Miltefosine

Miltefosine is an Antiparasitic Agent belonging to Phospholipid class

Miltefosine can be used in the treatment of Leishmaniasis.

Miltefosine Absolute bioavailability of miltefosine has not been determined. In patients with visceral leishmaniasis, maximum miltefosine concentrations following oral administration of miltefosine capsules were reached right before the next dose in many patients, indicating that the absorption of miltefosine may proceed throughout the dosing interval. The distribution of miltefosine has not been studied in humans. Human plasma protein binding of miltefosine, evaluated by an ultracentrifugation method, was 98% over the drug concentration range from 0.1 to 10 µg/mL. In rats, radioactivity of [14C] miltefosine is widely distributed after both single and repeated oral administration with highest uptake of radioactivity in kidney, liver, and spleen. Placental transfer and excretion into milk have not been investigated.No in vitro oxidative metabolism by 15 different human cytochrome P450 enzymes (1A1, 1A2, 1B1, 2A6, 2B6, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, 3A4, 3A5, 3A7, and 4A1) was observed.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-Larsson syndrome, which is caused by a genetic defect in fatty aldehyde dehydrogenase activity. Miltefosine is contraindicated in patients who have Sjögren-Larsson-Syndrome. There was little or no evidence of time or metabolism dependent inhibition of the cytochrome P450 enzymes examined at up to approximately 40 µg/mL miltefosine. Oral administration of miltefosine did not markedly induce the content of hepatic CYP3A assayed by demethylation activity of erythromycin in rats. In visceral leishmaniasis patients, <0.2% of the administered dose was excreted into the urine.

The common side effects associated with Miltefosine include Abdominal cramps, diarrhea, heartburn, nausea, vomiting.

Miltefosine is available in the form of oral solid.

The Miltefosine is available in India, USA, Germany, Japan.

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.

Miltefosine is available in Capsule

Oral: Administer higher doses preferably at late afternoon or as bedtime doses to minimize daytime sedation.

Miltefosine can be used in the treatment of Leishmaniasis.

Miltefosine is a phospholipid derivative thought to work by disrupting cell-membrane function.

Miltefosine is approved for use in the following clinical indications

Leishmaniasis: Treatment of visceral (caused by Leishmania donovani), cutaneous (caused by L. braziliensis, L. guyanensis, and L. panamensis), and mucosal leishmaniasis (caused by L. braziliensis) in adults and adolescents ≥12 years of age weighing ≥30 kg.

Limitations of use: Efficacy of miltefosine in the treatment of other Leishmania species has not been evaluated; there may be geographic variation in clinical response of the same Leishmania species to miltefosine.

• Although not approved there have been certain off labelled uses documented for Miltefosine which include:

Free-living ameba infection

Free-living ameba infection (granulomatous amebic encephalitis [Acanthamoeba spp., B. mandrillaris] and primary amebic meningoencephalitis [N. fowleri]) (off-label use): Oral:

<45 kg: 50 mg twice daily

≥45 kg: 50 mg 3 times daily

Leishmaniasis (cutaneous, mucosal, visceral):

Monotherapy: Note: Efficacy is species and locale dependent. For visceral leishmaniasis, reserve use for patients who are unable to use preferred therapy (Drugs for Parasitic Infections 2013; HHS [OI adult 2021]; IDSA/ASTMH [Aronson 2016]).

30 to 44 kg: Oral: 50 mg twice daily for 28 days.

≥45 kg: Oral: 50 mg 3 times daily for 28 days.

(The dosage and duration of treatment should be as per the clinical judgement of the treating physician).

50 mg

Capsule

• Dose Adjustment in Pediatric Patient:

Leishmaniasis: Children ≥12 years and Adolescents weighing ≥30 kg: Oral: Cutaneous, mucosal, visceral leishmaniasis: Note: Efficacy is species- and locale-dependent.

30 to 44 kg: 50 mg twice daily for 28 days.

≥45 kg: 50 mg 3 times daily 28 days.

Naegleria fowleri infection (free-living ameba): Very limited data available; efficacy results variable; Note: Due to the poor prognosis of infection and lack of successful treatment options, expert recommendations suggest adding miltefosine as a component of treatment regimen:

Children and Adolescents: Oral:

<45 kg: 50 mg twice daily for 28 days an 8-year-old (weight not reported) received 50 mg 3 times daily.

≥45 kg: 50 mg 3 times daily for 28 days.

The dietary restriction should be individualized as per patient requirements.

Hypersensitivity to miltefosine or any component of the formulation; Sjogren-Larsson syndrome; pregnancy.

The treating physician must closely monitor the patient and keep pharmacovigilance as follows

Concerns related to adverse effects:

• Dermatologic toxicity: Stevens-Johnson syndrome has been reported; discontinue miltefosine if an exfoliative or bullous rash occurs during therapy.

• Gastrointestinal effects: Nausea, vomiting and diarrhea may occur with use; administer with food to decrease GI effects. Ensure adequate fluid intake during therapy to prevent dehydration.

• Hematologic toxicity: Thrombocytopenia has been reported during therapy for visceral leishmaniasis; monitor platelet count during therapy in these patients.

• Hepatic effects: Increased liver transaminases and bilirubin have been reported during therapy for visceral leishmaniasis. Assess ALT, AST, and bilirubin during therapy.

• Renal toxicity: May increase serum creatinine. Assess kidney function weekly while on therapy and for 4 weeks after the end of therapy.

May enhance the sedative effect of alcohol.

When used orally, Miltefosine is poorly absorbed. According to the available data, Miltefosine may be used in nursing women if both the mother's and the infant's renal function is normal.

Bioavailability may be increased with food.

The adverse reactions related to Miltefosine can be categorized as

• Common

Leukocytosis; thrombocytosis; GI irritation, nausea, vomiting, diarrhea, constipation

• Less Common

Ocular, Hepatic, Renal toxicity

• Rare

Pruritis, Erythema, Scaling, Xerosis, Tightness of the skin, Dermatitis, Pain, Ulceration, Necrosis.

The common side of Miltefosine include the following

Leukocytosis, Thrombocytosis, GI Irritation, Nausea, Vomiting, Diarrhea, Constipation.

Pregnancy Category (FDA): Pregnancy Category D

• Risk Summary

Miltefosine may cause fetal harm. Human pregnancy data are not available, however, embryo-fetal toxicity including death and teratogenicity, was observed in embryo-fetal studies in rats and rabbits administered oral miltefosine during organogenesis at doses that were respectively 0.06 and 0.2 times the maximum recommended human dose (MRHD), based on body surface area (BSA) comparison. Numerous visceral and skeletal fetal malformations were observed in a fertility study in female rats administered miltefosine prior to mating through day 7 of pregnancy at doses 0.3 times the MRHD. Do not administer miltefosine to pregnant women.

• Clinical Considerations

During pregnancy, visceral leishmaniasis may be life-threatening for the mother and may result in adverse fetal outcomes, including spontaneous abortion, congenital disease due to vertical transmission, small for gestational age newborn, and severe anemia. During pregnancy, cutaneous leishmaniasis may manifest with larger and atypical appearing lesions and may be associated with increased risk for adverse fetal outcomes, including preterm births and stillbirths.

• Animal Data

Miltefosine administration in rat embryo-fetal toxicity studies during early embryonic development (Day 6 to Day 15 of gestation) caused embryo-fetal toxicity including death and teratogenicity at dosages of ≥ 1.2 mg/kg/day (0.06 times the MRHD based on BSA comparison). Teratogenic effects included undeveloped cerebrum, hemorrhagic fluid filling the lumina of the skull, cleft palate and generalized edema. Embryo-fetal toxicity was also observed in rabbits after oral administration of miltefosine during organogenesis (Day 6 to Day 18 of gestation) at doses ≥ 2.4 mg/kg/day (0.2 times the MRHD based on BSA comparison). In both rats and rabbits, there were no viable litters at miltefosine doses ≥ 6.0 mg/kg/day (0.3 or 0.6 times the MRHD based on BSA comparisons for rats and rabbits respectively).

In a separate female fertility study in rats, miltefosine doses ≥ 6.81 mg/kg/day (0.3 times the MRHD based on BSA comparison) administered for four weeks before mating and up to Day 7 of pregnancy produced numerous visceral (misshapen cerebral structures, dilated ventricles filled with brown masses, misshapen spinal cord, misshapen and malpositioned eyes, hypophysis, and absent inner ear) and skeletal (cleft palate, dumbbell-shaped ossification of thoracic vertebral centers, markedly enlarged skull bones, and markedly dilated suturae) fetal malformations.

Pharmacodynamics

Miltefosine has demonstrated activity against Leishmania parasites and neoplastic cells primarily due to its effects on apoptosis and disturbance of lipid-dependent cell signaling 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 signaling 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.

Pharmacokinetics

• Absorption 

Absolute bioavailability of miltefosine has not been determined. In patients with visceral leishmaniasis, maximum miltefosine concentrations following oral administration of miltefosine capsules were reached right before the next dose in many patients, indicating that the absorption of miltefosine may proceed throughout the dosing interval.

• Distribution

The distribution of miltefosine has not been studied in humans. Human plasma protein binding of miltefosine, evaluated by an ultracentrifugation method, was 98% over the drug concentration range from 0.1 to 10 µg/mL. In rats, radioactivity of [14C] miltefosine is widely distributed after both single and repeated oral administration with highest uptake of radioactivity in kidney, liver, and spleen. Placental transfer and excretion into milk have not been investigated.

• Metabolism and Excretion

No in vitro oxidative metabolism by 15 different human cytochrome P450 enzymes (1A1, 1A2, 1B1, 2A6, 2B6, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, 3A4, 3A5, 3A7, and 4A1) was observed.

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-Larsson syndrome, which is caused by a genetic defect in fatty aldehyde dehydrogenase activity. Miltefosine is contraindicated in patients who have Sjögren-Larsson-Syndrome.

There was little or no evidence of time or metabolism dependent inhibition of the cytochrome P450 enzymes examined at up to approximately 40 µg/mL miltefosine.

Oral administration of miltefosine did not markedly induce the content of hepatic CYP3A assayed by demethylation activity of erythromycin in rats.

In visceral leishmaniasis patients, <0.2% of the administered dose was excreted into the urine.

1. https://www.uptodate.com/contents/Miltefosine -drug-information?search=Miltefosine &source=panel_search_result&selectedTitle=1~148&usage_type=panel&kp_tab=drug_general&display_rank=1#F23890541
2. https://www.mims.com/india/drug/info/Miltefosine ?type=full
3. https://www.ncbi.nlm.nih.gov/books/NBK537225/
4. https://go.drugbank.com/drugs/DB00321
5. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/071297s030lbl.pdf