity (in rabbits and rats) and teratogenic desh),havebeenlargelyignoredintheevaluationofmiltefosine,
effects (in rats) of miltefosine at a lowest observed adverse with the exception of a studyconducted by Ritmeijeret al.157 in
effect level of 1.2mg/kg for 10days during gestation.29 The use northern Ethiopia, a study by Rahman et al.158 in Bangladesh,
of miltefosine is therefore strictly contraindicated in pregnant and a Phase II trial in adults and children in Brazil sponsored
females, and adequate contraceptive cover is mandatory for by the AB Foundation,159 which was terminated early and
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