Metreleptin

Metreleptin is an Anti-obesity agent.

Metreleptin is used in the treatment of Lipodystrophy.

Metreleptin is not absorbed from the GI tract and gets excreted Via faeces as insoluble complex w/ bile acids.

The Tmax of Metreleptin was found to be about approximately 4 hours.

Metreleptin shows common side effects like Hypoglycemia, weight loss, headache, abdominal pain, nausea.

Metreleptin is available in Solution.

Metreleptin is available in India, Germany, Canada, France, USA.

Recombinant human leptin analog that binds to and activates the human leptin receptor (ObR) (which belongs to the class I cytokine family of receptors that signals through the JAK/STAT transduction pathway) to treat complications of leptin deficiency associated with generalized lipodystrophy.

Metreleptin is available in the form of Solution.

Metreleptin is used in the treatment of Lipodystrophy.

Adipocytes store lipids to meet the fuel requirements of non-adipose tissues during fasting. In patients with generalized lipodystrophy, the deficiency of adipose tissue leads to hypertriglyceridemia and ectopic deposition of fat in non-adipose tissues such as liver and muscle, contributing to metabolic abnormalities including insulin resistance. Native leptin is a hormone predominantly secreted by adipose tissue that informs the central nervous system of the status of energy stores in the body. In patients with generalized lipodystrophy, leptin deficiency, resulting from the loss of adipose tissue, contributes to excess caloric intake, which exacerbates the metabolic abnormalities.

Metreleptin is approved for use in the following clinical indications

• Lipodystrophy: Replacement therapy to treat the complications of leptin deficiency, in addition to diet, in patients with congenital or acquired generalized lipodystrophy.
• Limitations of use: Not indicated for use in patients with HIV-related lipodystrophy or for use in patients with metabolic disease (e.g., diabetes mellitus, hypertriglyceridemia) without concurrent evidence of congenital or acquired generalized lipodystrophy.

Lipodystrophy:

• Baseline weight ≤40 kg: Subcutaneous: Initial: 0.06 mg/kg once daily; adjust dose by 0.02 mg/kg daily based on response and tolerability (maximum: 0.13 mg/kg once daily).
• Baseline weight >40 kg: Subcutaneous : Initial: 2.5 mg (males) or 5 mg (females) once daily; adjust dose by 1.25 to 2.5 mg daily based on response and tolerability (maximum: 10 mg once daily).

• Discontinuation: If metreleptin is to be discontinued in a patient who also has risk factors for pancreatitis (eg, history of pancreatitis, severe hypertriglyceridemia), taper the dose over a 1-week period and monitor triglyceride levels; consider initiating or adjusting the dose of lipid-lowering medications as needed.

Metreleptin is available in the dosage strength of 11.3 mg per vial.

Metreleptin is available in the form of Solution.

Dosage Adjustment in Hepatic Impairment Patient

• Pre-existing hepatic impairment: There are no dosage adjustments provided in the manufacturer’s labeling; avoid use in patients with preexisting hepatic impairment. Contraindicated for use in the presence of known hepatocyte dysfunction or bile duct abnormalities.
• Hepatotoxicity during treatment:
• Aminotransferase level 1.5 to 3 times ULN persisting for >3 to 6 months: Temporarily withhold treatment; resume when aminotransferase levels return to normal.
• Aminotransferase level >3 times ULN: Discontinue treatment immediately.

Dosage Adjustment for Pediatric Patients:

• Lipodystrophy: Infants, Children, and Adolescents: The manufacturer’s labeling describes use in infants; however, in trials, the minimal inclusion age was 6 months and the youngest subjects reported in trials and case series were at least 1 year of age. Note: Increase or decrease dose based on clinical response (eg, inadequate metabolic control) or other considerations (eg, tolerability issues, excessive weight loss).
• Baseline weight ≤40 kg, male and female patients: Subcutaneous : Initial: 0.06 mg/kg/dose once daily; adjust the dose (increase or decrease) in 0.02 mg/kg increments based on response or adverse effects. Maximum daily dose: 0.13 mg/kg/day
• Baseline weight >40 kg:
• Female patients: Subcutaneous : Initial: 5 mg once daily, adjust the dose (increase or decrease) in 1.25 to 2.5 mg increments based on response or adverse effects; maximum daily dose: 10 mg/day
• Male patients: Subcutaneous : Initial: 2.5 mg once daily, adjust the dose (increase or decrease) in 1.25 to 2.5 mg increments based on response or adverse effects; maximum daily dose: 10 mg/day
• Discontinuation: When discontinuing therapy in patients with risk factors for pancreatitis (e.g, history of pancreatitis, severe hypertriglyceridemia), taper the dose over a 1-week period and monitor triglyceride levels; consider initiating or adjusting the dose of lipid-lowering medications as needed.

Take after eating and with a full glass of water to decrease gastric upset.

Metreleptin is contraindicated in patients with:

Hypersensitivity (e.g, anaphylaxis, urticaria, generalized rash) to metreleptin or any component of the formulation; general obesity (not associated with congenital leptin deficiency).

Concerns related to adverse effects:

• Antibody development: Antimetreleptin antibodies with neutralizing activity have been identified with metreleptin use. Consequences could include inhibition of endogenous leptin action and/or loss of metreleptin efficacy; severe infection and/or worsening of metabolic control have been reported. Test patients who develop severe infections or show signs of loss of metreleptin efficacy for anti-metreleptin antibodies with neutralizing activity. Contact the manufacturer (1-866-216-1526) for neutralizing antibody testing of clinical samples.

• Hypersensitivity reactions: Generalized hypersensitivity (e.g, urticaria, generalized rash) has been reported; instruct patients to promptly seek medical advice regarding discontinuation of metreleptin if hypersensitivity reaction occurs.

• Lymphomas: T-cell lymphoma has been reported in patients with acquired generalized lipodystrophy (both treated and not treated with metreleptin). Consider the benefits and risks of metreleptin treatment in patients with significant hematologic abnormalities and/or acquired generalized lipodystrophy. A causal relationship has not been established; acquired lipodystrophies are associated with autoimmune disorders, and autoimmune disorders are associated with increased risk of malignancy (including lymphoma).

Metreleptin may cause liver problems, and using it with substantial quantities of ethanol may increase that risk.

Metreleptin is used off label to enhance leflunomide elimination. Use of the enhanced elimination procedure is recommended in all females of reproductive potential upon discontinuation of leflunomide. Pregnancy should be avoided until undetectable serum concentrations (<0.02 mg/L) of leflunomide are verified.

• Common Adverse effects:

Hypoglycemia, Weight Loss, Antibody Development, Neutralizing, Anaphylaxis, Headache.

• Less Common Adverse Effects:

Weight Loss , Anaphylaxis, Hypersensitivity Reaction.

• Rare Adverse effects

Membranoproliferative glomerulonephritis, optic infection, Urticaria at the injection site.

No formal drug interaction studies were performed. Leptin is a cytokine and may have the potential to alter the formation of cytochrome P450 (CYP450) enzymes. This should be taken into account when prescribing concomitant drugs metabolized by CYP450 (e.g., oral contraceptives and drugs with a narrow therapeutic index). The effect of metreleptin on CYP450 enzymes may be clinically relevant for CYP450 substrates with a narrow therapeutic index, where the dose is individually adjusted. Upon initiation or discontinuation of Metreleptin, in patients being treated with these types of agents, therapeutic monitoring of effect (e.g., warfarin) or drug concentration (e.g., cyclosporine or theophylline) should be performed and the individual dose of the agent adjusted as needed.

The common side effects of Metreleptin include the following:

Diarrhea, Hepatotoxicity, Colon Cancer, Gallstone Recurrence.

• Pharmacodynamic

Cholesterol is probably the sole precursor of bile acids. During normal digestion, bile acids are secreted into the intestines. A major portion of the bile acids is absorbed from the intestinal tract and returned to the liver via the enterohepatic circulation. Only very small amounts of bile acids are found in normal serum. Metreleptin resin adsorbs and combines with the bile acids in the intestine to form an insoluble complex which is excreted in the feces. This results in a partial removal of bile acids from the enterohepatic circulation by preventing their absorption.

• Pharmacokinetics

Absorption: Peak serum leptin concentration (Cmax) occurred approximately 4.0 to 4.3 hours after subcutaneous administration of single doses ranging from 0.1 to 0.3 mg/kg in healthy subjects. In a supportive trial in lipodystrophy patients, the median Tmax of metreleptin was 4 hours (range: 2 to 8 hours; N=5) following single-dose administration of metreleptin

Distribution: In studies of healthy adult subjects, following intravenous administration of metreleptin, leptin volume of distribution was approximately 4 to 5 times plasma volume; volumes (Vz) (mean ± SD) were 370 ± 184 mL/kg, 398 ± 92 mL/kg, and 463 ± 116 mL/kg for 0.3, 1.0, and 3.0 mg/kg/day doses, respectively.

Metabolism: No formal metabolism studies have been conducted with metreleptin. Nonclinical data indicate renal clearance is the major route of metreleptin elimination, with no apparent contribution of systemic metabolism or degradation.

Excretion: Nonclinical data indicate renal clearance is the major route of metreleptin elimination, with no apparent contribution of systemic metabolism or degradation.

1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1364710/
2. https://reference.medscape.com/drug/colestid-Metreleptin -342452
3. https://go.drugbank.com/drugs/DB00375
4. https://www.sciencedirect.com/topics/medicine-and-dentistry/Metreleptin
5. https://europepmc.org/article/med/6988203