Bosentan

Bosentan is a nonsulfonamide belonging to the Endothelin receptor antagonists

Bosentan is used in the treatment of Pulmonary arterial hypertension. It is also used to treat Digital ulcers in systemic sclerosis; Raynaud phenomenon in systemic sclerosis

Bosentan is absorbed from the gastrointestinal tract with a bioavailability of approx 50%.

The Volume of distribution was approx 18 L with plasma protein binding: >98%, mainly to albumin. Bosentan is metabolized in the liver by CYP2C9 and CYP3A4

and get excreted Via feces (as metabolites); urine (<3% as unchanged drug).

The Duration of Action of Bosentan was about 5 hours.

The Tmax of Bosentan was 3-5 hours, and Cmax was about 1317 ng/ mL

The common side effects are dizziness, drowsiness, headache, weakness, Nausea, strong irregular heartbeat, swelling, and dizziness upon standing.

Bosentan is available in dosage forms, such as tablets.

Bosentan is available in Europe, Japan, Australia, the USA, and India.

Bosentan, an endothelin receptor antagonist, improves exercise capacity and hemodynamic in patients with pulmonary arterial hypertension (PAH) by blocking endothelin-1 (ET-1) receptors, ETA, and ETB (with a slightly higher affinity for subtype A) on vascular endothelium and smooth muscle, thus promoting vasodilation.

Bosentan is available in the form of dosage forms, such as tablets.

Bosentan tablets were taken orally with or without food.

Bosentan is used in the treatment of Pulmonary arterial hypertension. It is also used to treat Digital ulcers in systemic sclerosis; Raynaud phenomenon in systemic sclerosis

Bosentan belongs to a class of drugs known as endothelin receptor antagonists (ERAs). Patients with PAH have elevated levels of endothelin, a potent blood vessel constrictor, in their plasma and lung tissue. Bosentan blocks the binding of endothelin to its receptors, thereby negating endothelin's deleterious effects.

Bosentan is approved for its use in the following clinical indications:-

Pulmonary arterial hypertension: Treatment of pulmonary artery hypertension (PAH) (WHO Group I) in adults with WHO-FC II, III, or IV symptoms to improve exercise ability and to decrease clinical deterioration; treatment of PAH (WHO Group 1) in pediatric patients ≥3 years with idiopathic or congenital PAH to improve pulmonary vascular resistance (PVR), resulting in an improvement in exercise ability.

Although not approved there have been certain off label use documented for Bosetan which includes:-

Digital ulcers in systemic sclerosis; Raynaud phenomenon in systemic sclerosis

Bosentan is available in various dosage strengths: 62.5 mg, 125 mg, 32 mg

Bosentan is available in the form of a dosage form, such as tablets

• Dose Adjustment in Kidney Patients:

No dosage adjustment is necessary. Bosentan is unlikely to be removed by dialysis (due to high molecular weight and extensive plasma protein binding).

• Dose Adjustment in Hepatic Impairment Patient

Hepatic impairment at treatment initiation:

• Mild impairment (Child-Pugh class A): No dosage adjustment necessary.
• Moderate to severe impairment (Child-Pugh class B and C) and/or baseline transaminase >3 times ULN: Avoid use; systemic exposure is significantly increased in patients with moderate impairment (has not been studied in severe impairment).
• Hepatotoxicity during treatment: Modification based on transaminase elevation:
• Transaminase elevations accompanied by clinical symptoms of hepatotoxicity (unusual fatigue, nausea, vomiting, abdominal pain, fever, or jaundice) or a serum bilirubin ≥2 times ULN: Discontinue treatment.
• AST/ALT >3 times but ≤5 times ULN: >40 kg: Confirm with additional test; if confirmed, reduce dose to 62.5 mg twice daily or interrupt treatment and monitor at least every 2 weeks. If transaminase levels return to pretreatment values, may continue or reintroduce treatment (at the starting dose), as appropriate. When reintroducing treatment, recheck transaminases within 3 days and at least every 2 weeks thereafter.
• AST/ALT >5 times but ≤8 times ULN: >40 kg: Confirm with additional test; if confirmed, stop treatment. Monitor transaminase levels at least every 2 weeks. If transaminase levels return to pretreatment values, may reintroduce treatment (at the starting dose) as appropriate. When reintroducing treatment, recheck transaminases within 3 days and at least every 2 weeks thereafter.
• AST/ALT >8 times ULN: Stop treatment and do not reintroduce

• Dose Adjustment in Pediatric Patients.

Pulmonary arterial hypertension:

Note: Doses >125 mg twice daily do not provide additional benefit sufficient to offset the increased risk of hepatic injury.

• Infants and Children <12 years: Oral: Initial: 1 mg/kg/dose twice daily; increase to a target dose of 2 mg/kg/dose twice daily; maximum dose: 125 mg/dose (AHA/ATS).
• Children ≥12 years and Adolescents (AHA/ATS): Oral:
• >20 to 40 kg: Initial: 31.25 mg twice daily; increase to a target dose of 62.5 mg twice daily.
• >40 kg: Initial: 62.5 mg twice daily; increase to a target dose of 125 mg twice daily.

Children ≥3 years:

• 4 to 8 kg: Oral: 16 mg twice daily.
• >8 to 16 kg: Oral: 32 mg twice daily.
• >16 to 24 kg: Oral: 48 mg twice daily.
• >24 to 40 kg: Oral: 64 mg twice daily.

Adolescents:

• ≤40 kg: Oral: 62.5 mg twice daily.
• >40 kg: Oral: Initial: 62.5 mg twice daily for 4 weeks; increase to target dose of 125 mg twice daily

Bosentan is approved for the treatment of Pulmonary Arterial Hypertension.

Heart-healthy foods include low-fat milk or yogurt, colorful fruits and vegetables, beans, whole-grain breads and nuts. These foods are important in people with PAH whose hearts are already working hard.Limiting salt and fluid is also important.

Bosentan may be contraindicated in the following.

Women of childbearing potential who are not using reliable methods of contraception. Moderate to severe hepatic impairment (Child-Pugh class B or C). Pregnancy. Concomitant use with ciclosporin and glibenclamide.

Concerns related to adverse effects:

• Fluid retention/peripheral edema:

Development of peripheral edema due to treatment and/or disease state (pulmonary arterial hypertension) may occur. There have also been postmarketing reports of fluid retention requiring treatment (eg, diuretics, fluid management, hospitalization) for heart failure. If clinically significant fluid retention develops (with or without weight gain), further evaluation is necessary to determine the cause and appropriate treatment or discontinuation of therapy. Use with caution in patients with underlying heart failure due to potential complications from fluid retention. In a scientific statement from the American Heart Association, bosentan has been determined to be an agent that may exacerbate underlying myocardial dysfunction (magnitude: major) (AHA).

· Hematologic effects:

Dose-related decreases in hematocrit/hemoglobin may be observed, usually within the first few weeks of therapy with subsequent stabilization of levels by 4 to 12 weeks of treatment. Monitor hemoglobin prior to treatment initiation, after 1 and 3 months, and every 3 months thereafter. Significant decreases in hemoglobin require further evaluation to determine the cause and specific management.

· Hepatotoxicity:

Bosentan is associated with transaminase elevations (ALT or AST ≥3 times ULN), and in a small number of cases may occur with elevations in bilirubin. Monitor transaminases at baseline and then monthly thereafter. Adjust dosage if elevations in liver enzymes occur without symptoms of hepatic injury or elevated bilirubin. In the postmarketing surveillance (with close monitoring), there have been rare cases of unexplained hepatic cirrhosis after prolonged therapy (>12 months) in patients with multiple comorbidities and drug therapies. There have also been cases of hepatic failure. Treatment should be stopped in patients who develop elevated transaminases either in combination with symptoms of hepatic injury (unusual fatigue, jaundice, nausea, vomiting, abdominal pain, and/or fever) or elevated bilirubin (≥2 times ULN); safety of reintroduction is unknown. Avoid use in patients with baseline serum transaminases >3 times ULN at baseline (monitoring for hepatotoxicity may be more difficult) or moderate to severe hepatic impairment. The combination of hepatocellular injury (transaminase elevations >3 times ULN) and bilirubin increased ≥2 times ULN are a marker for potential serious hepatotoxicity. Transaminase elevations are dose dependent, generally asymptomatic, occur both early and late in therapy, progress slowly, and are usually reversible after treatment interruption or discontinuation. Transaminase elevations may also spontaneously reverse while continuing bosentan treatment. Consider the benefits of treatment versus the risk of hepatotoxicity when initiating therapy in patients with WHO Class II symptoms.

• Hypersensitivity: Hypersensitivity reactions, including Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), anaphylaxis, rash and angioedema have been observed.

• Pulmonary veno-occlusive disease: If signs of pulmonary edema occur, consider the possibility of pulmonary venous-occlusive disease; may require discontinuation of bosentan.

Pregnancy Category X

Risk Summary

Bosentan may cause fetal harm when administered to a pregnant woman and is contraindicated during pregnancy.

Salt Substitutes: Those who are taking Bosentan should avoid sodium, calcium, and magnesium-rich foods. The salts may reduce the blood-pressure-lowering effect of Bosentan.

The adverse reactions related to molecule Bosentan can be categorized as

• Common Adverse effects: Fluid retention, peripheral oedema, decreased haematocrit/Hb (dose-related), elevated transaminase (ALT or AST ≥3 times ULN), hypersensitivity reactions (e.g. anaphylaxis, angioedema, rash, drug reaction with eosinophilia and systemic symptoms)
• Less Common adverse effects: Autoimmune hepatitis (e.g. exacerbation of underlying autoimmune hepatitis, hepatic injury, hepatic enzyme elevations), reduced Hb and haematocrit, fluid retention, peripheral oedema, acute pulmonary oedema, decreased sperm count.
• Rare Adverse effects: unexplained liver cirrhosis in patients with multiple comorbidities and drug therapies (prolonged use); liver failure.

The clinically relevant drug interactions of Bosentan are briefly summarized here.

May increase plasma concentration with CYP2C9 inhibitors (e.g. fluconazole, amiodarone), CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, ritonavir, erythromycin, diltiazem), tacrolimus and sirolimus. May decrease plasma concentration of hormonal contraceptives, warfarin, simvastatin, tadalafil and sildenafil. Decreased plasma concentration with rifampicin.

Potentially Fatal: Increased plasma concentration with ciclosporin. Enhanced hepatotoxic effect with glibenclamide.

Symptoms: Nausea, vomiting, dizziness, headache, sweating, blurred vision, hypotension.

Management: Supportive treatment (e.g. blood pressure support).

Pharmacodynamics:

Bosentan blocks the binding of endothelin to its receptors, thereby negating endothelin's deleterious effects.Endothelin-1 (ET-1) is a neurohormone, the effects of which are mediated by binding to ETA and ETB receptors in the endothelium and vascular smooth muscle. It displays a slightly higher affinity towards ETA receptors than ETB receptors. ET-1 concentrations are elevated in plasma and lung tissue of patients with pulmonary arterial hypertension, suggesting a pathogenic role for ET-1 in this disease. Bosentan is a specific and competitive antagonist at endothelin receptor types ETA and ETB.

Pharmacokinetics:

• Absorption: Absorbed from the gastrointestinal tract. Bioavailability: Approx 50%. Time to peak plasma concentration: 3-5 hours.
• Distribution: Volume of distribution: Approx 18 L. Plasma protein binding: >98%, mainly to albumin.
• Metabolism: Metabolised in the liver by CYP2C9 and CYP3A4.
• Excretion: Via faeces (as metabolites); urine (<3% as unchanged drug). Elimination half-life: Approx 5 hours.

1. https://go.drugbank.com/drugs/DB09235
2. https://www.uptodate.com/contents/Bosentan-drug-information?search=Bosentan &source=search_result&selectedTitle=1~20&usage_type=panel&kp_tab=drug_general&display_rank=1#F5032875
3. https://pubchem.ncbi.nlm.nih.gov/compound/Bosentan #section=MeSH-Pharmacological-Classification
4. https://www.medplusmart.com/product/efnocar-40mg-tab_efno0001