Ambrisentan for use in the treatment of acute renal failure
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Publication Number
US-11642307-B2
Publication Date
2023-05-09
Expiration Date
Abstract
Ambrisentan and formulations thereof for use in the treatment and prevention of acute renal failure associated with renal vasoconstriction.
Core Innovation
The invention relates to treating or preventing acute renal failure associated with renal vasoconstriction by administering a selective ETR-A antagonist, notably ambrisentan, at low plasma concentrations, preferably below about 100 ng/mL. The description states that administration at approved PAH doses achieves plasma levels that are insufficiently maintained for ETR-A selectivity and can significantly antagonize ETR-B, which can reduce vasodilation, urine formation, and worsen renal function.
The described approach targets renal vasoconstriction-associated indications including hepatorenal disorders/Hepatorenal Syndrome (HRS), delayed graft function, calcineurin-inhibitor nephrotoxicity, contrast-induced acute kidney injury, cardiorenal syndrome, renal failure after solid-organ transplantation, and acute kidney injury after cardiac surgery. The invention is directed to dosing ambrisentan such that plasma levels are maintained below about 100 ng/mL, while preserving an ETR-A antagonist profile and avoiding substantial ETR-B antagonism.
The invention further includes identifying subjects based on reduced renal function due to vasoconstriction using determination of renal function before and after treatment. The document also describes intravenous/parenteral administration and low-concentration liquid formulations, and provides experimental examples including a porcine kidney ischemia perfusion model and a human study comparing low versus high target plasma concentrations, reporting a diuretic effect at low target levels and fluid retention and greater ET-1 increases at higher target levels.
Claims Coverage
The provided material contains sixteen independent claims. Across these independent claims, the coverage is centered on administering an effective amount of ambrisentan to treat or prophylactically treat specific renal conditions or to identify reduced renal function due to vasoconstriction, with the key inventive constraint that plasma levels of ambrisentan are maintained below about 100 ng/mL. Some independent claims additionally require determining renal function before and after treatment.
Treating calcineurin-inhibitor nephrotoxicity with low plasma ambrisentan levels
Administer an effective amount of ambrisentan to a subject suffering from Calcineurin-Inhibitor Nephrotoxicity, wherein ambrisentan plasma levels are maintained below about 100 ng/ml.
Prophylactically treating calcineurin-inhibitor nephrotoxicity with low plasma ambrisentan levels
Prophylactically treat a subject who may develop Calcineurin-Inhibitor Nephrotoxicity by administering an effective amount of ambrisentan, wherein ambrisentan plasma levels are maintained below about 100 ng/ml.
Treating delayed graft function with low plasma ambrisentan levels
Treat a subject suffering from Delayed Graft Function by administering an effective amount of ambrisentan, wherein ambrisentan plasma levels are maintained below about 100 ng/ml.
Prophylactically treating delayed graft function following renal transplantation with low plasma ambrisentan levels
Prophylactically treat a subject who may develop Delayed Graft Function following renal transplantation by administering an effective amount of ambrisentan, wherein ambrisentan plasma levels are maintained below about 100 ng/ml.
Treating renal failure associated with solid-organ transplantation with low plasma ambrisentan levels
Treat a subject suffering from Renal Failure associated with Solid-Organ Transplantation by administering an effective amount of ambrisentan, wherein ambrisentan plasma levels are maintained below about 100 ng/ml.
Prophylactically treating renal failure associated with solid-organ transplantation with low plasma ambrisentan levels
Prophylactically treat a subject who may develop Renal Failure associated with Solid-Organ Transplantation by administering an effective amount of ambrisentan, wherein ambrisentan plasma levels are maintained below about 100 ng/ml.
Treating cardiorenal syndrome with low plasma ambrisentan levels
Treat a subject suffering from Cardiorenal Syndrome by administering an effective amount of ambrisentan, wherein ambrisentan plasma levels are maintained below about 100 ng/ml.
Treating acute kidney injury following cardiac surgery with low plasma ambrisentan levels
Treat a subject suffering from Acute Kidney Injury following Cardiac Surgery by administering an effective amount of ambrisentan, wherein ambrisentan plasma levels are maintained below about 100 ng/ml.
Prophylactically treating acute kidney injury following cardiac surgery with low plasma ambrisentan levels
Prophylactically treat a subject who may be at risk of developing Acute Kidney Injury following Cardiac Surgery by administering an effective amount of ambrisentan, wherein ambrisentan plasma levels are maintained below about 100 ng/ml.
Treating contrast-induced acute kidney injury with low plasma ambrisentan levels
Treat a subject suffering from Contrast-Induced Acute Kidney Injury by administering an effective amount of ambrisentan, wherein ambrisentan plasma levels are maintained below about 100 ng/ml.
Prophylactically treating contrast-induced acute kidney injury with low plasma ambrisentan levels
Prophylactically treat a subject who may be at risk of developing Contrast-Induced Acute Kidney Injury by administering an effective amount of ambrisentan, wherein ambrisentan plasma levels are maintained below about 100 ng/ml.
Treating and identifying reduced renal function due to vasoconstriction with low plasma ambrisentan levels
Administer an effective amount of ambrisentan to treat a subject and identify reduced renal function due to vasoconstriction, wherein renal function is determined before and after treatment and ambrisentan plasma levels are maintained below about 100 ng/ml.
Treating reduced renal function due to vasoconstriction with low plasma ambrisentan levels
Treat a subject suffering from reduced renal function due to vasoconstriction by administering an effective amount of ambrisentan, wherein ambrisentan plasma levels are maintained below about 100 ng/ml.
Treating acute renal failure with low plasma ambrisentan levels
Treat a subject suffering from acute renal failure by administering an effective amount of ambrisentan, wherein ambrisentan plasma levels are maintained below about 100 ng/ml.
Treating acute renal failure due to vasoconstriction with low plasma ambrisentan levels
Treat a subject suffering from acute renal failure due to vasoconstriction by administering an effective amount of ambrisentan, wherein ambrisentan plasma levels are maintained below about 100 ng/ml.
Treating and identifying reduced renal function due to vasoconstriction in renal transplant recipients with low plasma ambrisentan levels
Treat a subject who has previously received a renal transplant and identify reduced renal function due to vasoconstriction by administering an effective amount of ambrisentan, wherein renal function is determined before and after treatment and ambrisentan plasma levels are maintained below about 100 ng/ml.
Across the independent claims, the core coverage is ambrisentan administration for specific renal and cardio-renal conditions or for identification of reduced renal function due to vasoconstriction, with a unifying pharmacokinetic constraint that plasma levels of ambrisentan are maintained below about 100 ng/mL. Certain claims additionally require determining renal function before and after treatment to identify reduced renal function due to vasoconstriction.
Stated Advantages
Treating or preventing acute renal failure associated with renal vasoconstriction while maintaining ETR-A antagonist behavior by keeping ambrisentan plasma levels below about 100 ng/mL.
Avoiding significant ETR-B antagonism that may occur at plasma levels achieved with approved PAH doses.
Providing treatment or prophylaxis for multiple renal vasoconstriction-associated indications including calcineurin-inhibitor nephrotoxicity, delayed graft function, contrast-induced acute kidney injury, cardiorenal syndrome, renal failure after solid-organ transplantation, and acute kidney injury after cardiac surgery.
Supporting non-invasive identification of reduced renal function due to vasoconstriction by determining renal function before and after treatment.
Documented Applications
Treating calcineurin-inhibitor nephrotoxicity by administering ambrisentan with plasma levels maintained below about 100 ng/mL.
Prophylactically treating a subject who may develop calcineurin-inhibitor nephrotoxicity with ambrisentan and plasma levels maintained below about 100 ng/mL.
Treating delayed graft function by administering ambrisentan with plasma levels maintained below about 100 ng/mL.
Prophylactically treating a subject who may develop delayed graft function following renal transplantation with ambrisentan with plasma levels maintained below about 100 ng/mL.
Treating renal failure associated with solid-organ transplantation by administering ambrisentan with plasma levels maintained below about 100 ng/mL.
Prophylactically treating a subject who may develop renal failure associated with solid-organ transplantation with ambrisentan with plasma levels maintained below about 100 ng/mL.
Treating cardiorenal syndrome by administering ambrisentan with plasma levels maintained below about 100 ng/mL.
Treating acute kidney injury following cardiac surgery by administering ambrisentan with plasma levels maintained below about 100 ng/mL.
Prophylactically treating a subject who may be at risk of developing acute kidney injury following cardiac surgery with ambrisentan with plasma levels maintained below about 100 ng/mL.
Treating contrast-induced acute kidney injury by administering ambrisentan with plasma levels maintained below about 100 ng/mL.
Prophylactically treating a subject who may be at risk of developing contrast-induced acute kidney injury with ambrisentan with plasma levels maintained below about 100 ng/mL.
Treating a subject and identifying reduced renal function due to vasoconstriction by administering ambrisentan and determining renal function before and after treatment, with plasma levels maintained below about 100 ng/mL.
Treating reduced renal function due to vasoconstriction by administering ambrisentan with plasma levels maintained below about 100 ng/mL.
Treating acute renal failure by administering ambrisentan with plasma levels maintained below about 100 ng/mL.
Treating acute renal failure due to vasoconstriction by administering ambrisentan with plasma levels maintained below about 100 ng/mL.
Treating a subject who has previously received a renal transplant and identifying reduced renal function due to vasoconstriction by administering ambrisentan and determining renal function before and after treatment, with plasma levels maintained below about 100 ng/mL.
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