Prevention and / or treatment of contrast-induced acute kidney injury

Abstract

Methods for preventing, reducing and / or treating contrast-induced acute kidney injury are provided. [Solution] In one embodiment, a method for preventing, alleviating, and / or treating contrast-induced acute kidney injury is provided, comprising administering an inhibitor of fatty acid oxidation to a patient in need thereof. Also provided is a method comprising the use of trimetazidine or a pharmaceutically acceptable salt thereof for the prevention and / or treatment of contrast-induced acute kidney injury. Also provided is a method for preventing and / or treating contrast-induced acute kidney injury, comprising administering one or more of trimetazidine, etomoxir, oxfenicine, perhexiline, mildronate, or ranolazine, or a pharmaceutically acceptable salt of any of the foregoing.

Description

[Technical Field]

[0001] This invention relates to a method for preventing contrast-induced acute kidney injury by administering fatty acid oxidation inhibitors to patients who require them. [Background technology]

[0002] Contrast-induced acute kidney injury (CI-AKI), also known as contrast-induced nephropathy, is a sudden decline in renal function that may be associated with the use of contrast agents. A contrast medium (or contrast agent) is a substance used in medical imaging to enhance the contrast of structures or fluids within the body. Renal damage may be associated with a rapid decline in renal function over 48 to 72 hours and may potentially lead to chronic kidney disease over one year, increased mortality, and an increased rate of infarction / reinfarction and major adverse cardiovascular events (MACE). Symptoms may be similar to those of kidney disease and may include more severe fatigue, loss of appetite, swelling of the feet and ankles, swelling around the eyes, or dry and itchy skin. In some cases, this may lead to serious kidney problems as well as potential heart and vascular problems.

[0003] Numerous treatments for renal impairment have been investigated, including the use of statins, bicarbonates, N-acetylcysteine, ascorbic acid, theophylline and aminophylline, vasodilators, forced diuretics, and renal replacement therapy. Trimetazidine (1-(2,3,4-trimethoxybenzyl)piperazine) has been used for angina and has been marketed in over 90 countries outside the United States for over 35 years. However, trimetazidine has never been approved in the United States for any indication. It was developed by Les Laboratoires Servier (France) and was first approved in France in 1978. Three drug forms are available in Europe under the trade names Vastarel® and Vastarel MR®: 20 mg tablets, 20 mg / ml oral solution, and 35 mg controlled-release tablets (MR), and it is available in over 90 countries as generics or brand-name generics under various names. Trimetazidine is described as the first cytoprotective anti-ischemic agent that improves myocardial glucose utilization by inhibiting fatty acid metabolism. Trimetazidine has been tested for the prevention of contrast-induced nephropathy in patients with high serum creatinine levels undergoing coronary angiography / angiopathy, for example. For instance, a four-investigator-led phase 2 clinical trial tested trimetazidine for the prevention of contrast-induced nephropathy (CI-AKI). The results of these trials were published in peer-reviewed journals and demonstrated that trimetazidine was more effective than isotonic saline in reducing the risk of contrast-induced nephropathy (CIN). See Onbasili AO, et al., HEART, 2007. 93:698-702, Rahman MM, et al., MYMENSINGH MED J, 2012. 21(2):292-299, Shehata M, Am. J Cardiol, 2014. 114:389-394, and Liu W, et al., Am. J. Med Sci, 2015. 350:398-402. However, contrast-induced acute kidney injury (CI-AKI) remains a significant unmet medical need, and improvements in prevention methods for contrast-induced acute kidney injury are still required. [Overview of the project]

[0004] One embodiment provides a method for preventing, reducing the incidence of, and / or treating contrast-induced acute kidney injury, comprising administering a fatty acid oxidation inhibitor to a patient in need. Another embodiment provides a method for preventing, mitigating, and / or treating contrast-induced acute kidney injury, comprising administering trimetazidine or a pharmaceutically acceptable salt thereof to a patient in need. For example, a method for preventing contrast-induced acute kidney injury in a patient undergoing a cardiac procedure requiring the administration of a contrast agent for imaging is provided. Another embodiment provides a method for preventing, mitigating, and / or treating contrast-induced acute kidney injury, comprising administering trimetazidine or a pharmaceutically acceptable salt thereof in an amount exceeding 20 mg to a patient in need. Another embodiment provides a method for preventing, mitigating, and / or treating contrast-induced acute kidney injury, comprising administering trimetazidine or a pharmaceutically acceptable salt thereof in an amount exceeding 35 mg to a patient in need. One embodiment provides a method for preventing, mitigating, and / or treating contrast-induced acute kidney injury, comprising administering trimetazidine or a pharmaceutically acceptable salt thereof in combination with etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine, or a pharmaceutically acceptable salt thereof, to a patient in need. One embodiment provides a method for preventing, mitigating, and / or treating contrast-induced acute kidney injury, comprising administering etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine, or a pharmaceutically acceptable salt thereof, to a patient in need. One embodiment provides a method for preventing, mitigating, and / or treating contrast-induced acute kidney injury, comprising administering one or more of trimetazidine, etomoxyl, oxphenicin, perhexylline, mildronate, lanolazine, or a pharmaceutically acceptable salt thereof, to a patient in need.

[0005] In one embodiment, the patient is administered a fatty acid oxidation inhibitor before undergoing cardiac treatment. In one embodiment, the patient is administered trimetazidine, etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine, or a pharmaceutically acceptable salt of any of the above, before undergoing cardiac treatment. In one embodiment, the patient is administered trimetazidine or a pharmaceutically acceptable salt thereof before undergoing cardiac treatment. For example, the patient may be administered trimetazidine or a pharmaceutically acceptable salt thereof for more than 24, 48, or 72 hours before undergoing cardiac treatment. In other examples, the patient who requires it is administered trimetazidine or a pharmaceutically acceptable salt thereof for at least 96 hours before undergoing cardiac treatment. In one embodiment, trimetazidine or a pharmaceutically acceptable salt thereof may be administered once daily. In one embodiment, trimetazidine or a pharmaceutically acceptable salt thereof may be administered twice daily. In one embodiment, trimetazidine or a pharmaceutically acceptable salt thereof may be administered three times daily. In one embodiment, trimetazidine or a pharmaceutically acceptable salt thereof may be administered four times a day.

[0006] In one embodiment, the patient is administered etomoxyl, oxfenicin, perhexylline, mildronate, or lanolazine, or any pharmaceutically acceptable salt thereof, before undergoing cardiac treatment. For example, the patient may be administered etomoxyl, oxfenicin, perhexylline, mildronate, or lanolazine, or any pharmaceutically acceptable salt thereof, for example, for more than 24, 48, or 72 hours before undergoing cardiac treatment. In other examples, the patient who requires it is administered etomoxyl, oxfenicin, perhexylline, mildronate, or lanolazine, or any pharmaceutically acceptable salt thereof, for at least 96 hours before undergoing cardiac treatment. In one embodiment, etomoxyl, oxfenicin, perhexylline, mildronate, or lanolazine, or any pharmaceutically acceptable salt thereof, may be administered once, two, three, or four times a day. In one embodiment, trimetazidine or a pharmaceutically acceptable salt thereof may be administered together with etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine, or at least one of any of the pharmaceutically acceptable salts thereof.

[0007] In one embodiment, a patient may be administered a fatty acid oxidation inhibitor for, for example, 30, 45, 60, 75, or 90 days or more after a cardiac procedure. In one embodiment, a patient may be administered trimetazidine or a pharmaceutically acceptable salt thereof for, for example, 30, 45, 60, 75, or 90 days or more after a cardiac procedure. For example, a patient may be administered trimetazidine or a pharmaceutically acceptable salt thereof twice daily for a total of 60 days or more after a cardiac procedure. In another example, a patient may be administered trimetazidine or a pharmaceutically acceptable salt thereof twice daily for a total of 90 days. In one embodiment, a patient may be administered etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine or a pharmaceutically acceptable salt of any of the above for, for example, 30, 45, 60, 75, or 90 days or more after a cardiac procedure, such as computed tomography (CT). For example, a patient may be administered etomoxil, oxfenicin, perhexylline, mildronate, or lanolazine, or a pharmaceutically acceptable salt of any of the above, twice daily for more than 60 days after cardiac treatment. In other cases, a patient may be administered etomoxil, oxfenicin, perhexylline, mildronate, or lanolazine, or a pharmaceutically acceptable salt of any of the above, twice daily for a total of 90 days.

[0008] In one embodiment, a patient may be administered a fatty acid oxidation inhibitor three times daily for more than 48 hours prior to cardiac treatment, and trimetazidine or a pharmaceutically acceptable salt thereof twice daily for more than 60 days after cardiac treatment. In another embodiment, a patient may be administered trimetazidine or a pharmaceutically acceptable salt thereof three times daily for more than 48 hours prior to cardiac treatment, and trimetazidine or a pharmaceutically acceptable salt thereof twice daily for more than 60 days after cardiac treatment. In yet another embodiment, a patient may be administered etomoxyl, oxfenicin, perhexylline, mildronate, or lanolazine or a pharmaceutically acceptable salt thereof three times daily for more than 48 hours prior to cardiac treatment, and trimetazidine or a pharmaceutically acceptable salt thereof twice daily for more than 60 days after cardiac treatment.

[0009] In one embodiment, a method for preventing, mitigating, and / or treating contrast-induced acute kidney injury includes administering a fatty acid oxidation inhibitor to the patient non-enterally within 6 hours prior to administering the contrast agent to the patient. In one embodiment, a method for preventing, mitigating, and / or treating contrast-induced acute kidney injury includes administering a fatty acid oxidation inhibitor to the patient non-enterally within 5, 4, 3, 2, or 1 hours prior to administering the contrast agent to the patient. In one embodiment, a method for preventing, mitigating, and / or treating contrast-induced acute kidney injury includes administering trimetazidine or a pharmaceutically acceptable salt thereof to the patient non-enterally within 6 hours prior to administering the contrast agent to the patient. In one embodiment, a method for preventing, mitigating, and / or treating contrast-induced acute kidney injury includes administering trimetazidine or a pharmaceutically acceptable salt thereof to the patient non-enterally within 5, 4, 3, 2, or 1 hours prior to administering the contrast agent to the patient. In one embodiment, a method for preventing, mitigating, and / or treating contrast-induced acute kidney injury comprises administering to a patient, non-enterally, one or more etomoxyl, oxfenicin, perhexylline, mildronate, or lanolazine, or any pharmaceutically acceptable salt thereof, within 6 hours prior to administering a contrast agent to the patient. In one embodiment, a method for preventing, mitigating, and / or treating contrast-induced acute kidney injury comprises administering to a patient, non-enterally, one or more etomoxyl, oxfenicin, perhexylline, mildronate, or lanolazine, or any pharmaceutically acceptable salt thereof, within 5, 4, 3, 2, or 1 hours prior to administering a contrast agent to the patient. In one embodiment, a method for preventing, mitigating, and / or treating contrast-induced acute kidney injury comprises administering to a patient, by non-enteral administration, within 6 hours prior to administering a contrast agent, trimetazidine or a pharmaceutically acceptable salt thereof in combination with etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine, or one or more pharmaceutically acceptable salts thereof.In one embodiment, a method for preventing, mitigating, and / or treating contrast-induced acute kidney injury comprises administering to a patient, non-enterally, within 5, 4, 3, 2, or 1 hour prior to administering a contrast agent, trimetazidine or a pharmaceutically acceptable salt thereof in combination with etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine, or one or more pharmaceutically acceptable salts thereof. In one embodiment, non-enteral administration is intravenous administration.

[0010] In one embodiment, a method for preventing contrast-induced acute kidney injury comprises administering trimetazidine or a pharmaceutically acceptable salt thereof to a patient in need thereof, wherein the composition contains more than about 65 μg / ml of C max A method is provided for providing an in vivo plasma profile having the following characteristics.

[0011] In one embodiment, a method for preventing contrast-induced acute kidney injury is provided, comprising administering trimetazidine or a pharmaceutically acceptable salt thereof to a patient in need thereof, wherein the composition provides an in vivo plasma profile having an AUC greater than about 500 μg·hr / ml.

[0012] One embodiment provides a method for preventing, mitigating, and / or treating contrast-induced acute kidney injury by administering an effective amount of a fatty acid oxidation inhibitor to a patient in need before, during, and after a procedure involving the use of a device, such as a guidewire and intra-coronary pressure wire, cardiac catheter, atherectomy device, intra-coronary stent, thrombus aspiration catheter, embolic protection device, replacement heart valve and / or vascular closure device. Another embodiment provides a method for preventing, mitigating, and / or treating contrast-induced acute kidney injury by administering an effective amount of trimetazidine or a pharmaceutically acceptable salt thereof to a patient in need before, during, and after a procedure involving the use of a device, such as a guidewire and intra-coronary pressure wire, cardiac catheter, atherectomy device, intra-coronary stent, thrombus aspiration catheter, embolic protection device, replacement heart valve and / or vascular closure device. One embodiment provides a method for preventing, mitigating, and / or treating contrast-induced acute kidney injury by administering an effective amount of etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine, or a pharmaceutically acceptable salt thereof, to a patient in need before, during, and after a procedure involving the use of a device, such as a guidewire and intracoronary pressure wire, cardiac catheter, atherectomy device, intracoronary stent, thrombus aspiration catheter, embolic protection device, replacement cardiac valve, and / or vascular occlusion device.

[0013] In one embodiment, provided is a method for preventing, reducing and / or treating contrast agent-induced acute kidney injury by administering to a patient in need thereof an effective amount of an inhibitor of fatty acid oxidation, in combination with a contrast agent, an anticoagulant and an antiplatelet agent, or before and after administration thereof. In one embodiment, provided is a method for preventing, reducing and / or treating contrast agent-induced acute kidney injury by administering to a patient in need thereof an effective amount of trimetazidine or a pharmaceutically acceptable salt thereof, in combination with a contrast agent, an anticoagulant and an antiplatelet agent, or before and after administration thereof. In one embodiment, provided is a method for preventing, reducing and / or treating contrast agent-induced acute kidney injury by administering to a patient in need thereof an effective amount of etomoxir, oxyphenisatin, perhexiline, mildronate or ranolazine or a pharmaceutically acceptable salt of any of the foregoing, in combination with a contrast agent, an anticoagulant and an antiplatelet agent, or before and after administration thereof. In certain embodiments, for example, the following items are provided: (Item 1) A method for treating contrast-induced acute kidney injury, comprising administering more than 20 mg of trimetazidine or a pharmaceutically acceptable salt thereof to a patient undergoing a procedure requiring a contrast agent. (Item 2) The method according to item 1, wherein the patient is administered 60 mg of trimetazidine or a pharmaceutically acceptable salt thereof over 24 hours. (Item 3) The method according to item 1, wherein the patient is administered trimetazidine or a pharmaceutically acceptable salt thereof 48 hours prior to receiving the procedure. (Item 4) The method according to item 1, wherein trimetazidine or a pharmaceutically acceptable salt thereof is administered three times daily. (Item 5) The method according to item 1, wherein trimetazidine or a pharmaceutically acceptable salt thereof is administered as a 20 mg immediate-release dosage form. (Item 6) <00​​​​​​​​​​​​​​​​​​​ A method for reducing contrast-induced acute kidney injury in a patient undergoing a procedure requiring a contrast agent, comprising administering trimetazidine or a pharmaceutically acceptable salt thereof, wherein the composition contains more than approximately 65 μg / ml of C max A method for providing an in vivo plasma profile including the following. (Item 12) The method according to item 11, wherein the patient is administered 60 mg of trimetazidine or a pharmaceutically acceptable salt thereof over 24 hours. (Item 13) The method according to item 11, wherein the patient is administered trimetazidine or a pharmaceutically acceptable salt thereof 48 hours prior to receiving the procedure. (Item 14) The method according to item 11, wherein trimetazidine or a pharmaceutically acceptable salt thereof is administered three times daily. (Item 15) The method according to item 11, wherein trimetazidine or a pharmaceutically acceptable salt thereof is administered as a 20 mg immediate-release dosage form. (Item 16) The method according to item 11, wherein the patient is administered trimetazidine or a pharmaceutically acceptable salt thereof three times a day for more than 48 hours prior to the administration of a contrast agent. (Item 17) The method according to item 11, wherein a patient requiring treatment is administered trimetazidine or a pharmaceutically acceptable salt thereof for more than 60 days after treatment. (Item 18) The method according to item 11, wherein the patient is administered trimetazidine or a pharmaceutically acceptable salt thereof three times daily for a total of 90 days after treatment. (Item 19) The method according to item 11, wherein a patient requiring treatment is administered trimetazidine or a pharmaceutically acceptable salt thereof three times daily for more than 48 hours prior to receiving cardiac treatment, and trimetazidine or a pharmaceutically acceptable salt thereof three times daily for at least 60 days after receiving treatment. (Item 20) The method according to item 11, wherein administration of rimetazidine or a pharmaceutically acceptable salt thereof reduces the incidence of major adverse kidney or cardiac events. (Item 21) A method for mitigating contrast-induced acute kidney injury in a patient undergoing a contrast-enhanced procedure, comprising administering trimetazidine or a pharmaceutically acceptable salt thereof to the patient, wherein the composition provides an in vivo plasma profile containing an AUC greater than approximately 500 μg·hr / ml. (Item 22) The method according to item 21, wherein the patient is administered 60 mg of trimetazidine or a pharmaceutically acceptable salt thereof over 24 hours. (Item 23) The method according to item 21, wherein the patient is administered trimetazidine or a pharmaceutically acceptable salt thereof 48 hours prior to receiving the procedure. (Item 24) The method according to item 21, wherein trimetazidine or a pharmaceutically acceptable salt thereof is administered three times daily. (Item 25) The method according to item 21, wherein trimetazidine or a pharmaceutically acceptable salt thereof is administered as a 20 mg immediate-release dosage form. (Item 26) The method according to item 21, wherein the patient is administered trimetazidine or a pharmaceutically acceptable salt thereof three times a day for more than 48 hours prior to the administration of a contrast agent. (Item 27) The method according to item 21, wherein a patient requiring treatment is administered trimetazidine or a pharmaceutically acceptable salt thereof for more than 60 days after treatment. (Item 28) The method according to item 21, wherein the patient is administered trimetazidine or a pharmaceutically acceptable salt thereof three times daily for a total of 90 days after treatment. (Item 29) The method according to item 21, wherein the patient has renal impairment and is administered trimetazidine or a pharmaceutically acceptable salt thereof three times daily for more than 48 hours prior to receiving a cardiac procedure, and is administered trimetazidine or a pharmaceutically acceptable salt thereof three times daily for at least 60 days after the procedure. (Item 30) The method according to item 21, wherein administration of trimetazidine or a pharmaceutically acceptable salt thereof reduces the incidence of major adverse kidney or cardiac events. [Modes for carrying out the invention]

[0014] Methods for preventing, mitigating, and / or treating contrast-induced acute kidney injury include administering fatty acid oxidation inhibitors to patients who require them. Methods for preventing, mitigating, and / or treating contrast-induced acute kidney injury include administering trimetazidine or a pharmaceutically acceptable salt thereof to patients who require it. Methods for preventing, mitigating, and / or treating contrast-induced acute kidney injury include administering etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine, or a pharmaceutically acceptable salt thereof, to patients who require it. Methods for reducing the incidence of contrast-induced acute kidney injury include administering one or more of trimetazidine, etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine, or a pharmaceutically acceptable salt thereof, to patients who require it. The present invention describes a method for reducing the incidence of contrast-induced acute kidney injury, comprising administering trimetazidine or a pharmaceutically acceptable salt thereof to a patient in need, in combination with etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine, or one or more pharmaceutically acceptable salts thereof.

[0015] The present invention provides a method for preventing, mitigating, and / or treating contrast-induced acute kidney injury, comprising administering trimetazidine or a pharmaceutically acceptable salt thereof to a patient in need. One embodiment provides a method for preventing the progression of acute kidney injury (AKI) to chronic kidney disease (CKD). One embodiment provides a method for preventing contrast-induced acute kidney injury by administering trimetazidine or a pharmaceutically acceptable salt thereof to a patient. One embodiment provides a method for mitigating contrast-induced acute kidney injury. Several embodiments provide mitigation and / or prevention of major adverse kidney and cardiac events (MARCE) in subjects undergoing coronary angiography. A method provides reducing the incidence of major adverse kidney and cardiac events in subjects with renal impairment by administering trimetazidine or a pharmaceutically acceptable salt thereof to a patient. Several embodiments provide a method for mitigating and / or preventing contrast-induced acute kidney injury in subjects undergoing coronary angiography by administering trimetazidine or a pharmaceutically acceptable salt thereof to a patient. In some embodiments, a method is provided to mitigate and / or prevent contrast-induced acute kidney injury in a subject undergoing coronary angiography for acute coronary syndrome (ACS) by administering trimetazidine or a pharmaceutically acceptable salt thereof to the patient.

[0016] In some embodiments, a method is provided to reduce and / or prevent contrast-induced acute kidney injury in subjects with renal impairment by administering trimetazidine or a pharmaceutically acceptable salt thereof to the patient. In other embodiments, a method is provided to reduce and / or prevent contrast-induced acute kidney injury in subjects undergoing coronary angiography for acute coronary syndrome (ACS) excluding ST-elevation myocardial infarction by administering trimetazidine or a pharmaceutically acceptable salt thereof to the patient. In some embodiments, a method is provided to reduce and / or prevent contrast-induced acute kidney injury in subjects undergoing coronary angiography for acute coronary syndrome (ACS) excluding ST-elevation myocardial infarction with renal impairment by administering trimetazidine or a pharmaceutically acceptable salt thereof to the patient. In some embodiments, a method is provided to reduce and / or prevent major adverse kidney and cardiac events in subjects undergoing coronary angiography for acute coronary syndrome (ACS) excluding ST-elevation myocardial infarction with renal impairment by administering trimetazidine or a pharmaceutically acceptable salt thereof to the patient. In some embodiments, a method is provided to reduce the risk of CI-AKI and related MARCE in subjects undergoing coronary angiography for ACS.

[0017] In some embodiments, a method is provided for reducing and / or preventing contrast-agent-induced acute kidney injury in subjects with renal impairment by administering trimetazidine or a pharmaceutically acceptable salt thereof to a patient. In some embodiments, a method is provided for reducing and / or preventing contrast-agent-induced acute kidney injury in subjects with renal impairment by administering 60 mg of trimetazidine or a pharmaceutically acceptable salt thereof to a patient. In some embodiments, a method is provided for reducing and / or preventing contrast-agent-induced acute kidney injury in subjects with renal impairment by administering more than 40 mg of trimetazidine or a pharmaceutically acceptable salt thereof. For example, the method may include administering more than 40 mg of trimetazidine to a patient in doses once or more daily. In some embodiments, a method is provided for reducing and / or preventing contrast-agent-induced acute kidney injury in subjects with renal impairment by administering trimetazidine or a pharmaceutically acceptable salt thereof three times a day. In some embodiments, a method is provided for reducing and / or preventing contrast-agent-induced acute kidney injury in subjects with renal impairment by administering 20 mg of trimetazidine or a pharmaceutically acceptable salt thereof three times a day. In some embodiments, patients administered trimetazidine according to the disclosed method may have an estimated glomerular filtration rate (eGFR) of <45 mL / min and >15 mL / min as determined by the Modification of Diet in Renal Disease (MDRD) formula. In some embodiments, patients administered trimetazidine according to the disclosed method may have an eGFR of <60 mL / min and >15 mL / min as determined by the MDRD formula.

[0018] Many pharmaceuticals are administered at fixed intervals as a fixed dose to achieve a therapeutic effect. The duration of action is reflected by the plasma half-life. Because efficacy often depends on sufficient exposure, management may require frequent maintenance doses. Advantageously, a method for preventing contrast-induced acute kidney injury is disclosed herein by administering trimetazidine or a pharmaceutically acceptable salt thereof. For example, one embodiment provides a method for treating contrast-induced acute kidney injury, comprising administering a pharmaceutical composition containing about 20 mg to about 200 mg of trimetazidine or a pharmaceutically acceptable salt thereof to a patient in need.

[0019] In one embodiment, the patient is administered a fatty acid oxidation inhibitor before undergoing cardiac treatment. In another embodiment, the patient is administered trimetazidine or a pharmaceutically acceptable salt thereof before undergoing cardiac treatment. For example, the patient may be administered trimetazidine or a pharmaceutically acceptable salt thereof for more than 24, 48, or 72 hours before undergoing cardiac treatment. In another embodiment, the patient is administered trimetazidine or a pharmaceutically acceptable salt thereof for at least 96 hours before undergoing contrast treatment. In some embodiments, the patient is administered trimetazidine or a pharmaceutically acceptable salt thereof for at least 48 hours before undergoing contrast treatment.

[0020] In one embodiment, trimetazidine or a pharmaceutically acceptable salt thereof may be administered once daily. In one embodiment, trimetazidine or a pharmaceutically acceptable salt thereof may be administered twice daily. In one embodiment, trimetazidine or a pharmaceutically acceptable salt thereof may be administered three times daily. In one embodiment, trimetazidine or a pharmaceutically acceptable salt thereof may be administered four times daily. In one embodiment, a fatty acid oxidation inhibitor may be administered once, two, three, or four times daily.

[0021] In one embodiment, a patient may be administered etomoxyl, oxfenicin, perhexylline, mildronate, or lanolazine, or any pharmaceutically acceptable salt thereof, before undergoing cardiac treatment. For example, a patient may be administered etomoxyl, oxfenicin, perhexylline, mildronate, or lanolazine, or any pharmaceutically acceptable salt thereof, for example, for more than 24, 48, or 72 hours before undergoing cardiac treatment. In other examples, a patient who requires it may be administered etomoxyl, oxfenicin, perhexylline, mildronate, or lanolazine, or any pharmaceutically acceptable salt thereof, for at least 96 hours before undergoing cardiac treatment. In one embodiment, etomoxyl, oxfenicin, perhexylline, mildronate, or lanolazine, or any pharmaceutically acceptable salt thereof, may be administered once, two, three, or four times a day. In one embodiment, trimetazidine or a pharmaceutically acceptable salt thereof may be administered in combination with etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine, or one or more of the pharmaceutically acceptable salts thereof. In one embodiment, a patient may be administered trimetazidine or a pharmaceutically acceptable salt thereof in combination with etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine, or one or more of the pharmaceutically acceptable salts thereof, before undergoing a cardiac procedure. For example, a patient may be administered trimetazidine or a pharmaceutically acceptable salt thereof in combination with etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine, or one or more of the pharmaceutically acceptable salts thereof, for example, for more than 24, 48, or 72 hours before undergoing a cardiac procedure. In other cases, trimetazidine or a pharmaceutically acceptable salt thereof may be administered to patients requiring it at least 96 hours prior to cardiac treatment, in combination with etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine, or one or more pharmaceutically acceptable salts thereof.In one embodiment, trimetazidine or a pharmaceutically acceptable salt thereof may be administered once, two, three, or four times daily in combination with etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine, or one or more pharmaceutically acceptable salts thereof.

[0022] In one embodiment, a patient may be administered a fatty acid oxidation inhibitor for, for example, 30, 45, 60, 75, or 90 days after contrast-enhanced treatment. In one embodiment, a patient may be administered trimetazidine or a pharmaceutically acceptable salt thereof for, for example, 30, 45, 60, 75, or 90 days after cardiac treatment. For example, a patient may be administered trimetazidine or a pharmaceutically acceptable salt thereof twice daily for a total of 60 days after cardiac treatment. In another example, a patient may be administered trimetazidine or a pharmaceutically acceptable salt thereof twice daily for a total of 90 days. In one embodiment, a patient may be administered etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine, or a pharmaceutically acceptable salt of any of the above, for, for example, 30, 45, 60, 75, or 90 days after contrast-enhanced treatment. For example, a patient may be administered etomoxyl, oxfenicin, perhexylline, mildronate, or lanolazine, or a pharmaceutically acceptable salt of any of the above, twice daily for more than 60 days after cardiac treatment. In another example, a patient may be administered etomoxyl, oxfenicin, perhexylline, mildronate, or lanolazine, or a pharmaceutically acceptable salt of any of the above, twice daily for a total of 90 days. In one embodiment, trimetazidine or a pharmaceutically acceptable salt thereof may be administered in combination with one or more etomoxyl, oxfenicin, perhexylline, mildronate, or lanolazine, or a pharmaceutically acceptable salt of any of the above, for, for 30, 45, 60, 75, or 90 days after contrast treatment.

[0023] In one embodiment, a patient may be administered trimetazidine or a pharmaceutically acceptable salt thereof three times daily for more than 48 hours prior to cardiac treatment, and trimetazidine or a pharmaceutically acceptable salt thereof twice daily for more than 60 days after cardiac treatment. In one embodiment, a patient may be administered etomoxil, oxfenicin, perhexylline, mildronate, or lanolazine, or a pharmaceutically acceptable salt thereof, three times daily for more than 48 hours prior to cardiac treatment, and trimetazidine or a pharmaceutically acceptable salt thereof twice daily for more than 60 days after cardiac treatment. In one embodiment, trimetazidine or a pharmaceutically acceptable salt thereof may be administered in combination with one or more of etomoxil, oxfenicin, perhexylline, mildronate, or lanolazine, or a pharmaceutically acceptable salt thereof.

[0024] In one embodiment, a method for preventing, mitigating, and / or treating contrast-induced acute kidney injury includes administering a fatty acid oxidation inhibitor to a patient in need within 6 hours prior to administration of a contrast agent. In one embodiment, a method for preventing, mitigating, and / or treating contrast-induced acute kidney injury includes administering a fatty acid oxidation inhibitor to a patient in need within 5, 4, 3, 2, or 1 hours prior to administration of a contrast agent. In one embodiment, a method for preventing, mitigating, and / or treating contrast-induced acute kidney injury includes non-enteral administration of a fatty acid oxidation inhibitor to a patient in need within 6 hours prior to administration of a contrast agent. In one embodiment, such non-enteral administration is intravenous administration.

[0025] In one embodiment, a method for preventing, mitigating, and / or treating contrast-induced acute kidney injury includes administering trimetazidine or a pharmaceutically acceptable salt thereof alone, or in combination with etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine, or one or more of the pharmaceutically acceptable salts thereof, to a patient in need within 6 hours prior to administration of a contrast agent. In one embodiment, a method for preventing, mitigating, and / or treating contrast-induced acute kidney injury includes administering trimetazidine or a pharmaceutically acceptable salt thereof alone, or in combination with etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine, or one or more of the pharmaceutically acceptable salts thereof, to a patient in need within 5, 4, 3, 2, or 1 hour prior to administration of a contrast agent. In one embodiment, a method for preventing, mitigating, and / or treating contrast-induced acute kidney injury includes administering one or more etomoxyl, oxfenicin, perhexylline, mildronate, or lanolazine, or any pharmaceutically acceptable salt thereof, to a patient in need within 6 hours prior to administration of a contrast agent. In one embodiment, a method for preventing, mitigating, and / or treating contrast-induced acute kidney injury includes administering one or more etomoxyl, oxfenicin, perhexylline, mildronate, or lanolazine, or any pharmaceutically acceptable salt thereof, to a patient in need within 5, 4, 3, 2, or 1 hours prior to administration of a contrast agent. In one embodiment, a method for preventing, mitigating, and / or treating contrast-induced acute kidney injury includes administering one or more etomoxyl, oxfenicin, perhexylline, mildronate, or lanolazine, or any pharmaceutically acceptable salt thereof, to a patient in need via non-enteral administration within 6 hours prior to administration of a contrast agent. In one embodiment, a method for preventing, mitigating, and / or treating contrast-induced acute kidney injury comprises administering one or more etomoxyl, oxfenicin, perhexylline, mildronate, or lanolazine, or any pharmaceutically acceptable salt thereof, non-enterally to a patient in need within 5, 4, 3, 2, or 1 hours prior to administration of a contrast agent.In one embodiment, a method for preventing, mitigating, and / or treating contrast-induced acute kidney injury includes administering trimetazidine or a pharmaceutically acceptable salt thereof alone, or in combination with etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine, or one or more of the pharmaceutically acceptable salts thereof, to a patient in need within 6 hours prior to administration of a contrast agent. In one embodiment, a method for preventing, mitigating, and / or treating contrast-induced acute kidney injury includes administering trimetazidine or a pharmaceutically acceptable salt thereof alone, or in combination with etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine, or one or more of the pharmaceutically acceptable salts thereof, to a patient in need within 5, 4, 3, 2, or 1 hours prior to administration of a contrast agent. In one embodiment, such non-enteral administration is intravenous.

[0026] In one embodiment, trimetazidine or a pharmaceutically acceptable salt thereof is administered at least once daily in doses ranging from about 0.001 mg / kg to about 10 mg / kg per body weight of the patient requiring it, for example, in the range of about 0.01 mg / kg to 2.0 mg / kg. For example, the dosage includes amounts of trimetazidine or its pharmaceutically acceptable salts in the range of approximately 1 mg to 50 mg, 1 mg to 40 mg, 1 mg to 35 mg, 1 mg to 30 mg, 1 mg to 20 mg, 1 mg to 15 mg, 0.01 mg to 10 mg, 0.1 mg to 15 mg, 0.15 mg to 12.5 mg, or 0.2 mg to 10 mg, including 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.5 mg, 1.0 mg, 1.75 mg, 2 mg, 2.5 mg, 2.75 mg, 3 mg, 3.5 mg, 3.75 mg, 4 mg, 4.5 mg, 4.75 mg, 5 mg, 5.5 mg The following are specific examples of dosages: mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 10 mg, 11 mg, 12 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, and 200 mg.

[0027] Typically, the dosage of trimetazidine or a pharmaceutically acceptable salt thereof is administered to patients requiring it 1 to 4 times daily. The methods and compositions described herein may provide reduction of adverse events and / or increased efficacy. In one embodiment, the dosage is, for example, approximately 20-100 mg / day, 20-200 mg / day, or 21-100 mg / day, or 22-100 mg / day, or 23-100 mg / day, such as 21 mg / day, 42 mg / day, 63 mg / day, 22 mg / day, 44 mg / day, 66 mg / day, 23 mg / day, 46 mg / day, 69 mg / day, 24 mg / day, 48 mg / day, 72 mg / day, 25 mg / day, 50 mg / day, 60 mg / day, 75 mg / day, 80 mg / day, 90 mg / day, 100 mg / day, 125 mg / day, 150 mg / day, 175 mg / day, or 200 mg / day.

[0028] In some embodiments, a method is provided for preventing, mitigating, and / or treating contrast-induced acute kidney injury by administering 20 mg of trimetazidine or a pharmaceutically acceptable salt thereof to a patient in need. In some embodiments, trimetazidine or a pharmaceutically acceptable salt thereof is provided once, twice, or three times daily. In some embodiments, trimetazidine or a pharmaceutically acceptable salt thereof is provided three times daily. In other embodiments, trimetazidine or a pharmaceutically acceptable salt thereof is provided twice daily.

[0029] The present invention provides a method for preventing, mitigating, and / or treating contrast-agent-induced acute kidney injury by administering an effective amount of a fatty acid oxidation inhibitor to a subject in need. The present invention provides a method for preventing, mitigating, and / or treating contrast-agent-induced acute kidney injury by administering an effective amount of trimetazidine or a pharmaceutically acceptable salt, derivative, or analog thereof to a subject in need. The present invention provides a method for preventing, mitigating, and / or treating contrast-agent-induced acute kidney injury by administering an effective amount of etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine, or a pharmaceutically acceptable salt thereof, to a subject in need. The present invention provides a method for preventing, mitigating, and / or treating contrast-agent-induced acute kidney injury by administering an effective amount of trimetazidine or a pharmaceutically acceptable salt thereof in combination with one or more effective amounts of etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine, or a pharmaceutically acceptable salt thereof, to a subject in need. An effective dose or therapeutically effective dose may be a dose sufficient to treat, suppress, or alleviate one or more symptoms of contrast-induced acute kidney injury. One embodiment provides a method for preventing contrast-induced acute kidney injury (CI-AKI) in subjects with renal failure undergoing diagnostic or therapeutic interventional cardiac procedures requiring the administration of a contrast agent for imaging by computed tomography (CT) or angiography.

[0030] The present invention provides an administration regimen that enables the prevention and / or treatment of contrast-induced acute kidney injury with potentially limited or virtually no negative side effects, such as Parkinson's disease, symptoms of Parkinson's disease, or Parkinson's disease-like symptoms. Those skilled in the art may anticipate that the use and administration regimens provided herein may cause or increase the risk of symptoms of Parkinson's disease. Accordingly, the methods described herein may provide treatment for contrast-induced acute kidney injury that may be considered surprising and unexpected. For example, the present invention provides a method for preventing, mitigating, and / or treating contrast-induced acute kidney injury in patients requiring treatment, which may not cause Parkinson's disease-like symptoms, such as tremors, rigidity, bradykinesia, and impairments of balance and coordination.

[0031] Trimetazidine or pharmaceutically acceptable salts thereof may be provided as acid addition salts, zwitterionic hydrates, zwitterionic anhydrides, dihydrochlorides, hydrochlorides or hydrobromides, or as zwitterionic monohydrates. Acid addition salts include, but are not limited to, maleic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid, oxalic acid, bis-methylenesalicylic acid, methanesulfonic acid, ethane-disulfonic acid, acetic acid, propionic acid, tartaric acid, salicylic acid, citric acid, gluconic acid, lactic acid, malic acid, mandelic acid, cinnamic acid, citraconic acid, aspartic acid, stearic acid, palmitic acid, itaconic acid, glycolic acid, p-aminobenzoic acid, glutamic acid, benzenesulfonic acid or theophylline acetate addition salts, as well as 8-haloteophyllines, such as 8-bromo-theophylline. In one embodiment, inorganic acid addition salts, including but not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, or nitrate addition salts, may be used. In one embodiment, trimetazidine may be provided as a dihydrochloride salt. Those skilled in the art will readily understand that the amount of the active ingredient in the pharmaceutical composition depends on the form of trimetazidine provided.

[0032] Deuteration of pharmaceuticals to improve pharmacokinetic (PK), pharmacodynamic (PD), and toxicity profiles has been previously demonstrated in several classes of drugs. Therefore, the use of deuterium-enriched trimetazidine is contemplated and within the scope of the methods and compositions described herein. Deuterium can be synthetically incorporated at any position by hydrogen substitution according to synthetic procedures known in the art. For example, deuterium can be incorporated at various positions having exchangeable protons, such as amine N-H, by proton-deuterium equilibrium exchange. Thus, deuterium can be incorporated selectively or non-selectively by methods known in the art.

[0033] In one embodiment, a method for treating contrast-induced acute kidney injury includes administering a pharmaceutical composition containing about 20 mg to more than 200 mg of trimetazidine or a pharmaceutically acceptable salt thereof to a patient in need. In one embodiment, a method for treating contrast-induced acute kidney injury includes administering a pharmaceutical composition containing more than 20 mg of trimetazidine or a pharmaceutically acceptable salt thereof to a patient in need. In one embodiment, a method for treating contrast-induced acute kidney injury includes administering a pharmaceutical composition containing more than 35 mg of trimetazidine or a pharmaceutically acceptable salt thereof to a patient in need.

[0034] One embodiment provides a method for preventing, mitigating, and / or treating contrast-induced acute kidney injury, comprising administering a first and second dose regimen of a fatty acid oxidation inhibitor to a patient in need. Another embodiment provides a method for preventing, mitigating, and / or treating contrast-induced acute kidney injury, comprising administering a first and second dose regimen of trimetazidine or a pharmaceutically acceptable salt thereof to a patient in need. Another embodiment provides a method for preventing, mitigating, and / or treating contrast-induced acute kidney injury, comprising administering one or more first and second dose regimens of trimetazidine, etomoxyl, oxfenicin, perhexylline, mildronate, or lanolazine or a pharmaceutically acceptable salt of any of the above to a patient in need. One embodiment provides a method for preventing, mitigating, and / or treating contrast-induced acute kidney injury, comprising administering a first dose regimen of trimetazidine or a pharmaceutically acceptable salt thereof and a second dose regimen of one or more trimetazidine, etomoxyl, oxfenicin, perhexylline, mildronate, or lanolazine, or a pharmaceutically acceptable salt thereof, to a patient in need.

[0035] For example, the first-dose regimen may be a loading or initiation dose to achieve a specific exposure in a patient with trimetazidine alone or in combination with one or more of etomoxyl, oxfenicin, perhexylline, mildronate, or lanozine.

[0036] In one embodiment, trimetazidine or a pharmaceutically acceptable salt thereof may be administered several days before contrast agent administration, for example, one, two, three, four, or five days before contrast agent administration. For example, trimetazidine or a pharmaceutically acceptable salt thereof may be administered for three days prior to contrast agent administration. In one embodiment, a method for preventing, mitigating, and / or treating contrast agent-induced acute kidney injury includes administering trimetazidine or a pharmaceutically acceptable salt thereof to a patient in need at least five days before contrast agent administration.

[0037] In one embodiment, trimetazidine or a pharmaceutically acceptable salt thereof may be administered before contrast agent administration, for example, the patient may be administered 2, 3, 4, 6, 9, 10, or 12 doses of trimetazidine before contrast agent administration. For example, the method may include administering 20 mg of trimetazidine or a pharmaceutically acceptable salt thereof three times a day for 3 days (e.g., dose 9) before contrast agent administration. In another example, the method may include administering 20 mg of trimetazidine or a pharmaceutically acceptable salt thereof three times a day for 4 days (e.g., dose 12) before contrast agent administration. In yet another example, the method may include administering 20 mg of trimetazidine or a pharmaceutically acceptable salt thereof twice a day for 3 days (e.g., dose 6) before contrast agent administration.

[0038] A loading or initiation dose may be initiated before contrast agent administration and may provide sufficient exposure to prevent contrast agent-induced acute injury. In one embodiment, the loading dose may be achieved by a bolus injection of trimetazidine or a pharmaceutically acceptable salt thereof alone, or in combination with etomoxyl, oxfenicin, perhexylline, mildronate, or lanolazine, or one or more of the pharmaceutically acceptable salts thereof. In one embodiment, the loading dose may be achieved by administering trimetazidine or a pharmaceutically acceptable salt thereof alone, or in combination with etomoxyl, oxfenicin, perhexylline, mildronate, or lanolazine, or one or more of the pharmaceutically acceptable salts thereof, over a period of time prior to contrast agent administration. For example, trimetazidine or a pharmaceutically acceptable salt thereof alone, or in combination with etomoxyl, oxfenicin, perhexylline, mildronate, or lanolazine, or one or more of the pharmaceutically acceptable salts thereof, may be administered 6, 12, or 24 hours before contrast agent administration. In one embodiment, trimetazidine or a pharmaceutically acceptable salt thereof alone, or in combination with etomoxyl, oxfenicin, perhexylline, mildronate, or lanolazine, or one or more of the pharmaceutically acceptable salts thereof, may be administered non-enterally 6, 12, or 24 hours prior to contrast agent administration. In one embodiment, trimetazidine or a pharmaceutically acceptable salt thereof alone, or in combination with etomoxyl, oxfenicin, perhexylline, mildronate, or lanolazine, or one or more of the pharmaceutically acceptable salts thereof, may be administered intravenously 6, 12, or 24 hours prior to contrast agent administration. In one embodiment, trimetazidine or a pharmaceutically acceptable salt thereof alone, or in combination with etomoxyl, oxfenicin, perhexylline, mildronate, or lanolazine, or one or more of the pharmaceutically acceptable salts thereof, may be administered within 6 hours prior to contrast agent administration. In one embodiment, trimetazidine or a pharmaceutically acceptable salt thereof alone, or in combination with etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine, or one or more of the pharmaceutically acceptable salts thereof, may be administered within 5 hours prior to the administration of the contrast agent.In one embodiment, trimetazidine or a pharmaceutically acceptable salt thereof alone, or in combination with etomoxil, oxfenicin, perhexylline, mildronate, or lanolazine, or one or more of the pharmaceutically acceptable salts thereof, may be administered within 4 hours prior to administration of the contrast agent. In one embodiment, trimetazidine or a pharmaceutically acceptable salt thereof alone, or in combination with etomoxil, oxfenicin, perhexylline, mildronate, or lanolazine, or one or more of the pharmaceutically acceptable salts thereof, may be administered within 3 hours prior to administration of the contrast agent. In one embodiment, trimetazidine or a pharmaceutically acceptable salt thereof alone, or in combination with etomoxil, oxfenicin, perhexylline, mildronate, or lanolazine, or one or more of the pharmaceutically acceptable salts thereof, may be administered within 2 hours prior to administration of the contrast agent. In one embodiment, trimetazidine or a pharmaceutically acceptable salt thereof alone, or in combination with etomoxyl, oxfenicin, perhexylline, mildronate, or lanolazine, or one or more of the pharmaceutically acceptable salts thereof, may be administered within one hour prior to administration of a contrast agent. In one embodiment, trimetazidine or a pharmaceutically acceptable salt thereof alone, or in combination with etomoxyl, oxfenicin, perhexylline, mildronate, or lanolazine, or one or more of the pharmaceutically acceptable salts thereof, may be administered non-enterally when administered within, for example, six hours or less than 5.75 hours, 5.5 hours, 5.25 hours, 5 hours, 4.75 hours, 4.5 hours, 4.25 hours, 3 hours, 2.75 hours, 2.5 hours, 2.25 hours, 2 hours, 1.75 hours, 1.5 hours, 1.25 hours, 1 hour, 0.75 hours, 0.5 hours, or 0.25 hours.In one embodiment, one or more of the following pharmaceutically acceptable salts may be administered non-enterally, for example, within 6 hours, or less than 5.75 hours, 5.5 hours, 5.25 hours, 5 hours, 4.75 hours, 4.5 hours, 4.25 hours, 3 hours, 2.75 hours, 2.5 hours, 2.25 hours, 2 hours, 1.75 hours, 1.5 hours, 1.25 hours, 1 hour, 0.75 hours, 0.5 hours, or 0.25 hours. In one embodiment, trimetazidine or a pharmaceutically acceptable salt thereof alone, or in combination with etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine, or one or more of the pharmaceutically acceptable salts thereof, may be administered intravenously, for example, within 6 hours, or less than 5.75 hours, 5.5 hours, 5.25 hours, 5 hours, 4.75 hours, 4.5 hours, 4.25 hours, 3 hours, 2.75 hours, 2.5 hours, 2.25 hours, 2 hours, 1.75 hours, 1.5 hours, 1.25 hours, 1 hour, 0.75 hours, 0.5 hours, or 0.25 hours. In one embodiment, trimetazidine, etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine, or one or more pharmaceutically acceptable salts thereof, may be administered intravenously, for example, within 6 hours, or less than 5.75 hours, 5.5 hours, 5.25 hours, 5 hours, 4.75 hours, 4.5 hours, 4.25 hours, 3 hours, 2.75 hours, 2.5 hours, 2.25 hours, 2 hours, 1.75 hours, 1.5 hours, 1.25 hours, 1 hour, 0.75 hours, 0.5 hours, or 0.25 hours. In one embodiment, trimetazidine or a pharmaceutically acceptable salt thereof, or in combination with etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine, or one or more pharmaceutically acceptable salts thereof, may be administered intravenously regardless of the time of administration. In one embodiment, trimetazidine or a pharmaceutically acceptable salt thereof, etomoxyl, oxphenicin, perhexylline, mildronate, or lanozine may be administered several days before contrast agent administration, for example, one, two, three, four, five, or six days before contrast agent administration.In one embodiment, the loading or initiation regimen is administered three days before the contrast agent procedure.

[0039] A second dosing regimen may be a maintenance dose to achieve and / or maintain a specific exposure in a patient to trimezidine, etomoxyl, oxfenicin, perhexylline, mildronate, or lanolazine. The maintenance dose may be initiated immediately after contrast agent administration and may provide sufficient exposure to prevent contrast agent-induced acute injury. The maintenance dose may be achieved by administering trimezidine or a pharmaceutically acceptable salt thereof alone, or in combination with etomoxyl, oxfenicin, perhexylline, mildronate, or lanolazine, or one or more of the pharmaceutically acceptable salts thereof, over a period of time after contrast agent administration. For example, trimezidine or a pharmaceutically acceptable salt thereof alone, or in combination with etomoxyl, oxfenicin, perhexylline, mildronate, or lanolazine, or one or more of the pharmaceutically acceptable salts thereof, may be administered at 6, 12, or 24 hours after contrast agent administration. In one embodiment, trimetazidine or a pharmaceutically acceptable salt thereof alone, or in combination with etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine, or one or more pharmaceutically acceptable salts thereof, may be administered over several days after contrast agent treatment, for example, on days 1, 2, 3, 4, 5, or 6 after contrast agent treatment. In one embodiment, a maintenance dose regimen is administered for a certain number of weeks after contrast agent treatment, for example, 6, 8, 10, or 12 weeks. In some examples, the maintenance dose is administered for about 90 days. In specific examples, the maintenance dose is administered for about 87 days. For example, in one embodiment, the initial dose may be administered for 3 days prior to contrast agent treatment, and the maintenance dose may be administered for 87 days. Thus, in some examples, the method of disclosure intends to administer the doses and profiles described herein over a period of 90 days.

[0040] In one embodiment, trimetazidine or a pharmaceutically acceptable salt thereof may be administered for several days after contrast agent administration, for example, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 65, 70, 75, 80, 85, 90, 95, or 100 days after contrast agent administration. For example, trimetazidine or a pharmaceutically acceptable salt thereof may be administered for 90 days after contrast agent administration. In one embodiment, a method for preventing, mitigating, and / or treating contrast agent-induced acute kidney injury includes administering trimetazidine or a pharmaceutically acceptable salt thereof to a patient in need for at least 90 days.

[0041] In one embodiment, the first and second dosing regimens may be the same or different doses of trimetazidine or a pharmaceutically acceptable salt thereof alone, or in combination with etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine, or one or more of the pharmaceutically acceptable salts thereof. Thus, the first and second dosing regimens may be the same or different profiles of trimetazidine, etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine in the patient as described herein (e.g., C max、 AUC 0-∞ ) may provide. In one embodiment, the first and second dose regimens provide identical exposure to trimetazidine, etomoxyl, oxphenicin, perhexylline, mildronate, or lanozine.

[0042] In one embodiment, the method and pharmaceutical composition contain 21 mg to 25 mg, 21 mg to 23 mg, 21 mg to 35 mg, 20.5 mg to 25 mg, 22 mg to 30 mg, 20 to 45 mg, 21 mg to 75 mg, 21 mg to 50 mg, 21 mg to 45 mg, 22 mg to 75 mg, 22 mg to 50 mg, 22 mg to 45 mg, 22 mg to 35 mg, 21 mg to 30 mg, 23 mg to 75 mg, 23 mg to 55 mg, 23 mg to 40 mg, 23 mg to 55 mg, 24 mg to 35 mg, 24 mg to 50 mg, and 24 mg to 35 mg of trimetazidine or a pharmaceutically acceptable salt thereof.

[0043] In one embodiment, the method and pharmaceutical composition contain 20 mg to 30 mg, 21 mg to 30 mg, 22 mg to 30 mg, 23 mg to 30 mg, 24 mg to 25 mg, 21 mg to 50 mg, 21 mg to 24 mg, 21 mg to 23 mg, or 21 mg to 22 mg of trimetazidine or a pharmaceutically acceptable salt thereof.

[0044] In one embodiment, the method and pharmaceutical composition include, for example, 20.1 mg, 20.25 mg, 20.5 mg, 21 mg, 21.5 mg, 23 mg, 24 mg, 25 mg, 22 mg, 22.5 mg, 23 mg, 23.5 mg, 24 mg, 24.5 mg, 25.5 mg, 26 mg, 26.5 mg, 27 mg, 27.5 mg, 28 mg, 28.5 mg, 29 mg, 29.5 mg, 30 mg, 30.5 mg, 31 mg, 31.5 mg, 32 mg, 32.5 mg, 33 mg, 33.5 mg, 34 mg, 34.5 mg, or 35 mg of trimetazidine or a pharmaceutically acceptable salt thereof, or an amount that is a multiple of such doses. In one embodiment, the pharmaceutical composition includes 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, or 26 mg of trimetazidine or a pharmaceutically acceptable salt thereof.

[0045] The pharmaceutical compositions herein may be provided with immediate-release, delayed-release, sustained-release, or regulated-release profiles. The compositions herein may also be provided for non-enteral administration (e.g., intramuscular, intravenous, subcutaneous, intraperitoneal, or intrathecal). In one embodiment, a pharmaceutical composition may be provided with an immediate-release profile. In one embodiment, pharmaceutical compositions having different drug-release profiles may be combined to create a two-phase or three-phase release profile. For example, a pharmaceutical composition may be provided with both immediate-release and sustained-release profiles. In one embodiment, a pharmaceutical composition may be provided with sustained-release and delayed-release profiles. Such compositions may be provided as pulse formulations, multilayer tablets, or capsules containing tablets, beads, or granules. The compositions may be manufactured using a pharmaceutically acceptable “carrier” composed of substances considered safe and effective. The “carrier” includes all components present in the pharmaceutical formulation other than one or more active ingredients. The term “carrier” includes, but is not limited to, diluents, binders, lubricants, disintegrants, excipients, and coating compositions.

[0046] Non-enteral compositions must be sterile for administration by injection, infusion, or implantation into the body and may be packaged in either single-dose or multi-dose containers. In one embodiment, a liquid pharmaceutical composition for non-enteral administration to a subject comprises an active substance, for example, an inhibitor of fatty acid oxidation. In one embodiment, a liquid pharmaceutical composition for non-enteral administration to a subject comprises an active substance, for example, trimetazidine or a pharmaceutically acceptable salt thereof alone, or in combination with etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine or one or more pharmaceutically acceptable salts thereof, in any respective amounts as described herein. In one embodiment, the pharmaceutical composition for non-enteral administration is formulated as a total volume, for example, approximately 10 ml, 20 ml, 25 ml, 50 ml, 100 ml, 200 ml, 250 ml, or 500 ml. In one embodiment, the composition is contained in a bag, glass vial, plastic vial, or bottle.

[0047] In one embodiment, the pharmaceutical composition for non-enteral administration comprises about 0.05 mg to about 100 mg of an active substance, for example, an inhibitor of fatty acid oxidation. In another embodiment, the pharmaceutical composition for non-enteral administration comprises about 0.05 mg to about 100 mg of an active substance, for example, trimetazidine or a pharmaceutically acceptable salt thereof alone, or in combination with one or more etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine or any of the pharmaceutically acceptable salts thereof. In one embodiment, a pharmaceutical composition for non-enteral administration may be, for example, approximately 0.1 mg to 50 mg, 0.1 mg to 40 mg, 0.1 mg to 35 mg, 0.5 mg to 25 mg, 0.5 mg to 20 mg, 0.5 to 15 mg, 0.5 to 35 mg, 1 mg to 35 mg, 1 mg to 30 mg, 1 mg to 25 mg, 1 mg to 20 mg, 1 mg to 15 mg, 1.5 mg to 35 mg, 1.5 mg to 30 mg, 1.5 mg to 25 mg, 1.5 mg to 20 mg, 1.5 mg to 15 mg, 2 mg to 35 mg, 2 mg to 30 mg, 2 mg to 25 mg The active substance comprises mg, 2mg-20mg, 2mg-15mg, 2.5mg-35mg, 2.5mg-30mg, 2.5mg-25mg, 2.5mg-20mg, 2.5mg-15mg, 3mg-35mg, 3mg-30mg, 3mg-25mg, 3mg-20mg, and 3mg-15mg, for example, trimetazidine or a pharmaceutically acceptable salt thereof alone, or in combination with etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine or one or more pharmaceutically acceptable salts thereof.

[0048] In one embodiment, the pharmaceutical composition for non-enteral administration to a subject contains an active substance, for example, trimetazidine or a pharmaceutically acceptable salt thereof alone, or in combination with one or more etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine or any of the pharmaceutically acceptable salts thereof, at concentrations ranging from approximately 0.005 mg / ml to approximately 500 mg / ml. In one embodiment, the pharmaceutical composition for non-enteral administration contains an active substance, for example, trimetazidine or a pharmaceutically acceptable salt thereof alone, or in combination with one or more etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine or any of the pharmaceutically acceptable salts thereof, at concentrations, for example, about 0.05 mg / ml to about 50 mg / ml, about 0.1 mg / ml to about 50 mg / ml, about 0.1 mg / ml to about 10 mg / ml, about 0.05 mg / ml to about 25 mg / ml, about 0.05 mg / ml to about 10 mg / ml, about 0.05 mg / ml to about 5 mg / ml, or about 0.05 mg / ml to about 1 mg / ml. In one embodiment, the pharmaceutical composition for non-enteral administration contains an active substance, for example, trimetazidin or a pharmaceutically acceptable salt thereof alone, or in combination with one or more etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine or any of the pharmaceutically acceptable salts thereof, at concentrations of, for example, about 0.05 mg / ml to about 15 mg / ml, about 0.5 mg / ml to about 10 mg / ml, about 0.25 mg / ml to about 5 mg / ml, about 0.5 mg / ml to about 7 mg / ml, about 1 mg / ml to about 10 mg / ml, about 5 mg / ml to about 10 mg / ml, or about 5 mg / ml to about 15 mg / ml. In one embodiment, the pharmaceutical composition for non-enteral administration is formulated in total volume, for example, about 10 ml, 20 ml, 25 ml, 50 ml, 100 ml, 200 ml, 250 ml, or 500 ml. In one embodiment, the composition is packaged and stored in a bag, glass vial, plastic vial, or bottle.

[0049] In one embodiment, the solubility of an active substance, such as a fatty acid oxidation inhibitor, in a pharmaceutical composition for non-enteral administration may be higher than, for example, about 10 mg / mL, about 15 mg / mL, about 20 mg / mL, about 25 mg / mL, about 30 mg / mL, about 40 mg / mL, about 50 mg / mL, about 75 mg / mL, about 100 mg / mL, or about 150 mg / mL when measured in water at 25°C. In one embodiment, the solubility of an active substance in a pharmaceutical composition for non-enteral administration, such as trimetazidin or a pharmaceutically acceptable salt thereof alone, or in combination with etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine or one or more of the pharmaceutically acceptable salts thereof, may be higher than, for example, about 10 mg / mL, about 15 mg / mL, about 20 mg / mL, about 25 mg / mL, about 30 mg / mL, about 40 mg / mL, about 50 mg / mL, about 75 mg / mL, about 100 mg / mL, or about 150 mg / mL, when measured in water at 25°C. In one embodiment, the solubility of the active substance in the composition, for example, a fatty acid oxidation inhibitor, may be, for example, about 1 mg / mL to about 50 mg / mL, about 5 mg / mL to about 50 mg / mL, about 10 mg / mL to about 50 mg / mL, about 20 mg / mL to about 50 mg / mL, about 20 mg / mL to about 30 mg / mL, or about 10 mg / mL to about 45 mg / mL when measured in water at 25°C.

[0050] In one embodiment, the solubility of the active substance in the composition, for example, trimetazidin or a pharmaceutically acceptable salt thereof alone, or in combination with etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine or one or more of the pharmaceutically acceptable salts thereof, may be, for example, about 1 mg / mL to about 50 mg / mL, about 5 mg / mL to about 50 mg / mL, about 10 mg / mL to about 50 mg / mL, about 20 mg / mL to about 50 mg / mL, about 20 mg / mL to about 30 mg / mL, or about 10 mg / mL to about 45 mg / mL when measured in water at 25°C.

[0051] In one embodiment, a pharmaceutical composition for non-enteral administration is provided, which is stable for at least six months. In one embodiment, the pharmaceutical composition for non-enteral administration exhibits a decrease of approximately 5% or less of the active substance, such as trimetazidin or a pharmaceutically acceptable salt thereof alone, or in combination with etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine, or one or more of the pharmaceutically acceptable salts thereof, over, for example, three or six months. In one embodiment, the amount of trimetazidin or a pharmaceutically acceptable salt thereof alone, or in combination with etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine, or one or more of the pharmaceutically acceptable salts thereof, degrades by, for example, approximately 2.5%, 1%, 0.5%, or 0.1% or less. In one embodiment, the degradation is, for example, less than approximately 5%, 2.5%, 1%, 0.5%, 0.25%, or 0.1% over at least six months.

[0052] In one embodiment, a pharmaceutical composition for non-enteral administration is provided, in which the pharmaceutical composition remains soluble. In one embodiment, a pharmaceutical composition for non-enteral administration is provided, which is stable, soluble, site-compatible, and / or ready for use. In one embodiment, the pharmaceutical composition herein is ready for use for direct administration to a patient in need.

[0053] The non-enteral compositions provided herein may contain one or more additives, such as solvents, solubility enhancers, suspending agents, buffers, isotonic agents, stabilizers, or antimicrobial preservatives. When used, the additives of the non-enteral compositions do not adversely affect the stability, bioavailability, safety, and / or efficacy of trimetazidin or its pharmaceutically acceptable salt used in the composition alone, or in combination with etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine or one or more of the pharmaceutically acceptable salts thereof. Thus, non-enteral compositions are provided that are incompatible with any of the components of the dosage form.

[0054] In one embodiment, a non-enteral composition comprising trimetazidine or a pharmaceutically acceptable salt thereof alone, or in combination with etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine, or one or more pharmaceutically acceptable salts thereof, comprises at least one additive in a stabilizing amount. For example, the additive may include buffers, solubilizers, isotonic agents, antioxidants, chelating agents, antimicrobial agents, and preservatives. Those skilled in the art will understand that the additive has one or more functions and falls into one or more defined groups.

[0055] One embodiment provides a non-enteral composition comprising trimetazidine or a pharmaceutically acceptable salt thereof alone, or in combination with etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine or one or more pharmaceutically acceptable salts thereof, and an additive, wherein the additive is present in, for example, about 10%, 5%, 2.5%, 1%, or less than 0.5% by weight (w / v). One embodiment provides the additive being present in, for example, about 1.0% to 10%, 10% to 25%, 15% to 35%, 0.5% to 5%, 0.001% to 1%, 0.01% to 1%, 0.1% to 1%, or 0.5% to 1% by weight. One embodiment provides the additive being present in, for example, about 0.001% to 1%, 0.01% to 1%, 1.0% to 5%, 10% to 15%, or 1% to 15% by weight.

[0056] In one embodiment, the non-enteral composition may be administered, for example, once, two, three, or four times a day, or more times, or continuously, as needed by the patient.

[0057] In one embodiment, a non-enteral composition is provided comprising an active substance, for example, trimetazidine or a pharmaceutically acceptable salt thereof alone, or in combination with etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine or one or more pharmaceutically acceptable salts thereof, wherein the pH of the composition is about 4.0 to about 8.0. In one embodiment, the pH of the composition is, for example, about 5.0 to about 8.0, about 6.0 to about 8.0, or about 6.5 to about 8.0. In one embodiment, the pH of the composition is, for example, about 6.5 to about 7.5, about 7.0 to about 7.8, about 7.2 to about 7.8, or about 7.3 to about 7.6. In one embodiment, the pH of the aqueous solution is, for example, about 6.8, about 7.0, about 7.2, about 7.4, about 7.6, about 7.7, about 7.8, about 8.0, about 8.2, about 8.4, or about 8.6.

[0058] In one embodiment, the methods and pharmaceutical compositions described herein may be administered once, two, three, or four times a day or every other day. In one embodiment, the pharmaceutical composition described herein is provided to the patient in the morning. In one embodiment, the pharmaceutical composition described herein is provided to the patient once at night and once in the morning.

[0059] In one embodiment, the total amount of trimetazidine or a pharmaceutically acceptable salt administered to the subject over 24 hours is 20 mg to 200 mg. In one embodiment, the total amount of trimetazidine or a pharmaceutically acceptable salt administered to the subject over 24 hours is 20 mg to 100 mg. In one embodiment, the total amount of trimetazidine or a pharmaceutically acceptable salt administered to the subject over 24 hours is 20 mg to 80 mg. In one embodiment, the total amount of trimetazidine or a pharmaceutically acceptable salt administered to the subject over 24 hours is approximately 20 mg, 40 mg, or more than 60 mg. In one embodiment, the total amount of trimetazidine or a pharmaceutically acceptable salt administered to the subject over 24 hours is approximately 20 mg to more than 60 mg.

[0060] In one embodiment, a method is provided for preventing, mitigating, and / or treating contrast-induced acute kidney injury by administering an effective dose of trimetazidine or a pharmaceutically acceptable salt thereof alone, or in combination with etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine, or one or more pharmaceutically acceptable salts thereof, to patients in need. An effective dose or therapeutically effective dose may be a dose sufficient to treat, suppress, or mitigate one or more symptoms of contrast-induced acute kidney injury. For example, an effective dose of trimetazidine may be established by measuring the percentage of patients who experience a relative decrease of 30% or more in estimated or measured glomerular filtration rate (GFR) after a certain period of time (e.g., 15, 30, 60, or 90 days) following contrast agent administration. In other examples, an effective dose of trimetazidine, etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine may be established by measuring the percentage of patients who experience decreased or lost renal function after contrast agent administration. In one embodiment, the method is, for example, 90 mL / min / 1.73 m 2 Less than approximately 15-90 mL / min / 1.73 m 2 , about 60~90mL / min / 1.73m 2 Alternatively, approximately 15-60 mL / min / 1.73 m 2 This includes administering trimetazidine or a pharmaceutically acceptable salt thereof to patients with an estimated glomerular filtration rate of [value missing].

[0061] In one embodiment, impaired or lost renal function may be determined by measuring an absolute increase of 0.3 mg / dL or more in serum creatinine concentration between baseline and any point in time after contrast agent administration (e.g., up to 7 days). In one embodiment, the method comprises administering trimetazidine or a pharmaceutically acceptable salt thereof to a patient having a creatinine level of 0.4–1.3 mg / dL.

[0062] In one embodiment, the method includes administering trimetazidine or a pharmaceutically acceptable salt thereof to a patient having a creatinine level of less than 1.5 mg / dL. In one embodiment, the method includes administering trimetazidine or a pharmaceutically acceptable salt thereof to a patient having a creatinine level of 1.5 to 2.0 mg / dL. In one embodiment, the method includes administering trimetazidine or a pharmaceutically acceptable salt thereof to a patient having a creatinine level of 2.0 to 5.0 mg / dL. In one embodiment, the method includes administering trimetazidine or a pharmaceutically acceptable salt thereof to a patient having a creatinine level of 5.0 to 8.0 mg / dL. In one embodiment, the method includes administering trimetazidine or a pharmaceutically acceptable salt thereof to a patient having a creatinine level greater than 8.0 mg / dL.

[0063] In one embodiment, impaired or lost renal function may be determined by measuring a relative increase of 50% or more in serum creatinine concentration between baseline and any point in time after contrast agent administration (e.g., up to 7 days). In one embodiment, impaired or lost renal function may be determined by measuring a relative decrease of 30% or more in estimated or measured glomerular filtration rate (GFR) between baseline and any point in time after contrast agent administration (e.g., up to 7 days).

[0064] One embodiment provides a method for preventing, mitigating, and / or treating contrast-induced acute kidney injury by administering an effective amount of a fatty acid oxidation inhibitor to a patient in need before, during, and after a procedure, including the use of a device, e.g., a guidewire and an intracoronary pressure wire; a cardiac catheter, e.g., a balloon catheter; an atherectomy device, e.g., a rotational atherectomy catheter; an intracoronary stent (including bare-metal stents, drug-eluting stents (e.g., sirolimus, paclitaxel, everolimus, and zotarolimus), stents coated with bioabsorbable polymers, and stents having a fully bioabsorbable scaffold); a thrombus aspiration catheter; an embolic protection device; a replacement cardiac valve and / or vascular closure device. In one embodiment, a method is provided for preventing, mitigating, and / or treating contrast-induced acute kidney injury by administering to a patient in need an effective amount of trimetazidine or a pharmaceutically acceptable salt thereof alone, or in combination with etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine or one or more pharmaceutically acceptable salts thereof, before, during, and after the procedure, to a patient in need, including a device, e.g., a guidewire and an intracoronary pressure wire, a cardiac catheter, e.g., a balloon catheter, an atherectomy device, e.g., a rotational atherectomy catheter, an intracoronary stent (including bare metal stents, drug (e.g., sirolimus, paclitaxel, everolimus, and zotarolimus) eluting stents, stents coated with bioabsorbable polymers, and stents having a fully bioabsorbable scaffold), a thrombus aspiration catheter, an embolic protection device, a replacement cardiac valve, and / or vascular closure device.

[0065] In one embodiment, an effective amount of trimetazidine or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof in combination with or before and / or after administration of a contrast agent, such as barium sulfate, iodine, and gadolinium, an anticoagulant, such as acetylsalicylic acid, unfractionated heparin, low molecular weight heparin (enoxaparin), synthetic pentasaccharide / Xa factor inhibitor (including fondaparinux), dipyridamole, argatroban, and / or bivalirudin, ticlopidine, cilostazol, and an antiplatelet agent, such as cangrelol, clopidogrel, prasugrel, ticagrelor, aspirin, and / or a glycoprotein IIb / IIIa antagonist, such as abciximab, eptifibatide, and tirofiban, to prevent, mitigate, and / or treat contrast agent-induced acute kidney injury.

[0066] In one embodiment, a method for preventing, mitigating, and / or treating contrast agent-induced acute kidney injury, comprising administering trimetazidine or a pharmaceutically acceptable salt thereof to a patient in need thereof, wherein the composition has a C max in vivo plasma profile greater than about 65 μg / ml.

[0067] In one embodiment, the composition provides an in vivo plasma profile having a C greater than, for example, 75 μg / ml, 85 ng / ml, 90 ng / ml, or 100 ng / ml. In one embodiment, the composition provides an in vivo plasma profile having a C max less than, for example, 250 μg / ml, 200 μg / ml, 150 μg / ml, or 100 μg / ml. In one embodiment, a method for treating contrast agent-induced acute kidney injury, comprising administering a pharmaceutical composition comprising an active substance, such as trimetazidine or a pharmaceutically acceptable salt, to a patient in need thereof, wherein the composition has a C max in vivo plasma profile greater than about 100 μg / ml. max in vivo plasma profile greater than about 100 μg / ml.

[0068] The effective dose of fatty acid oxidation inhibitor required for administration can depend on many factors. The effective dose of trimetazidine or a pharmaceutically acceptable salt required for administration can depend on many factors. The effective dose of etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine or a pharmaceutically acceptable salt of any of the above required for administration can depend on many factors. For example, the dose sufficient to treat, suppress, or alleviate one or more symptoms of contrast-induced acute kidney injury depends on the actual exposure (AUC) received by the patient. Therefore, in some cases, subjects with renal failure undergoing diagnostic or interventional cardiac procedures requiring contrast administration may require less fatty acid oxidation inhibitor to achieve an effective dose of exposure. In some cases, subjects with renal failure undergoing diagnostic or interventional cardiac procedures requiring contrast administration may require less trimetazidine or a pharmaceutically acceptable salt thereof to achieve an effective dose of exposure. In some cases, subjects with renal failure undergoing diagnostic or interventional cardiac procedures requiring contrast agent administration may require less etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine, or any pharmaceutically acceptable salt thereof, to achieve an effective dose of exposure.

[0069] In one embodiment, a method is provided for preventing, mitigating, and / or treating contrast-induced acute kidney injury, comprising administering trimetazidine or a pharmaceutically acceptable salt thereof to a patient in need thereof, wherein the composition provides an in vivo plasma profile having an AUC greater than about 500 μg·hr / ml.

[0070] In one embodiment, a method for preventing, mitigating, and / or treating contrast-induced acute kidney injury comprises administering a pharmaceutical composition to a patient in need thereof, wherein the AUC is greater than approximately 500 μg·hr / ml. 0-∞ A method is provided for providing a consistent in vivo plasma profile having [a certain characteristic].

[0071] In one embodiment, the composition has an AUC of approximately 550 μg·hr / ml, 600 μg·hr / ml, 650 μg·hr / ml, 850 μg·hr / ml, 800 μg·hr / ml, 750 μg·hr / ml, or 700 μg·hr / ml, 900 μg·hr / ml, 1000 μg·hr / ml, 1250 μg·hr / ml, 1500 μg·hr / ml, 2000 μg·hr / ml, 3000 μg·hr / ml, 4000 μg·hr / ml, or greater than 5000 μg·hr / ml. 0-∞ It provides an in vivo plasma profile having the following characteristics.

[0072] In one embodiment, a patient requiring it should have AUC more than 48 hours prior to receiving cardiac treatment. 0-∞ To maintain this, trimetazidine or a pharmaceutically acceptable salt thereof is administered. For example, the method is to maintain an AUC of approximately 500 μg·hr / ml, 600 μg·hr / ml, 750 μg·hr / ml or greater than 1000 μg·hr / ml. 0-∞ It may be possible to provide and maintain an in vivo plasma profile having [specific characteristics].

[0073] In one embodiment, patients who require it have a longer AUC than 30 days after receiving cardiac treatment. 0-∞ To maintain this, trimetazidine or a pharmaceutically acceptable salt thereof is administered. In one embodiment, patients requiring this are given a longer AUC than 60 days after cardiac treatment. 0-∞ To maintain this, trimetazidine or a pharmaceutically acceptable salt thereof is administered. In one embodiment, patients requiring this are given a maximum AUC of 75 days after cardiac treatment. 0-∞ To maintain this, trimetazidine or a pharmaceutically acceptable salt thereof is administered. In one embodiment, patients requiring this are given AUC for more than 90 days after cardiac treatment. 0-∞ To maintain this, trimetazidine or a pharmaceutically acceptable salt thereof is administered. For example, the method is to maintain an AUC of approximately 500 μg·hr / ml, 600 μg·hr / ml, 750 μg·hr / ml or greater than 1000 μg·hr / ml. 0-∞It may provide and maintain an in vivo plasma profile having AUC for a total of 90 days. In one embodiment, a patient requiring it may have a total AUC 0-∞ To maintain this condition, trimetazidine or a pharmaceutically acceptable salt thereof is administered.

[0074] In one embodiment, a method is provided for preventing, mitigating, and / or treating contrast-induced acute kidney injury, comprising administering more than 20 mg of trimetazidine or a pharmaceutically acceptable salt thereof to a patient in need. The patient may be undergoing a cardiac procedure requiring the administration of a contrast agent for imaging. In some embodiments, the patient may be administered trimetazidine or a pharmaceutically acceptable salt thereof before undergoing the cardiac procedure. For example, the patient may be administered trimetazidine or a pharmaceutically acceptable salt thereof for more than 48 hours before undergoing the cardiac procedure. In some examples, the patient in need may be administered trimetazidine or a pharmaceutically acceptable salt thereof for at least 96 hours before undergoing the cardiac procedure (e.g., being given a contrast agent). Trimetazidine or a pharmaceutically acceptable salt thereof may be administered twice daily. In some embodiments, trimetazidine or a pharmaceutically acceptable salt thereof may be administered three times daily. In some embodiments, the patient in need is administered trimetazidine or a pharmaceutically acceptable salt thereof three times daily for 48 hours before undergoing the cardiac procedure (e.g., being given a contrast agent). In some embodiments, patients are administered trimetazidine or a pharmaceutically acceptable salt thereof for more than 60 days after cardiac treatment. In some embodiments, patients who require it are administered trimetazidine or a pharmaceutically acceptable salt thereof three times daily for 90 days after contrast agent administration. For example, the total amount of trimetazidine or a pharmaceutically acceptable salt thereof administered to a patient over 24 hours may be about 60 mg.

[0075] In some embodiments, trimetazidine or a pharmaceutically acceptable salt thereof is administered to the patient before, during, and / or after a surgical procedure, including the use of one or more guidewires, intracoronary pressure wires, cardiac catheters, atherectomy devices, intracoronary stents, thrombus aspiration catheters, embolic protection devices, replacement heart valves, or vascular closure devices. In some embodiments, trimetazidine or a pharmaceutically acceptable salt thereof is administered to the patient before, during, and / or after a cardiac procedure, including contrast agents, anticoagulants, and / or antiplatelet agents. In some embodiments, trimetazidine or a pharmaceutically acceptable salt thereof is administered in combination with etomoxyl, oxphenicin, perhexylline, mildronate, or lanolazine, or one or more of the pharmaceutically acceptable salts thereof.

[0076] In some embodiments, a method for preventing and / or treating contrast-induced acute kidney injury comprises administering trimetazidine or a pharmaceutically acceptable salt thereof to a patient in need thereof, wherein the composition contains more than about 65 μg / ml of C maxA method is provided for providing an in vivo plasma profile that defines a contrast agent-induced acute kidney injury. In some embodiments, a method is provided for preventing and / or treating contrast agent-induced acute kidney injury, comprising administering trimetazidine or a pharmaceutically acceptable salt thereof to a patient in need thereof, wherein the composition provides an in vivo plasma profile that defines an AUC greater than about 500 μg·hr / ml. For example, a patient may be undergoing a cardiac procedure that requires the administration of a contrast agent for imaging. In some embodiments, the patient is administered trimetazidine or a pharmaceutically acceptable salt thereof for 48 hours before undergoing the cardiac procedure (e.g., being given a contrast agent). In some examples, a patient in need thereof may be administered trimetazidine or a pharmaceutically acceptable salt thereof for at least 96 hours before undergoing the cardiac procedure (e.g., being given a contrast agent). Trimetazidine or a pharmaceutically acceptable salt thereof may be administered twice daily. In some embodiments, trimetazidine or a pharmaceutically acceptable salt thereof may be administered three times daily. In some embodiments, patients requiring it are administered trimetazidine or a pharmaceutically acceptable salt thereof three times daily for 48 hours prior to cardiac treatment (e.g., administration of a contrast agent). In some embodiments, patients are administered trimetazidine or a pharmaceutically acceptable salt thereof for more than 60 days after cardiac treatment. In some embodiments, patients requiring it are administered trimetazidine or a pharmaceutically acceptable salt thereof three times daily for 90 days after administration of a contrast agent. For example, the total amount of trimetazidine or a pharmaceutically acceptable salt thereof administered to a patient over 24 hours may be about 60 mg.

[0077] In one embodiment, a method for treating and / or preventing contrast-induced acute kidney injury comprises the administration of trimetazidine or a pharmaceutically acceptable salt, derivative, and / or analog thereof in combination with one or more other activators. The combination therapy may comprise the administration of activators in the same mixture or in separate mixtures. In one embodiment, the pharmaceutical composition comprises two, three, or more activators.

[0078] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art of the field to which this disclosure belongs.

[0079] As used herein, the terms “about” or “approximately” mean a range of acceptable error for a particular value as determined by those skilled in the art, which depends in part on how the value is measured or determined, i.e., on the limits of the measurement system. For example, “about” may mean within 3 or more than 3 standard deviations, according to convention in the art. Alternatively, “about” may mean a range of up to 20%, preferably up to 10%, more preferably up to 5%, and even more preferably up to 1% of a given value. Or, particularly with respect to biological systems or processes, the term may mean within one order of magnitude of the value, preferably up to 5 times, and more preferably up to 2 times.

[0080] As used herein, the terms “to treat” or “treatment” mean reducing, attenuating, or delaying the onset of clinical symptoms of a disease or condition in an object that may have or be predisposed to the disease or condition but has not yet experienced or shown any clinical or subclinical symptoms of the disease or condition. In one embodiment, “to treat” or “treatment” may mean preventing the onset of clinical symptoms of a disease or condition in an object that may have or be predisposed to the disease or condition but has not yet experienced or shown any clinical or subclinical symptoms of the disease or condition. “To treat” or “treatment” may also mean suppressing the disease or condition, for example, blocking or reducing at least one of its clinical or subclinical symptoms. “To treat” or “treatment” may further mean alleviating the disease or condition, for example, causing regression of the disease or condition or at least one of its clinical or subclinical symptoms. The benefit to the treated object may be statistically significant, mathematically significant, or at least perceptible to the object and / or the physician. However, preventive and therapeutic measures are two separate embodiments of the disclosure herein.

[0081] "Effective dose" or "therapeutic effective dose" means a dose sufficient to alleviate one or more symptoms of the disorder, disease, or condition to be treated, or otherwise to provide the desired pharmacological and / or physiological effect.

[0082] "MARCE" refers to "Major Adverse Renal and Cardiac Events" and is defined as one or more of the following events: cardiovascular death, non-fatal myocardial infarction or non-fatal stroke, heart failure, need for renal replacement therapy, hospitalization for cardiac or renal reasons, sustained >25% decline in eGFR, or prolonged hospitalization or readmission.

[0083] "Medically acceptable" means molecular entities and compositions that, when administered to humans, are "generally considered safe," e.g., physiologically acceptable and do not typically cause allergic or similar adverse reactions, such as stomach upset. In one embodiment, this term means molecular entities and compositions approved by a federal or state regulatory authority as a GRAS (Generally Recognized As Safe) list under Sections 204(s) and 409 of the Federal Food, Drug and Cosmetic Act, subject to premarket review or approval by the FDA or a similar list, the United States Pharmacopeia, or another generally accepted pharmacopoeia for use in animals, more specifically in humans.

[0084] The terms "co-administered with," "administered in combination with," "combined with," or "administered together" can be used interchangeably to mean that two or more drugs are administered in the course of treatment. The drugs may be administered simultaneously or separately at intervals. The drugs may be administered in a single dosage form or in separate dosage forms.

[0085] "Contrast agents" or "contrast media" include, but are not limited to, iodine, barium, and gadolinium. For example, iodine-based and barium sulfate compounds are commonly used in X-ray and computed tomography (CT) imaging. The methods described herein may be used in any procedure using contrast agents (including, but not limited to, X-ray imaging and magnetic resonance imaging), cardiac procedures, and imaging of the gastrointestinal tract (including computed tomography, angiography, venography, VCUG (excretory cystourethrography), HSG (hysterosalpingography), and IVU (intravenous urography)).

[0086] As used herein, the terms “prevention” or “prevention” mean administering a composition to an organism or system at risk of or predisposed to one or more symptoms caused by a disease or disorder to promote the discontinuation of a particular symptom of the disease or disorder, the reduction or prevention of one or more symptoms of the disease or disorder, the reduction of the severity of the disease or disorder, the complete resection of the disease or disorder, or the stabilization or delay of the epilepsy or progression of the disease or disorder.

[0087] As used herein, "prodrug" refers to a pharmacological substance (drug) administered to a target organism in an inactive (or significantly less active) form. Upon administration, the prodrug is metabolized in the body (in vivo) into a compound with the desired pharmacological activity.

[0088] "Analogs" and "derivatives" refer to compounds that are interchangeable and have the same nucleus as the parent compound, but may differ from the parent compound in terms of bond order, the presence or absence of one or more atoms and / or groups of atoms and their combinations. Derivatives may differ from the parent compound, for example, in one or more substituents present in the nucleus, which may include one or more atoms, functional groups, or substructures. Generally, it can be inferred that derivatives are formed from the parent compound, at least theoretically, through chemical and / or physical processes.

[0089] As used herein, “stereoisomers” refer to isomeric molecules that have the same molecular formula and bond order (composition) but differ in the three-dimensional orientation of their atoms in space. Examples of stereoisomers include enantiomers and diastereomers. As used herein, an enantiomer refers to one of two enantiomers of an optically active or chiral molecule. A diastereomer (or diastereoisomer) is a stereoisomer that is not an enantiomer (it is a mirror image that cannot be superimposed on each other). A chiral molecule contains a chiral center, also called a stereocenter or stereogenic center, which is any point in a molecule having groups such that the exchange of any two groups results in a stereoisomer, and is not necessarily an atom. In organic compounds, the chiral center is typically a carbon, phosphorus, or sulfur atom, but other atoms can also be stereocenters in organic and inorganic compounds. A molecule may have multiple stereocenters and provide many stereoisomers. In compounds where stereoisomerism is due to tetrahedral stereogenic centers (e.g., tetrahedral carbons), the hypothetically possible total number of stereoisomers is not greater than 2n, where n is the number of tetrahedral stereocenters. Molecules with symmetry often have a smaller maximum number of possible stereoisomers. A 50:50 mixture of enantiomers is called a racemic mixture. Alternatively, a mixture of enantiomers can be enantiomerically enriched such that one enantiomer is present in greater than 50% of the mixture. Enantiomers and / or diastereomers can be divided or separated using techniques known in the art. "Chirality" also includes axial or planar chirality.

[0090] As used herein, the term "pharmaceutically acceptable salt" refers to a derivative of a compound described herein, which is modified by forming an acid salt or base salt of the parent compound. Examples of pharmaceutically acceptable salts include, but are not limited to, metal or organic acid salts of basic residues such as amines, and alkali or organic salts of acidic residues such as carboxylic acids. pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts of the parent compound, for example, formed from non-toxic inorganic or organic acids. Such conventional non-toxic salts include those derived from inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitric acid; as well as salts produced from organic acids, such as acetic acid, propionic acid, gojiacin, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetooxybenzoic acid, fumaric acid, toluenesulfonic acid, naphthalenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, and isethionates. [Examples]

[0091] The examples provided herein are included solely to enhance the disclosure herein and should not be considered limiting in any way.

[0092] Example 1 The following prophetic example may be used to evaluate the effect of trimetazidine on the prevention of contrast-induced acute kidney injury in high-risk patients undergoing percutaneous coronary intervention (PCI) or peripheral transcatheter angioplasty (PTA). This multicenter, randomized, double-blind, placebo-controlled trial may be used to evaluate the efficacy of trimetazidine in reducing the incidence of CI-AKI in high-risk patients undergoing planned percutaneous coronary intervention (PCI) or peripheral transcatheter angioplasty (PTA). This trial may also be used to determine the efficacy of trimetazidine in reducing the incidence of clinical adverse events (death, RRT, MI, stroke, clinically driven revascularization, or major adverse cardiovascular events) at 30 days in high-risk patients undergoing planned PCI or PTA. This trial may be used to determine the efficacy of trimetazidine in reducing the incidence of clinical adverse events (death, RRT, MI, stroke, clinically necessary revascularization, or major adverse cardiovascular events) at 90 days in high-risk patients undergoing planned PCI or PTA. This trial may also be used to determine the efficacy of trimetazidine in reducing the incidence of clinical adverse events (death, RRT, MI, stroke, clinically necessary revascularization, or major adverse cardiovascular events) at 1 year in high-risk patients undergoing planned PCI or PTA.

[0093] The primary efficacy endpoint of this study may include the incidence of CI-AKI at 72 hours post-contrast exposure. CI-AKI may be defined as an increase in serum creatinine >0.5 mg / dl (44.2 μmol / L) or a percentage increase of 50% or more in serum creatinine from baseline blood sample taken before contrast exposure. The primary efficacy endpoint may include a composite incidence of clinical adverse events at 30 days, including death, RRT, MI, stroke, clinically required revascularization, or major adverse cardiovascular events. Further efficacy endpoints may optionally include a composite incidence of clinical adverse events at 90 days, including death, RRT, MI, stroke, clinically required revascularization, or major adverse cardiovascular events. Further efficacy endpoints may optionally include a composite incidence of clinical adverse events at 1 year, including death, RRT, MI, stroke, clinically required revascularization, or major adverse cardiovascular events.

[0094] Secondary endpoints may include one or more of the following clinical events within 30 days: all-cause mortality; myocardial infarction; dialysis-dependent renal failure; unplanned readmission; repeated coronary revascularization of target lesions; massive bleeding (unrelated to coronary artery bypass procedure); major adverse cardiovascular events and strokes. Further secondary endpoints may include the following laboratory-based metrics at 72 hours: percentage of subjects with >0.5 mg / dl (44.2 μmol) SCr increase; percentage of subjects with >25% SCr increase; percentage of subjects with >100% SCr increase; percentage of subjects with >200% SCr increase; and mean change in eGFR.

[0095] Example 2 The following hypothetical example could be used to evaluate the effect of trimetazidine on reducing the risk of contrast-induced acute kidney injury (CI-AKI) and associated major adverse renal and cardiac events (MARCEs). This multicenter, randomized, double-blind, placebo-controlled trial could be used to evaluate the proportion of subjects experiencing any adverse renal and cardiac event (MARCE) over 90 days following the day of contrast administration in the trimetazidine group and the placebo group. MARCEs are defined as cardiovascular death, non-fatal myocardial infarction, heart failure, need for renal replacement therapy, hospitalization for cardiac or renal reasons, and a decrease of ≥25% in eGFR. Further outcome measures may include differences between subjects treated with trimetazidine and placebo in one or more of the following: (1) the incidence of CI-AKI based on the KDIGO definition of CI-AKI; (2) the total number of MARCE events, as each subject may experience multiple events; (3) the proportion of subjects experiencing cardiovascular death; (4) the proportion of subjects experiencing non-fatal myocardial infarction; (5) the proportion of subjects experiencing heart failure; (6) the proportion of subjects requiring renal replacement therapy; (7) the number of days alive after discharge; (8) the proportion of subjects readmitted for cardiac or renal reasons; (9) the proportion of subjects maintaining an eGFR decline of ≥25% at 90 days; and / or (10) the change from baseline in the subjects' QoL.

[0096] Within approximately 48 hours prior to the estimated start of angiography (e.g., arterial sheath insertion), trimetazidine may be administered in a planned range, e.g., 3–6 doses, according to the planned schedule. Administration may continue for up to 120 days from the date of treatment, e.g., 90 days, based on the results observed during follow-up visits. For example, follow-up may occur at 1, 2, 4, 7, 30, 60, 90, or 120 days. Subjects may have one or more of the following criteria: eGFR <45 mL / min and >15 mL / min as determined by the Modification of Diet in Renal Disease (MDRD) formula, or eGFR <60 mL / min and ≥45 mL / min as determined by the MDRD formula, and diabetes mellitus, congestive heart failure, or anemia.

[0097] Example 3 The following hypothetical example could be used to evaluate the effect of trimetazidine on reducing the risk of contrast-induced acute kidney injury (CI-AKI) and related major adverse kidney and cardiac events (MARCE). This multicenter, randomized, double-blind, placebo-controlled trial could be used to evaluate the efficacy of trimetazidine for reducing major adverse kidney and cardiac events (MARCE), preventing contrast-induced acute kidney injury (CI-AKI), and / or for reducing individual components of MARCE. The primary outcome measure may include determining the difference in time to the first major adverse kidney and cardiac event (MARCE) between trimetazidine and placebo over a certain period (e.g., 90 days) after the day of contrast treatment. Other outcome measures may include differences between subjects treated with trimetazidine and placebo in the following: (1) the incidence of CI-AKI based on the KDIGO definition of CI-AKI from baseline to end of treatment (e.g., day 90); (2) the proportion of subjects experiencing any MARCE event; (3) the total number of MARCE events, as each subject may experience multiple events; (4) time to cardiovascular death; (5) time to non-fatal myocardial infarction; (6) time to non-fatal stroke; (7) time to heart failure; (8) time to renal replacement therapy; (9) duration of index hospitalization; (10) days alive after discharge; (11) the proportion of subjects maintaining an eGFR decline of >20%; (12) the proportion of subjects with prolonged hospitalization or readmission events; and / or (13) time to readmission for cardiac or renal reasons. During this theoretical trial, subjects may receive either trimetazidine (e.g., 20 mg three times daily) or a placebo daily. During index hospitalization, all subjects will be given intravenous isotonic crystalloid solution (normal saline or sodium bicarbonate) in accordance with the standards for conducting clinical trials of pharmaceuticals. For example, within approximately 48 hours prior to the estimated start of angiography, trimetazidine may be administered in a planned range of 3–6 doses (e.g., 20 mg three times daily for 1–2 days). Subsequently, subjects may continue to receive trimetazidine from the day of index treatment for the treatment period (e.g., a further 90 days).One or more outcome measures may be evaluated at regular intervals between the start of the study and the total treatment time, for example, at 1, 2, 4, 7, 14, 30, 60, and / or 90 days.

[0098] Those skilled in the art will be able to identify and verify many equivalents to the embodiments and examples described herein by means of routine experiments. Such equivalents are intended to be included in the claims.

Claims

1. A composition for use in a method to achieve reduction and / or prevention of contrast-induced acute kidney injury (CI-AKI) resulting from a procedure using a contrast agent in a patient having renal impairment, the composition comprising an effective amount of trimetazidine (TMZ) or a pharmaceutically acceptable salt thereof as an active ingredient, the method comprising administering the composition to the patient one to twelve hours before the patient undergoes the procedure, and continuing administration of the composition for at least about ninety days after the procedure.

2. The composition for use according to claim 1, wherein the patient having renal impairment has an estimated glomerular filtration rate (eGFR) of less than 90 mL / min / 1.73 m².

3. The composition for use according to claim 2, wherein the eGFR is between approximately 15 and 90 mL / min / 1.73 m², between approximately 60 and 90 mL / min / 1.73 m², or between approximately 15 and 60 mL / min / 1.73 m².

4. The composition for use according to claim 1, wherein the treatment is a cardiac treatment.

5. The composition for use according to claim 4, wherein the cardiac procedure is coronary angiography.

6. The composition for use according to claim 4, wherein the cardiac procedure is percutaneous coronary intervention.

7. The composition for use according to claim 4, wherein the cardiac procedure is peripheral transcatheter angioplasty.

8. The composition for use according to claim 4, which reduces the risk of major adverse kidney and cardiac events.