"The U.S. Food and Drug Administration today approved Impavido (miltefosine) to treat a tropical disease called leishmaniasis.
Leishmaniasis is a disease caused by Leishmania, a parasite which is transmitted to humans through sand fly bites."...
Mechanism Of Action
Miltefosine is an anti-leishmanial agent.
The pharmacokinetic parameters of miltefosine in patients with visceral and cutaneous leishmaniasis treated for 28 days with IMPAVIDO are listed in Table 5. Due to the long half-life of miltefosine ( > 6 days), trough plasma concentrations did not appear to reach a steady state at the end of treatment (i.e., Day 28).
Table 5: Mean (%CV) Pharmacokinetic Parameters for
Miltefosine Following Oral Capsule Administration to Adult Patients with
Visceral and Cutaneous Leishmaniasis
|Dose||Cmax (μg/mL)||Tmaxd (hr)||AUC taue
|Visceral Leishmaniasis (on Day 23)||50 mg BID (4 wks)a||66.2 (28.5)||7(2-12)||636 (26.7)||6.4 (31.1)|
|50 mg BID (1 wk)/ 50 mg TID (3 wks)b||75.9 (17.6)||4 (2-8)||486 (18.1)||8.5 (28.9)|
|Cutaneous Leishmaniasisc (on Day 27)||50 mg TID (4 wks)||37.3 (22)f||295 (22)f||6.8 (5.8)g,h||30.7 (18.3)g,h|
|a Adolescent ( ≥ 12 years)/Adults, mean
dose per kg was 3.1 mg/kg/day
b Adolescent ( ≥ 12 years)/Adults, mean dose per kg was 3.6 mg/kg/day
c Adults, mean dose per kg was 1.8 mg/kg/day
d median (range)
e AUC0-12h for BID, AUC0-8h for TID
f t½,α = distribution phase half-life; t1/2,β = terminal elimination phase half-life
g Estimates based on a population PK model
h mean (% standard error)
Absolute bioavailability of miltefosine has not been determined. In patients with visceral leishmaniasis, maximum miltefosine concentrations following oral administration of IMPAVIDO 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.
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 alcoholcontaining 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. IMPAVIDO is contraindicated in patients who have Sjögren-Larsson-Syndrome [see CONTRAINDICATIONS].
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.
Mechanism of Action
The specific mode of action of miltefosine against Leishmania species is unknown. The mechanism of action of miltefosine is likely to involve interaction with lipids (phospholipids and sterols), including membrane lipids, inhibition of cytochrome c oxidase (mitochondrial function), and apoptosis-like cell death.
Activity In Vitro and In Vivo
Miltefosine has anti-leishmanial activity in vitro and in clinical infections [see Clinical Studies]. Sensitivity of different Leishmania species as well as different strains of a Leishmania species to miltefosine may vary in different geographic regions.
In vitro studies show a potential for development of resistance to miltefosine. Some strains of L. braziliensis with intrinsic resistance to miltefosine have been identified. However, the clinical relevance of these observations is not known.
Drug resistance could be due to a decrease in miltefosine accumulation within Leishmania parasite which is thought to be due to either an increase in drug efflux, mediated by the overexpression of the ABC transporter P-glycoprotein and/or a decrease in drug uptake by the inactivation of the miltefosine transport machinery that consists of the miltefosine transporter and its beta subunit. Mutation in the transporter gene was reported in the isolates from a relapsed patient in one study. However, the clinical relevance of these findings is not known.
Animal Toxicology And/Or Pharmacology
Toxicological studies with miltefosine have been performed in mice, rats, dogs, and rabbits. Adverse reactions not observed in clinical studies but seen in animals at exposure levels similar to clinical exposure levels and with possible relevance to clinical use were as follows:
Acute and chronic toxicity: The oral administration of miltefosine in rats was associated with lesions affecting the eyes (retinal degeneration). Retinal degeneration was observed after 8- weeks treatment at doses of 10 mg/kg/day (0.5 times the MRHD based on BSA comparison). Juvenile rats were more sensitive to the miltefosine-induced effects, especially on eyes and kidneys, than adult rats with retinal degeneration occurring at doses ≥ 2.15 mg/kg/day (0.1 times the MRHD based on BSA comparison), and reversible damage to proximal tubule epithelium occurring at doses ≥ 4.64 mg/kg/day (0.2 times the MRHD based on BSA comparison).
Treatment Of Visceral Leishmaniasis
One randomized, open-label, active-controlled study was conducted to evaluate the efficacy of IMPAVIDO in the treatment of visceral leishmaniasis in Bihar, India, an area where L. donovani is known epidemiologically to be the prevalent infecting species. Patients ≥ 12 years of age with clinical signs and symptoms compatible with visceral leishmaniasis (fever, splenomegaly, and cytopenia) confirmed by the presence of Leishmania amastigotes in aspirates of spleen or bone marrow were randomized to receive oral IMPAVIDO or intravenous amphotericin B deoxycholate in a 3:1 ratio. Patients weighing ≥ 25 kg received an IMPAVIDO 50 mg capsule with meals twice a day. Patients weighing < 25 kg received an IMPAVIDO 50 mg capsule with meals once a day in the morning. Weight ranged between 15 and 67 kg (mean weight 38.6 kg) and BMI ranged between 8.2 and 24 (mean 16.1). No patient weighed more than 70kg. Amphotericin B was administered intravenously over 6 continuous hours at 1 mg/kg every other day for 15 doses. Patients were hospitalized for the duration of therapy.
Exclusion criteria included platelet count < 50 × 109/L, white cell count < 1 × 109/L, hemoglobin < 6 g/100 mL, AST or ALT ≥ 3 times upper limit of the normal range, bilirubin ≥ 2 times upper limit of the normal range, serum creatinine or BUN > 1.5 times upper limit of the normal range, prothrombin time > 5 seconds above control, and any non-compensated or uncontrolled condition including human immunodeficiency virus (HIV) infection. Women of reproductive potential were required to use effective contraception for the duration of therapy and for 2 months post therapy.
Final cure was defined as initial cure at end of therapy plus absence of signs and symptoms of visceral leishmaniasis at 6 months follow up. Initial cure at the end of therapy was evaluated by repeat spleen or bone marrow aspiration. Patients with initial parasitologic cure were followed for 6 months; patients without absence of clinical signs and symptoms of visceral leishmaniasis were to be evaluated with repeat spleen or bone marrow aspiration to determine final cure.
Two hundred and ninety nine (299) patients received IMPAVIDO and 99 patients received amphotericin B. Approximately, 70% of patients in each arm had previously failed treatment with pentavalent antimony. Initial cure was achieved in 98% of patients in each treatment arm. At 6 months after therapy, 88 (29.5%) IMPAVIDO recipients and 12 (12.1%) amphotericin B recipients continued to have signs and symptoms suggestive of visceral leishmaniasis. These signs or symptoms were attributed to alternative diagnosis in 73 patients. The remaining 27 patients, all in the IMPAVIDO arm, underwent evaluation with splenic or bone marrow aspiration, and 9 (3.0%) were positive for Leishmania amastigotes, indicating relapse. The final cure rates for IMPAVIDO and amphotericin B were 94% and 97%, respectively.
Table 6: Efficacy of IMPAVIDO in Visceral
Leishmaniasis in Patients ≥ 12 years of Age in India
N = 299
|Amphotericin B Deoxycholate
N = 99
|End of therapy|
|Initial Cure||293 (98%)||97 (98%)|
|6 months after therapy|
|Final Cure*||282 (94%)||96 (97%)|
|Treatment Failure||9 (3%)||0 (0)|
|Not Assessable||8 (3%)||3 (3%)|
|* The 95% exact confidence interval for the difference (IV Amphotericin B – IMPAVIDO) in final cure is (-3.0%, 6.8%).|
Treatment Of Cutaneous Leishmaniasis
A placebo controlled study was performed in Colombia where L. panamensis and L. braziliensis are epidemiologically known to be the prevalent infecting Leishmania species, and in Guatemala where L. braziliensis is epidemiologically known to be the prevalent infecting species. The study included male and female patients older than 12 years of age who had newly diagnosed or relapsing cutaneous leishmaniasis without mucosal involvement, parasitologically confirmed, presenting with at least one skin ulcer with minimum area of 50 mm². Exclusion criteria were AST or ALT ≥ 2 times upper limit of normal range, bilirubin ≥ 1.5 times upper limit of normal range, and serum creatinine or BUN > 1.5 times upper limit of normal range. Women of reproductive potential were required to use effective contraception for the duration of therapy and for 2 months post therapy.
Patients were randomized to receive IMPAVIDO or placebo in a 2:1 allocation. Patients who weighed < 45 kg received IMPAVIDO 50 mg capsule twice a day, and patients who weighed ≥ 45 kg received IMPAVIDO 50 mg capsule three times a day. No patient weighed more than 84 kg. Definite cure was defined as apparent (complete epithelialization of all lesions) or partial cure (incomplete epithelialization, no enlargement by > 50% in lesions, no appearance of new lesions, and negative parasitology if done) at 2 weeks after end of therapy and complete epithelialization of all ulcers at 6 months after end of therapy. The definite cure rate for IMPAVIDO was statistically significantly higher than the cure rate for placebo.
Table 7: Efficacy of IMPAVIDO Compared to Placebo in
the Treatment of Cutaneous Leishmaniasis in Colombia and Guatemala
|Definite Cure*||59/89 (66%)||13/44 (30%)|
|Colombia||40/49 (82%)||9/24 (38%)|
|Guatemala||19/40 (48%)||4/20 (20%)|
|* The difference (95% CI) between groups is 36.8% (20.1%, 53.4%) with P-value < 0.0001.|
An additional study of IMPAVIDO was conducted in Bahia and Manaus, two regions in Brazil where respectively L. braziliensis and L. guyanensis are epidemiologically the prevalent infecting pathogens. Adolescent/adult patients aged 12-65 years received IMPAVIDO orally for 28 days. IMPAVIDO target dose was 2.5 mg/kg/day: patients weighing 15-29 kg received 50 mg once daily, patients weighing 30-45 kg received 50 twice mg daily and patients weighing > 46 kg received 50 mg three times daily. The efficacy criteria were initial cure (complete reepithelialization of the ulcer at 2 months after the end of therapy) followed by definite cure (complete re-epithelialization at 6 months after the end of therapy). Definite cure rate in patients aged ≥ 12 years was 27/40 (67.5%) for Manaus, Brazil and 34/40 (85%) for Bahia, Brazil.
Treatment Of Mucosal Leishmaniasis
A single arm study was conducted to evaluate the efficacy of IMPAVIDO capsules for the treatment of mucosal leishmaniasis. The study was conducted in Bolivia where L. braziliensis is epidemiologically the prevalent species.
Seventy nine (79) patients ≥ 18 years of age with a cutaneous leishmaniasis scar plus parasites observed or cultured from lesion material or a positive skin test, and no clinically significant concomitant disease received miltefosine at a target dose of 2.5 mg/kg/day for 28 days. By 12 months after the end of therapy, 49 of the patients (62%) had complete resolution of edema, erythema, infiltration and erosion from the involved mucosal sites.
Last reviewed on RxList: 3/31/2014
This monograph has been modified to include the generic and brand name in many instances.
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