PLATERO

Indications

• Pulmonary arterial hypertension (PAH)

Dosage

Children: Refer to the BNF for Children for appropriate dosing information in paediatric patients.

Adults: Initially 10 mg once daily, may be increased to 30 mg once daily after 4 weeks based on clinical response and tolerability.

Mechanism of action

Macitentan exerts its therapeutic effects through complete blockade of endothelin receptors A and B (E_A and E_B). This blockade protects tissues from the damaging effects of elevated endothelin levels, particularly within the cardiovascular system. By inhibiting endothelin signaling, macitentan reduces vasoconstriction and cellular proliferation, which are implicated in the pathophysiology of pulmonary arterial hypertension. The drug mitigates the adverse effects of endothelin-1 and -2, which contribute to endothelial dysfunction and increased pulmonary vascular resistance.

Pharmacodynamics

Macitentan primarily reduces vasoconstriction and cell proliferation associated with endothelin overexpression. By antagonizing endothelin receptors, it leads to vasodilation, decreased pulmonary arterial pressure, and improved hemodynamic parameters. This action not only alleviates symptoms but may also enhance exercise capacity for patients suffering from pulmonary arterial hypertension.

Pharmacokinetics

Macitentan is well absorbed following oral administration, with peak plasma concentrations occurring approximately 1 hour post-dose. It has a long half-life, allowing for once-daily dosing. The drug is metabolized primarily by the liver, with a significant role played by cytochrome P450 enzymes. It is excreted mainly via bile, with a minor proportion eliminated via the urine. Due to its extensive hepatic metabolism, caution is advised in patients with hepatic impairment.

Contra-indications

• Severe anaemia
• Acute porphyrias
• Pregnancy

Adverse effects

• Headache
• Decreased haemoglobin concentration
• Liver enzyme elevation
• Symptoms of liver impairment

Interactions

• St John's Wort (severe decrease in exposure)
• Rifampicin (severe decrease in exposure)
• Antifungals, azoles (e.g., fluconazole, isavuconazole, miconazole, posaconazole - unknown effect on exposure)
• Cobicistat (unknown effect on exposure)
• Crizotinib (unknown effect on exposure)
• Idelalisib (unknown effect on exposure)
• Imatinib (unknown effect on exposure)
• Letermovir (unknown effect on exposure)
• Mitotane (unknown decrease in exposure)
• Nilotinib (unknown increase in exposure)

Precautions

• Use with caution in hepatic impairment
• Monitor liver function before and during treatment
• Monitor haemoglobin concentration or haematocrit after 1 month and 3 months of starting treatment, and periodically thereafter
• Avoid abrupt withdrawal; discontinue treatment gradually
• Patient alert card should be provided
• Monthly pregnancy tests advised, and effective contraception during and for one month after stopping treatment

Pregnancy

Avoid (teratogenic in animal studies)

Breast-feeding

Manufacturer advises to avoid

Storage

Store in a cool, dry place away from direct sunlight

Formulations

• Tablets: 10 mg, 20 mg

Mechanism of action

Through complete blockade of tissular endothelin, Actelion-1 is expected to protect tissue from the damaging effect of elevated endothelin, specifically in the cardiovascular system. In pre-clinical studies, Actelion-1 also exhibited effects suggesting that it maintains the integrity of the vascular wall and improves long-term outcome. Accordingly, Actelion-1 may provide therapeutic benefit in a wide range of cardiovascular indications. Macitentan is an antagonist which binds to the endothelin A and B receptors (E_A and E_B) and blocks signaling from endothelin-1 and -2. Pulmonary arterial hypertension has many different mechanisms which contribute to the development of endothelial dysfunction including elevated cytosolic calcium, genetic factors, epigenetic changes, and mitochondrial dysfunction. The focus of macitentan's mechanism relates to the role of overexpressed endothelin from the vascular endothelium. Endothelins are released in both a constitutive fashion from secretory vesicles and in response to stimuli via Weibel-Palade storage granules. Endothelins bind to the E_A and E_B receptors, with endothelins -1 and -2 having more affinity than endothelin-3. Binding to the Gq coupled E_A receptor triggers Ca2+ release from the sarcoplasmic reticulum of smooth muscle cells via the phospholipase C (PLC) pathway. Downstream protein kinase C activation may also contribute to increased Ca2+ sensitivity of the contractile apparatus. E_A receptor activation is also known to contribute to pulmonary artery smooth muscle cell proliferation. The binding of endothelins to the E_B receptors acts in opposition to E_A signaling by activating the same PLC cascade in endothelial cells to activate endothelial nitric oxide synthase. The subsequent release of nitric oxide produces vasodilation through the cyclic guanosine monophosphate cascade. Despite the greater presence of E_B receptors on endothelial cells, they are still present on smooth muscle cells and may contribute to cell proliferation through the same mechanisms as E_A receptors. Macitentan is thought to provide its therapeutic effect primarily via blocking signaling through E_A which produces both decreased vasoconstriction via reduced smooth muscle cell contractility and attenuation of the hyperproliferation of smooth muscle cells found in PAH. Blockade of E_B is less likely to contribute to a therapeutic effect as this signaling is responsible for the counter-regulatory vasodilatory signal.

Pharmacodynamics

Macitentan acts primarily by reducing vasoconstriction and cell proliferation due to endothelin overexpression.