MABRATEN 5

Indications

• Pulmonary arterial hypertension (PAH), either as monotherapy or in combination with other therapies.

Dosage

Children: Refer

Adults: Initially, 5 mg once daily, which may be increased to 10 mg once daily if necessary, based on clinical response and tolerability.

Mechanism of action

Ambrisentan selectively targets the endothelin type A (ETA) receptor, which mediates vasoconstriction and cell proliferation when activated by endothelin-1 (ET-1). In pulmonary arterial hypertension, elevated ET-1 levels contribute to increased right arterial pressure and disease severity. By inhibiting the ETA receptor, ambrisentan prevents vasoconstriction and cell proliferation, while preserving the function of endothelin type B (ETB) receptors, which mediate vasodilation and ET-1 clearance.

Pharmacodynamics

In clinical studies, ambrisentan has demonstrated a significant reduction in plasma concentrations of B-type natriuretic peptide (BNP), a marker of cardiac stress, indicating its efficacy in reducing the burden of pulmonary hypertension. Doses of 10 mg daily showed no significant effect on the QTc interval, while higher doses of 40 mg resulted in a slight increase, but significant QTc prolongation is not expected with regular use. Overall, ambrisentan positively affects hemodynamic parameters and patient-reported outcomes.

Pharmacokinetics

Ambrisentan is well absorbed after oral administration, with peak plasma concentrations typically occurring within 1 to 2 hours. It has a long half-life, allowing for once-daily dosing. The drug undergoes extensive hepatic metabolism, primarily via the cytochrome P450 enzyme system, and has an elimination pathway that involves both renal and biliary excretion. Dose adjustments may be necessary in the presence of hepatic impairment or when used with certain interacting medications.

Contra-indications

• Cerebrovascular event (within the last 3 months)
• Congenital or acquired valvular defects with myocardial function disorders (not related to pulmonary hypertension)
• Decompensated cardiac failure (unless under close medical supervision)
• Myocardial infarction within 6 months
• Severe pulmonary hypertension with significant right heart failure

Adverse effects

• Abdominal pain
• Anaemia
• Appetite decreased
• Arthralgia
• Diarrhoea
• Flushing
• Headache
• Hyperthyroidism
• Hypotension
• Myalgia
• Nasal congestion
• Nasopharyngitis
• Nausea
• Pain
• Skin reactions
• Vomiting
• Weight decreased
• Uncommon: Sinus tachycardia

Interactions

• Moderate interaction with vemurafenib (increases exposure)
• Unknown interaction with ciclosporin (increases exposure)
• Unknown interaction with rifampicin (transiently increases exposure)

Precautions

• Elderly patients (limited information available)
• Use with caution in patients with hepatic impairment
• Monitor closely with concurrent use of ciclosporin

Pregnancy

Manufacturer advises to avoid-no information available.

Breast-feeding

Manufacturer advises to avoid-present in milk in animal studies.

Storage

Store in a cool, dry place away from direct sunlight. Keep out of reach of children.

Formulations

• Tablets: 5 mg, 10 mg

Mechanism of action

Endothelin-1 (ET-1) is an endogenous peptide that acts on the endothelin type A (ETA) and endothelin type B (ETB) receptors in vascular smooth muscle and endothelium. ETA-mediated actions include vasoconstriction and cell proliferation, whereas ETB predominantly mediates vasodilation, anti-proliferation, and ET-1 clearance. In patients with pulmonary arterial hypertension, ET-1 levels are increased and correlate with increased right arterial pressure and severity of disease. Ambrisentan is one of several newly developed vasodilator drugs that selectively target the endothelin type A (ETA) receptor, inhibiting its action and preventing vasoconstriction. Selective inhibition of the ETA receptor prevents phospholipase C-mediated vasoconstriction and protein kinase C-mediated cell proliferation. Endothelin type B (ETB) receptor function is not significantly inhibited, and nitric oxide and prostacyclin production, cyclic GMP- and cyclic AMP-mediated vasodilation, and endothelin-1 (ET-1) clearance is preserved.

Pharmacodynamics

Ambrisentan 10 mg daily had no significant effect on the QTc interval, whereas a 40 mg daily dose of 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.