Ambrisan 5

Indications

Ambrisan is prescribed for managing Pulmonary Arterial Hypertension (PAH) (WHO Group 1) to enhance exercise capacity and delay clinical deterioration.

Pharmacology

Endothelin-1 (ET-1) is a potent peptide acting as both autocrine and paracrine agent. Its effects on vascular smooth muscle and endothelium are mediated by two receptor subtypes, ETA and ETB. ETA primarily induces vasoconstriction and cell proliferation, while ETB predominantly leads to vasodilation, anti-proliferation, and ET-1 clearance. Ambrisentan, a high-affinity ETA receptor antagonist, exhibits notable selectivity for the ETA receptor over ETB (>4000-fold). The clinical implications of this high selectivity remain uncertain.

The pharmacokinetics of Ambrisentan (S-Ambrisentan) show dose-proportional behavior in healthy individuals. While its absolute bioavailability remains unknown, Ambrisentan is absorbed with peak concentrations reached approximately 2 hours post oral administration, unaffected by food intake. In vitro studies suggest Ambrisentan as a P-gp substrate. It binds extensively to plasma proteins (99%) and is primarily eliminated through non-renal pathways, with metabolism and biliary excretion contributing significantly. The conversion of S-Ambrisentan to R-Ambrisentan in vivo is negligible. The mean oral clearance is 38 mL/min in healthy subjects and 19 mL/min in PAH patients, with a terminal half-life of approximately 15 hours. However, steady-state trough concentrations represent around 15% of peak concentrations, indicating an effective half-life of about 9 hours.

Dosage & Administration

For adults, initiate treatment with 5 mg once daily, potentially increased to 10 mg once daily if well-tolerated, with or without food.

Pediatric patients

The safety and efficacy of Ambrisentan in pediatric populations have not been established.

Interactions

Co-administration of Ambrisan and Cyclosporine may lead to a roughly 2-fold increase in Ambrisan exposure in healthy volunteers, necessitating a dose limitation of 5 mg once daily when used concomitantly.

Contraindications

Ambrisentan is contraindicated in pregnant women due to potential fetal harm. It should be avoided in women who are pregnant or planning pregnancy, with pregnancy testing recommended before initiation and during treatment cessation. Additionally, it is contraindicated in patients with Idiopathic Pulmonary Fibrosis (IPF), including those with pulmonary hypertension (WHO Group 3).

Side Effects

Clinical studies have reported decreases in hemoglobin concentration and hematocrit with Ambrisan use, consistent with other endothelin receptor antagonists.

Pregnancy & Lactation

Ambrisentan falls under Pregnancy Category X, with its excretion in human milk remaining unknown. Breastfeeding while on Ambrisentan is not advised.

Precautions & Warnings

Peripheral edema, a recognized class effect of endothelin receptor antagonists, and a consequence of PAH, should be monitored. In case of acute pulmonary edema during therapy initiation with vasodilators like Ambrisan, consider the possibility of pulmonary veno-occlusive disease and discontinue if confirmed. Hematological changes and hepatic impairment warrant caution with Ambrisan use.

Therapeutic Class

Ambrisentan belongs to the class of anti-hypertensives known as endothelin receptor antagonists.

Storage Conditions

Keep Ambrisentan in a cool, dry place below 30°C, shielded from light and moisture.