Miltefosine

Chemical formula: C₂₁H₄₆NO₄P  Molecular mass: 407.576 g/mol  PubChem compound: 3599

Mechanism of action

The specific mode of action of miltefosine in leishmaniasisis unknown. Among others, miltefosine can inhibit the metabolism of phospholipids in cell membranes of parasites.

Pharmacodynamic properties

Miltefosine has a marked direct antileishmanial activity in vitro and in animal models. Leishmania donovani was the most sensitive species in promastigote and amastigote testsystems, with the ED50 concentrations around 1µmol/l.

For promastigotes the sensitivity decreased in the following order: Leishmania donovani > Leishmania aethiopica > Leishmania tropica > Leishmania panamensis > Leishmania mexicana > Leishmania major. For amastigotesthe ranking was: Leishmania donovani > Leishmania aethiopica > Leishmania tropica > Leishmania mexicana > Leishmania panamensis > Leishmania major.

Pharmacokinetic properties

Due to the hemolytic nature of miltefosine, no study in humans with intravenous administration can be performed to assessthe bioavailability after oral use. In rats and dogs, however, an absolute bioavailability of 82% and 94%, respectively, has been shown with tmax valuesranging from 4 to 48 h.

Miltefosine is widely distributed in the body, however, without evidence of melanin binding in pigment containing tissues. Placental transfer and excretion in milk have not been investigated but can be assumed.

No data are available from pharmacokinetic studies in healthy subjects. The following table summarizes the results of studies in patients with visceral leishmaniasis. Because of the severity of the disease only limited blood sampling wasfeasible, particularly in children. Therefore, only a subset of the typical pharmacokinetic parameters could be determined.

ParameterAdultsChildren (above 12 years old)
tmax8-24 hours(not determined)
Plasma concentration after repeateddosingCmax,day 23 = 70 µg/ml (Dosage: 100mg/day)Cmin,day 26-28=24 µg/ml (Dosage: 2.5mg/kg/day)
t1/2150-200 hours180 hours
Excretion (urine, day 23)<0.2% of applied dose(not determined)

* The plasma concentrations were determined before dosing on days 26-28; only a small fluctuation of concentrations is expected after repeated dosing.

After repeated dosing accumulation of plasma concentration waslowerin children than in adults. No relevantsex differences of pharmacokinetic parameters were observed.

Distribution studiesin rats, using radioactively labelledmiltefosine,showed highest uptake of radioactivity in kidney, liver and spleen. Slow elimination of radioactivity from tissues(half lives 8-16 days) is partially explained by metabolism of miltefosine and incorporation of the labelled choline fragmentinto physiological lipids.

No oxidative metabolism by 15 different cytochrome P450 isozymes was observed in vitro. No CYP3A induction by miltefosine wasfound in vivo, in rats. Thus, no interaction hasto be expected between miltefosine and drugs, like contraceptive hormones, that are metabolised by CYP3A. A slow metabolic breakdown could be shown in human hepatocytes, resulting in the release of choline by Phospholipase D like cleavage of the miltefosine molecule. The fatty alcohol containing fragment of miltefosine can enter the metabolism of fatty acids after being oxidized to palmitic acid. This Oxidation is blocked in patients with Sjögren-Larrson syndrome, which is caused by a genetic defect in fatty aldeyhdedehydrogenase activity.

Preclinical and clinical studies suggest that only a veryminor part of the administered dose will be excreted asthe unchanged drug substance. Instead, choline and choline-containing metabolites are the mostlikely excretion products.

Preclinical safety data

Toxicological studies with miltefosine have been performed in mice,rats, dogs and rabbits. Adverse reactions not observed in clinicalstudies, but seen in animals at exposure levels similar to clinical exposure levels and with possible relevance to clinical use were asfollows:

Acute and chronic toxicity

The oral administration of miltefosine in rats was associated with regressive and/or progressive lesions especially affecting the eyes(retinal degeneration), kidneys(acute resp. chronic nephropathy) and organs with rapidly dividing cell tissues(atrophy/hyperplasia), as well asreproductive organs(atrophy). These alterations were observed after 8 weeks treatment at doses of 10 mg/kg/day which led to plasma drug levels of about 52 µg/ml. Juvenile rats were more sensitive than adultratsto the miltefosine induced effects, especially on eyes and kidneys.

Reproductiontoxicity

Testicular atrophy and impaired fertility were observed in rats following daily oral doses of 8.25 mg/kg. These findings were reversible within a recovery period of 10 weeks.

Reproductive toxicity studiesin rats during the early embryonic development (up to day 7 of pregnancy) indicate an embryotoxic, fetotoxic and teratogenic risk following miltefosine dosages of 1.2 mg/kg/day and higher. Embryo- and fetotoxic findings were also observed in rabbits after oral administration of miltefosine during the phase of organogenesis (2.4 mg/kg/day and higher).

Mutagenicity / Carcinogenicity

Miltefosine tested negative in 6 of 7 of mutagenicity tests(AMES-Salmonella test, DNA-amplification test, chromosomal aberration test in vitro, UDS-test in vivo/in vitro, oral mouse-micronucleustestin vivo). The V 79 mammalian cell HPRT gene mutation testshowed an increase in mutant frequency without dose dependency. In view of all mutagenicity test results, the single positive finding in the V 79 HPRT test is considered to be not of toxicologicalrelevance with respect to a mutagenic risk to humans. The results of the mutagenicity testsruled out a genotoxicity-mediated carcinogenic potential of miltefosine. Carcinogenicity studies were not performed.

Related medicines

© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.