Drug information of ambrisentan
Mechanism of effect
Ambrisentan is rapidly absorbed with peak plasma concentrations occuring around 2 hours after oral administration. Cmax and AUC increase proportionally with dose across the therapeutic dosing range. Absolute oral bioavailability of ambrisentan is unknown. Absorption is not affected by food.Volume of distribution
Ambrisentan has a low distribution into red blow cells, with a mean blood:plasma ratio of 0.57 and 0.61 in males and females, respectively.Protein binding
Ambrisentan is 99% plasma protein bound, primarily to albumin (96.5%) and to a lesser degree alpha1-acid glycoprotein.Metabolism
Ambrisentan is a metabolized primarily by uridine 5’-diphosphate glucuronosyltransferases (UGTs) 1A9S, 2B7S,1A3S to form ambrisentan glucuronide. Ambrisentan is also metabolized to a lesser extent by CYP3A4, CYP3A5 and CYP2C19 to form 4- hydroxymethyl ambrisentan which is further glucuronidated to 4-hydroxymethyl ambrisentan glucuronide.
Route of elimination
Ambrisentan is primarily cleared by non-renal pathways. Along with its metabolites, ambrisentan is primarily found in the feces following hepatic and/or extra-hepatic metabolism. Approximately 22% of the administered dose is recovered in the urine following oral administration with 3.3% being unchanged ambrisentan.Half-life
Ambrisentan has a terminal half-life of 15 hours. It is thought that steady state is achieved after around 4 days of repeat-dosing.Clearance
The mean oral clearance of ambrisentan was found to be 38 mL/min in healthy subjects and 19 mL/min in patients with pulmonary artery hypertension.
Idiopathic pulmonary fibrosis
InteractionsRemdesivir , Sarecycline , Epirubicin , Posaconazole , Tizanidine , Thioguanine , Rifampin , Cyclosporine , Venetoclax , Brentuximab , Troleandomycin , riociguat , Cannabidiol , lasmiditan , vemurafenib , lefamulin , Erdafitinib , trabectedine , encorafenib , midostaurin , pexidartinib , Avanafil , ritonavir , Ponatinib , Dabrafenib , Mibefradil , Ertugliflozin , Letermovir , Minoxidil , Modafinil , Miconazole , Enzalutamide , Mipomersen , teriflunomide
• Fluid retention/peripheral edema: Development of peripheral edema due to treatment and/or disease state (pulmonary arterial hypertension) may occur; a higher incidence is seen with concomitant use of tadalafil and in elderly patients. There have also been postmarketing reports of fluid retention requiring treatment (eg, diuretics, fluid management, hospitalization). Further evaluation may be necessary to determine cause and appropriate treatment or discontinuation of therapy.
• Hematologic changes: A reduction in hematocrit/hemoglobin may be observed within the first few weeks of therapy with subsequent stabilization of levels. Hemoglobin reductions >15% have been observed in some patients. Measure hemoglobin prior to initiating therapy, at 1 month, and periodically thereafter. Significant decreases in hemoglobin in the absence of other causes may warrant the discontinuation of therapy. Use not recommended in patients with clinically significant anemia.
• Hepatic effects: Increases in serum liver aminotransferases have been reported during postmarketing use; however, in the majority of the cases, alternative causes of hepatotoxicity could be identified. Perform liver enzyme testing when clinically indicated. Discontinue therapy if signs/symptoms of hepatic injury appear, if serum liver aminotransferases >5 times ULN (US labeling) or >3 times ULN (Canadian labeling) are observed, or if aminotransferases are increased in the presence of bilirubin >2 times ULN. Hepatotoxicity has been reported with other endothelin receptor antagonists (eg, bosentan); however, ambrisentan may be tried in patients that have experienced asymptomatic increases in liver enzymes caused by another endothelin receptor antagonist after the liver enzymes have returned to normal.