Macitentan

Breast Feeding; Lactation; Milk, Human; Phosphodiesterase 5 Inhibitors; Urologic Agents; Vasodilator Agents

Breast Feeding; Lactation; Milk, Human; Antihypertensive Agents; Cardiovascular Agents; Vasodilator Agents

FDA approved drugs -> Active ingredient

EMA approved medicines: Human medicine

EMA approved medicines: Human medicine

EMA approved medicines: Human medicine

Danger

H360 (95.7%): May damage fertility or the unborn child [Danger Reproductive toxicity]

P203, P280, P318, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 46 reports by companies from 4 notifications to the ECHA C&L Inventory.

Macitentan is associated with a low rate of serum aminotransferase elevations (0% to 4%) that, in clinical trials, was similar to the rate among placebo recipients. These elevations were usually mild, transient and not associated with symptoms, but were above 8 times the ULN in 2% of subjects (vs 0.4% of controls) in at least one long term study. For these reasons, the product label recommends that patients have serum enzymes tested before starting therapy and be alerted to the possibility and symptoms of liver injury during therapy. While there have been no published reports of clinically apparent liver injury with jaundice associated with macitentan, it has had limited general use. Other endothelin receptor antagonists (bosentan, sitaxentan) have been linked to several instances of acute liver injury, some of which have been severe. The onset of illness was usually within 1 to 6 months of starting bosentan and the enzyme pattern was typically hepatocellular or mixed. Immunoallergic features were not present and autoantibodies absent or present in low titer. Macitentan and ambrisentan have not been linked to similar cases.

Drug Induced Liver Injury Rank (DILIrank 2.0)

Macitentan

vMost-DILI-concern

7

Warnings & precautions

DOI:10.1016/j.drudis.2016.02.015

◉ Summary of Use during Lactation

◉ Summary of Use during Lactation

C02KX04

C - Cardiovascular system

QC - Cardiovascular system

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.

Macitentan undergoes oxidative depropylation of the sulfonamide moiety via CYP3A4, 2C8, 2C9, and 2C19 to form the active metabolite M6. The ethylene glycol moiety undergoes oxidative cleavage via CYP2C9 to the alcohol metabolite M4. M4 is oxidized to its corresponding acid, M5, then hydrolyzed to the metabolite termed m/z 324. Oxidative depropylation of a distal carbon atom via CYP2C8, 2C9, and 2C19 forms M7. Hydrolysis of both macitentan and M5 produces M3. Finally M5 may be further metabolized via hydrolysis and hydroxylation to M2 or via glucuronidation to a glucuronide metabolite, M1.

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MACITENTAN

Established Pharmacologic Class [EPC] - Endothelin Receptor Antagonist

Mechanisms of Action [MoA] - Endothelin Receptor Antagonists

Macitentan is an Endothelin Receptor Antagonist. The mechanism of action of macitentan is as an Endothelin Receptor Antagonist.

MACITENTAN

Compounds and drugs that bind to and inhibit or block the activation of ENDOTHELIN A RECECPTORS.

Compounds and drugs that bind to and inhibit or block the activation of ENDOTHELIN B RECEPTORS.

Macitentan has a median Tmax of 8h although some studies have found up to 30h at higher doses. Although the bioavailability has not been experimentally determined, pharmacokinetic modeling has estimated it at 74%. Food has not been found to have a significant effect on absorption.

Eliminated 50% through urine and 24% through feces. Of the 50% excreted through the urine, none of the recovered dose was in the form of the parent drug nor the active metabolite.

Macitentan has an apparent volume of distribution of 40-50L.

Clearance data was not found.