Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1        Pharmacodynamic properties


Pharmacotherapeutic group: Antiprotozoal, ATC code: P01CX
Miltefosine has a marked direct antileishmanial activity in vitro and in animal models.
Leishmania donovani was the most sensitive species in promastigote and amastigote test systems, with 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 amastigotes the ranking was: Leishmania donovani > Leishmania aethiopica > Leishmania tropica > Leishmania mexicana > Leishmania panamensis > Leishmania major.

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

Pharmacokinetic Properties

5.2      Pharmacokinetic properties

Due to the hemolytic nature of miltefosine after intravenous administration, studies in humans to assess the bioavailability after oral use cannot be performed. In rats and dogs, however, an absolute bioavailability of 82% and 94%, respectively, has been shown with tmax values ranging 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 was feasible, particularly in children. Therefore, only a subset of the typical pharmacokinetic parameters could be determined.


Parameter                              Adults                        Children( above 12 years old) tmax                                   8 -24 hours                   (not determined) Plasma concentration                   Cmax,day 23 = 70              C min,day26-28= 24 µg/ml *) after repeated dosing                  µg/ml                         (Dosage: 2.5 mg/kg/day) (Dosage: 100 mg/day) t1/2                                   150 - 200 hours               180 hours 
Excretion (urine, day 23)              < 0.2% of applied             (not determined) dose
*) 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 was lower in children than in adults. No relevant sex differences of pharmacokinetic parameters were observed.


Distribution studies in rats, using radioactively labelled miltefosine, 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 fragment into physiological lipids.

No oxidative metabolism by 15 different cytochrome P450 isozymes was observed in vitro. No CYP3A induction by miltefosine was found in vivo in rats. Thus, no interaction has to be expected between miltefosine and drugs, like contraceptive hormones, that are metabolised by CYP3A. A slow metabolic breakdown could be 8/8
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-Larsson syndrome, which is caused by a genetic defect in fatty aldehyde dehydrogenase activity.

Preclinical and clinical studies suggest that only a very minor part of the administered dose will be excreted as the unchanged drug substance. Instead, choline and choline- containing metabolites are the most likely excretion products.