Ambrisentan

Ambrisentan is a nonsulfonamide belonging to the Endothelin receptor antagonists.

Ambrisentan is used in the treatment of Pulmonary arterial hypertension.

Ambrisentan is absorbed rapidly from the GI tract. The Plasma protein binding is 99%, mainly to albumin and to a lesser extent to α₁-acid glycoprotein, and gets metabolized via glucuronidation by several uridine diphosphate glucuronosyltransferase (UGT) isoenzymes to ambrisentan glucuronide and via oxidation, mainly by CYP3A4 and to a lesser extent by CYP3A5 and CYP2C19, to form 4-hydroxymethyl Ambrisentan. It mainly gets excreted via bile; urine (22%, 3.3% as unchanged drug).

The Duration of Action of Ambrisentan was longer than 6 hours.

The Tmax of Ambrisentan was approx 2 hr, and Cmax was about 0.2 – 20 microgram/mL.

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

Ambrisentan is available in dosage forms, such as tablets.

Ambrisentan is available in Europe, Japan, China, USA, and India.

Ambrisentan, an endothelin antagonist, is selective on endothelin type A (ETA) receptors. Endothelin is a potent vasoconstrictor that plays a pathogenic role in pulmonary arterial hypertension (PAH). Blockade of the endothelin receptor leads to vasodilation and inhibition of smooth muscle proliferation.

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

Ambrisentan tablets were taken orally with or without food.

Ambrisentan works by blocking endothelin, a substance made by the body. Endothelin causes blood vessels to narrow (constrict). It also causes abnormal growth of the muscle in the walls of the blood vessels in the lungs. This narrowing increases the pressure required to push the blood through the lungs to get oxygen. By blocking the action of endothelin, causing vessels to relax, Ambrisentan decreases the pulmonary blood pressure to the heart and improves its function.

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

Pulmonary arterial hypertension: Treatment of pulmonary artery hypertension (PAH) (World Health Organization [WHO] Group I) to improve exercise ability and delay clinical worsening; in combination with tadalafil to reduce the risks of disease progression and hospitalization for worsening PAH, and to improve exercise ability. Studies establishing effectiveness included predominantly patients with WHO Functional Class II to III symptoms and etiologies of idiopathic or heritable PAH (60%) or PAH associated with connective tissue diseases (34%).

Ambrisentan is available in various dosage strengths: 5 mg, 10 mg

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

• Dose Adjustment in Kidney Patients:

Mild-to-moderate impairment: No dosage adjustment necessary.

Severe impairment: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

• Dose Adjustment in Hepatic Impairment Patient

Preexisting impairment:

Mild impairment: There are no dosage adjustments provided in the manufacturer’s labeling; exposure may be increased.

Moderate or severe impairment: Use not recommended.

Impairment developing during therapy:

● ALT or AST >5 times ULN: Discontinue therapy.

● ALT or AST increased with signs/symptoms of hepatic injury or with bilirubin >2 times ULN: Discontinue therapy.

● ALT or AST >3 times ULN: Discontinue therapy.

● ALT or AST increased with signs/symptoms of hepatic injury or with bilirubin >2 times ULN: Discontinue therapy.

● May consider reinitiation after ALT or AST levels normalize and if there are no signs/symptoms of hepatic injury or jaundice

• Dose Adjustment in Pediatric Patients.

Ambrisentan is not recommended to Pediatric Patient.

Ambrisentan 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.

Ambrisentan may be contraindicated in the following:

Pregnancy; idiopathic pulmonary fibrosis, including idiopathic pulmonary fibrosis with pulmonary hypertension (WHO Group 3)

Hypersensitivity to Ambrisentan or any component of the formulation; severe hepatic impairment (with or without cirrhosis); ALT or AST >3 times ULN at baseline; breastfeeding

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; a higher incidence is seen with concomitant use of tadalafil and in elderly patients. There have also been postmarketing reports of fluid retention requiring treatment (eg, diuretics, fluid management, hospitalization). Further evaluation may be necessary to determine the cause and appropriate treatment or discontinuation of therapy.

• Hematologic changes: A reduction in hematocrit/hemoglobin may be observed within the first few weeks of therapy with subsequent stabilization of levels. Hemoglobin reductions >15% have been observed in some patients. Measure hemoglobin prior to initiating therapy, at 1 month, and periodically thereafter. Significant decreases in hemoglobin in the absence of other causes may warrant the discontinuation of therapy. Use not recommended in patients with clinically significant anemia.

• Hepatic effects: Increases in serum liver aminotransferases have been reported during postmarketing use; however, in the majority of the cases, alternative causes of hepatotoxicity could be identified. Perform liver enzyme testing when clinically indicated. Discontinue therapy if signs/symptoms of hepatic injury appear, if serum liver aminotransferases >5 times ULN (US labeling) or >3 times ULN (Canadian labeling) are observed, or if aminotransferases are increased in the presence of bilirubin >2 times ULN. Hepatotoxicity has been reported with other endothelin receptor antagonists (eg, bosentan); however, Ambrisentan may be tried in patients that have experienced asymptomatic increases in liver enzymes caused by another endothelin receptor antagonist after the liver enzymes have returned to normal.

Disease-related concerns:

• Hepatic impairment: Use caution in patients with mild hepatic impairment; ambrisentan exposure may be increased. The US labeling does not recommend use in patients with moderate or severe impairment. The Canadian labeling recommends use with caution in moderate impairment with monthly monitoring of ALT/AST during therapy and contraindicates use in severe hepatic impairment (with or without cirrhosis) and in patients with ALT or AST >3 times ULN at baseline.

• Pulmonary veno-occlusive disease (PVOD): Discontinue in any patient with pulmonary edema suggestive of PVOD.

Pregnancy Category X

Risk Summary

Ambrisentan may cause fetal harm when administered to a pregnant woman and is contraindicated during pregnancy. Ambrisentan was teratogenic in rats and rabbits at doses which resulted in exposures of 3.5 and 1.7 times, respectively, the human dose of 10 mg per day. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, advise the patient of the potential hazard to a fetus

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

The adverse reactions related to molecule Ambrisentan can be categorized as

• Common Adverse effects: Headache (usually transitory), flushing, dizziness, nausea, vomiting and weakness
• Less Common adverse effects: Hematocrit, fluid retention, peripheral edema, acute pulmonary edema, decreased sperm count.
• Rare Adverse effects: Dyspnea, nasopharyngitis, nasal congestion, epistaxis, sinusitis, rhinitis.

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

• Cyclosporine (Systemic): May increase the serum concentration of Ambrisentan. Management: Limit ambrisentan dose to 5 mg daily and monitor for ambrisentan adverse reactions in patients receiving cyclosporine. Risk D: Consider therapy modification

• Darolutamide: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapy
• Eltrombopag: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapy
• Encorafenib: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapy
• Gemfibrozil: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapy
• Leflunomide: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapy
• Teriflunomide: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapy
• Voclosporin: May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapy

Symptoms: Headache, dizziness, flushing, nausea, nasal congestion, and potential hypotension.

Management: In case of hypotension, give active CV support.

Pharmacodynamics:

Ambrisentan increased mean QTc at tmax by 5 ms with an upper 95% confidence limit of 9 ms. Significant QTc prolongation is not expected in patients taking Ambrisentan without concomitant metabolic inhibitors. Plasma concentrations of B-type natriuretic peptide (BNP) in patients who received Ambrisentan for 12 weeks were significantly decreased. Two Phase III placebo-controlled studies demonstrated a decrease in BNP plasma concentrations by 29% in the 2.5 mg group, 30% in the 5 mg group, and 45% in the 10 mg group (p < 0.001 for each dose group) and an increase by 11% in the placebo group.

Pharmacokinetics:

• Absorption: Absorbed rapidly from the GI tract. Time to peak plasma concentration: Approx 2 hr.
• Distribution: Plasma protein binding: 99%, mainly to albumin and to a lesser extent to α₁-acid glycoprotein.
• Metabolism: Metabolised via glucuronidation by several uridine diphosphate glucuronosyltransferase (UGT) isoenzymes to ambrisentan glucuronide and via oxidation, mainly by CYP3A4 and to a lesser extent by CYP3A5 and CYP2C19, to form 4-hydroxymethyl Ambrisentan.
• Excretion: Mainly via bile; urine (22%, 3.3% as unchanged drug). Terminal elimination half-life: Approx 15 hr.

1. https://go.drugbank.com/drugs/DB09235
2. https://www.uptodate.com/contents/ambrisentan-drug-information?search=Ambrisentan&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/Ambrisentan #section=MeSH-Pharmacological-Classification
4. https://www.medplusmart.com/product/efnocar-40mg-tab_efno0001