Ambrisentan is used for the treatment of Pulmonary Arterial Hypertension (PAH) (WHO Group 1) to improve exercise capacity and slow down disease progression.

Endothelin-1 (ET-1) is a powerful autocrine and paracrine peptide. It acts through two receptor subtypes, ETA and ETB, which are found in vascular smooth muscle and endothelium. Activation of ETA receptors mainly causes vasoconstriction and cell proliferation, whereas ETB receptors are responsible for vasodilation, antiproliferative effects, and clearance of ET-1. Ambrisentan is a highly selective ETA receptor antagonist with over 4000-fold selectivity for ETA compared to ETB receptors. However, the clinical significance of this high selectivity is not fully established.

The pharmacokinetics of Ambrisentan (S-Ambrisentan) are dose-proportional in healthy individuals. Its absolute bioavailability is not clearly known. After oral administration, peak plasma concentrations are reached within approximately 2 hours in both healthy subjects and PAH patients. Food does not significantly affect its absorption. In vitro studies show that Ambrisentan is a substrate of P-glycoprotein (P-gp). It is highly bound to plasma proteins (about 99%). The drug is mainly eliminated through non-renal pathways, although the exact roles of metabolism and biliary excretion are not fully defined. In plasma, the metabolite 4-hydroxymethyl Ambrisentan contributes about 4% of the total drug exposure compared to the parent compound. Conversion of S-Ambrisentan to R-Ambrisentan in vivo is minimal. The average oral clearance is approximately 38 mL/min in healthy individuals and 19 mL/min in PAH patients. Although the terminal half-life is around 15 hours, the effective half-life is about 9 hours, with steady-state trough levels reaching approximately 15% of peak concentrations and minimal accumulation during long-term use.

Adult dose: Initial treatment is 5 mg once daily, and can be increased to 10 mg once daily if 5 mg is tolerated. Ambrisentan may be administered with or without food.

Pediatric patients: The safety and effectiveness of Ambrisentan in pediatric patients have not been established.

Co-administration of multiple doses of Ambrisentan with Cyclosporine leads to approximately a two-fold increase in Ambrisentan exposure in healthy individuals. Therefore, when used together with Cyclosporine, the dose of Ambrisentan should be limited to 5 mg once daily.

Ambrisentan can cause serious harm to the fetus if used during pregnancy. It is contraindicated in women who are pregnant or may become pregnant. If pregnancy occurs during treatment, the patient must be informed about the potential risk to the fetus. Pregnancy should be ruled out before starting therapy and must be avoided during treatment and for one month after discontinuation. Ambrisentan is also contraindicated in patients with Idiopathic Pulmonary Fibrosis (IPF), including those with associated pulmonary hypertension (WHO Group 3).

Reduction in hemoglobin levels and hematocrit has been observed with endothelin receptor antagonists, including Ambrisentan, during clinical studies.

Pregnancy Category X. It is unknown whether Ambrisentan passes into human breast milk. Breastfeeding is not recommended during treatment with this medication.

Fluid Retention: Peripheral edema is a known effect of endothelin receptor antagonists and may also result from or worsen PAH.

Pulmonary Veno-occlusive Disease: If acute pulmonary edema develops after starting vasodilator therapy like Ambrisentan, pulmonary veno-occlusive disease should be suspected and, if confirmed, treatment must be discontinued.

Hematological Changes: Decreases in hemoglobin and hematocrit have been reported with Ambrisentan use.

Hepatic Impairment: Use of Ambrisentan is not recommended in patients with moderate to severe liver impairment.

Anti-hypertensive, Endothelin receptor antagonist

Store in a cool and dry place below 30°C. Protect from light and moisture.