WO2022261102A1 - Method of treating patients with hepatorenal syndrome type 1 - Google Patents
Method of treating patients with hepatorenal syndrome type 1 Download PDFInfo
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- WO2022261102A1 WO2022261102A1 PCT/US2022/032511 US2022032511W WO2022261102A1 WO 2022261102 A1 WO2022261102 A1 WO 2022261102A1 US 2022032511 W US2022032511 W US 2022032511W WO 2022261102 A1 WO2022261102 A1 WO 2022261102A1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/08—Peptides having 5 to 11 amino acids
- A61K38/095—Oxytocins; Vasopressins; Related peptides
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P13/12—Drugs for disorders of the urinary system of the kidneys
Definitions
- a computer readable text file entitled “105870_726724_SequenceListing_ST25.txt” created on or about 6 June 2022, with a file size of about 1 kilobyte contains the sequence listing for this application and is hereby incorporated by reference in its entirety.
- Principles and embodiments of the present disclosure relate generally to methods of treating patients with type-1 hepatorenal syndrome.
- Hepatorenal Syndrome Type-1 (HRS Type 1 or HRS-1) is the development of acute kidney failure in patients with late-stage liver cirrhosis in the absence of any other cause. It is characterized by rapid onset of renal failure with a high mortality rate that exceeds 80% with within three months. Renal failure is an identified complication of cirrhosis of the liver; and, acute renal failure is known to have poor prognosis for patients with cirrhosis of the liver. In various instances, the renal failure may be caused by hypovolemia, hepatorenal syndrome without ongoing infection, or hepatorenal syndrome with an ongoing infection. Unfortunately, patients with HRS Type-1 may die from renal failure while waiting for a liver transplant.
- HRS Hepatorenal Syndrome
- HRS is indicated by low glomerular filtration rate due to renal vasoconstriction, splanchnic and peripheral arterial vasodilatation producing decreased vascular resistance, and portal hypertension.
- HRS is indicated by cirrhosis with ascites, serum levels of creatinine>133 pmol/l (1.5 mg/dL), no improvement of serum levels of creatinine (decrease to a level of £133 pmol/l) after at least 2 days of diuretic withdrawal and volume expansion with albumin, and the absence of shock and parenchymal kidney disease.
- HRS Type 1 is indicated by doubling of the initial serum levels of creatinine to >226 pmol/l (2.56 mg/dL) in ⁇ 2 weeks.
- kidney function such as sodium and solute-free water retention, which can lead to ascites and edema, and to renal failure by causing intrarenal vasoconstriction and hypoperfusion.
- Ascites can result from the combination of portal hypertension and splanchnic arterial vasodilation that alters intestinal capillary pressure and permeability, which facilitates the accumulation of the retained fluid in the abdominal cavity.
- a factor contributing to ascites formation is a splanchnic vasodilation that results in a decreased effective arterial blood volume.
- Portal hypertension also results from increased hepatic resistance to portal blood flow in cirrhotic livers, and may induce splanchnic vasodilation.
- SIRS Systemic Inflammatory Response Syndrome
- Sepsis has been defined as a systemic inflammatory response to infection, and septic shock is sepsis complicated by either hypotension that is refractory to fluid resuscitation or by hyperlactatemia.
- Terlipressin is a synthetic analogue of vasopressin having a prolonged effect, which acts as a peptidic vasopressin Via receptor agonist.
- Terlipressin is a derivative of vasotocin prepared by extending the N-terminal by three amino acid residues, and used as a vasoactive drug in the management of hypotension.
- Terlipressin may be synthesized by coupling amino acids stepwise to one another in a liquid or solid phase with a peptide synthesizer.
- Terlipressin is a prodrug that slowly metabolizes to lysine-vasopressin and in this way provides prolonged biological effect.
- the half-life of terlipressin is 6 hours (the duration of action is 2-10 hr), as opposed to the short half-life of vasopressin, which is only 6 minutes (the duration of action is 30-60 min).
- N — [N — (N-glycylglycyl)glycyl]-8-L- lysinevasopressin is a synthetically manufactured hormonogen of 8-lysine vasopressin, composed of 12 amino acids and having the characteristic ring structure of a cyclic nonapeptide with a disulfide bridge between the fourth and the ninth amino acid.
- Terlipressin may be present in pharmaceutical compositions as a salt, diacetate salt, hydrate, and/or free base, such as terlipressin acetate or terlipressin diacetate pentahydrate.
- Principles and embodiments of the present disclosure relate generally to methods of treating patients having HRS-1 by administering terlipressin to the patients to obtain reversal of the HRS-1.
- response criteria provide a new and useful function of indicating a likelihood of improved response by a patient to the administration of terlipressin.
- Some aspects of the disclosure relate to a method of treating a patient with hepatorenal syndrome Type 1 (HRS-1) comprising: administering a dose of terlipressin to the patient by intravenous (IV) injection, when the patient is listed for transplant at baseline and has a baseline model end stage liver disease (MELD) score of less than 35; and discontinuing administration or reducing the dose of terlipressin in patients with serum creatinine (SCr) > 5 mg/dl and/or an acute-on-chronic liver failure (ACLF) Grade > 3.
- the terlipressin may be administered every 6 hours by IV bolus injection over 2 minutes.
- the method may further comprise acquiring the baseline MELD score of the patient. In additional aspects, the method may further comprising acquiring the SCr level in the patient prior to administering the dose of terlipressin to determine a baseline SCr level. In some examples, the terlipressin may not be administered if the baseline SCr > 5 mg/dl and/or the baseline ACLF grade > 3.
- the patient’s risk of mortality is decreased.
- the patient’s place on a transplant list may not be compromised or impacted by the administration of terlipressin.
- the patient may have an increased risk of their place on a transplant list being compromised or impacted due to the administration of terlipressin.
- the patient’s ICU stay, non-ICU stay, and/or total length of hospital stay may be shortened.
- terlipressin administration is continued until there is a complete response or a partial response.
- discontinuing administration or reducing the dose of terlipressin occurs in patients with respiratory failure.
- the patient may also have severe kidney disease, pulmonary edema, dyspnea, or a combination thereof.
- the method may further comprise monitoring the patient’s oxygen saturation during treatment with terlipressin. The monitoring of the oxygen saturation decreases the occurrence of adverse events.
- Additional aspects of the disclosure relate to a method of treating a patient with hepatorenal syndrome Type 1 (HRS-1) comprising: administering a dose of terlipressin to the patient by intravenous (IV) injection when the patient has a baseline model end stage liver disease (MELD) score of less than 35 and is listed for transplant.
- the method may further comprise acquiring the baseline MELD score of the patient.
- the method may further comprise not administering, discontinuing administration, or reducing the dose of terlipressin in patients with serum creatinine (SCr) > 5 mg/dl and/or an acute-on-chronic liver failure (ACLF) Grade > 3.
- SCr serum creatinine
- ACLF acute-on-chronic liver failure
- HRS-1 hepatorenal syndrome Type 1
- HRS-1 hepatorenal syndrome Type 1
- a method of treating a patient with hepatorenal syndrome Type 1 comprising: acquiring a baseline model end stage liver disease (MELD) score of the patient; acquiring a SCr level in the patient prior to administering a dose of terlipressin to determine a baseline SCr level; and administering a dose of terlipressin to the patient if the baseline MELD score is ⁇
- MELD model end stage liver disease
- the baseline SCr level is ⁇ 5 mg/dl
- the patient has an ACLF Grade ⁇ 3, or a combination thereof.
- the patient may be listed for transplant.
- the patient may have a MELD score > 35 if the patient is not listed for transplant at baseline.
- the terlipressin may be administered to the patient by intravenous (IV) injection.
- HRS-1 hepatorenal syndrome Type 1
- IV intravenous
- SCr serum creatinine
- the method may further comprise: monitoring the patient for fluid overload during treatment with the terlipressin; and reducing or discontinuing the terlipressin dose if fluid overload develops.
- the method may further comprise administering diuretics to the patient and/or measuring the SCr level in the patient.
- aspects of the disclosure relate to a method of increasing overall survival of a patient with hepatorenal syndrome Type 1 (HRS-1), the method comprising: acquiring a baseline model end stage liver disease (MELD) score of the patient; acquiring a SCr level in the patient to determine a baseline SCr level; and administering a dose of terlipressin to the patient if the patient’s baseline MELD score is ⁇ 35 and the baseline SCr level is ⁇ 5 mg/dl.
- the patient may be listed for transplant at baseline.
- the patient may have a MELD score > 35 if the patient is not listed for transplant at baseline.
- Additional aspects of the disclosure relate to a method of decreasing an overall ICU or hospital stay of a patient with hepatorenal syndrome Type 1 (HRS-1 ), the method comprising: acquiring a baseline model end stage liver disease (MELD) score of the patient; acquiring a SCr level in the patient to determine a baseline SCr level; and administering a dose of terlipressin to the patient if the patient’s baseline MELD score is ⁇ 35 and the baseline SCr level is ⁇ 5 mg/dl.
- the patient may be listed for transplant at baseline.
- the patient may have a MELD score > 35 if the patient is not listed for transplant at baseline.
- Additional aspects of the disclosure relate to a method of increasing a complete response of a patient with hepatorenal syndrome Type 1 (HRS-1), the method comprising: acquiring a baseline model end stage liver disease (MELD) score of the patient; acquiring a SCr level in the patient to determine a baseline SCr level; administering a dose of terlipressin to a patient by intravenous (IV) injection if the patient’s baseline MELD score is ⁇ 35 and the patient’s baseline SCr level is ⁇ 5 mg/dl; measuring the SCr level in the patient during administration of terlipressin; and continuing administration of terlipressin until the patient’s SCr level is £1.5 mg/dl.
- the patient may be listed for transplant at baseline.
- the patient may have a MELD score > 35 if the patient is not listed for transplant at baseline.
- Further aspects of the disclosure relate to a method of increasing a partial response of a patient with hepatorenal syndrome Type 1 (HRS-1), the method comprising: acquiring a baseline model end stage liver disease (MELD) score of the patient; acquiring a SCr level in the patient to determine a baseline SCr level; administering a dose of terlipressin to a patient by intravenous (IV) injection if the patient’s baseline MELD score is ⁇ 35 and the patient’s baseline SCr level is ⁇ 5 mg/dl; measuring the SCr level in the patient during administration of terlipressin; and continuing administration of terlipressin until the patient experiences greater than 20% improvement in serum creatinine. The administration may be continued until the patient experiences greater than 30% improvement in serum creatinine.
- the patient may be listed for transplant at baseline.
- the patient may have a MELD score > 35 if the patient is not listed for transplant at baseline.
- HRS-1 hepatorenal syndrome Type 1
- IV intravenous
- HRS-1 hepatorenal syndrome Type 1
- IV intravenous
- Yet further aspects of the disclosure relate to a method of treating a patient with hepatorenal syndrome Type 1 (HRS-1) comprising: administering a dose of terlipressin to the patient by intravenous (IV) injection, wherein the patient is excluded from treatment if the patient belongs to a patient population that has median waiting time from listing to transplant of 0.23 months or less.
- HRS-1 hepatorenal syndrome Type 1
- Some aspects of the disclosure relate to a method of treating a patient with hepatorenal syndrome Type 1 (HRS-1) comprising: narrowing the population of eligible patients for treatment to a mitigated population to reduce the risks selected from the group consisting of respiratory failure, serious adverse events, death, and combinations thereof; and administering a dose of terlipressin to the patient of the mitigated population by intravenous (IV) injection.
- HRS-1 hepatorenal syndrome Type 1
- IV intravenous
- Additional aspects of the disclosure relate to a method of administering terlipressin to treat a patient with hepatorenal syndrome Type 1 (HRS-1), the patient being listed for transplant at a baseline model end state liver disease (MELD) score of less than 35, the method comprising: administering to the patient a dose of terlipressin by intravenous (IV) injection; and discontinuing administration or reducing the dose of terlipressin in patients with a serum creatinine (SCr) level > 5 mg/dl and/or an acute-on- chronic liver failure (ACLF) Grade > 3.
- the method may further comprise acquiring the SCr level in the patient prior to administering the dose of terlipressin to determine a baseline SCr level.
- the patient’s risk of mortality may be decreased.
- the patient’s place on a transplant list may not be compromised or impacted.
- the patient’s ICU stay, non-ICU stay, and/or total length of hospital stay may be shortened.
- terlipressin administration is continued until there is a complete response or a partial response.
- discontinuing administration or reducing the dose of terlipressin occurs in patients with respiratory failure.
- the patient may also have severe kidney disease, pulmonary edema, dyspnea, or a combination thereof.
- the terlipressin may be administered every 6 hours by IV bolus injection over 2 minutes.
- the method may further comprise monitoring the patient’s oxygenation level via pulse oximetry during treatment with the terlipressin. The monitoring of the oxygenation level decreases the occurrence of adverse events.
- Some aspects of the disclosure relate to a method of treating a patient with hepatorenal syndrome Type 1 (HRS-1) comprising: obtaining a baseline oxygenation level (SpC ) via pulse oximetry; administering a dose of terlipressin to the patient by intravenous (IV) injection if the patient is not experiencing hypoxia; and monitoring the patient’s SpC during treatment with the terlipressin.
- the monitoring of the oxygenation level may decrease the occurrence of adverse events.
- the patient’s oxygen saturation is monitored for hypoxia.
- the method may further comprise discontinuing administration or reducing the dose of terlipressin if hypoxia is detected.
- terlipressin may not be administered or may be discontinued if the patient’s SpC at baseline or during treatment is less than 90% and/or the patient’s F1O2 is greater than 0.36.
- the patient’s Sp02 may be monitored at least 3 times a day during administration of terlipressin.
- FIRS-1 hepatorenal syndrome Type 1
- IV intravenous
- SCr serum creatinine
- Additional aspects of the disclosure relate to a method of treating a patient with hepatorenal syndrome Type 1 (FIRS-1) comprising: measuring a serum creatinine (SCr) level in the patient; and administering a dose of terlipressin to the patient if the patient has serum creatinine (SCr) ⁇ 5 mg/dl, the patient has an ACLF Grade ⁇ 3, or a combination thereof.
- the terlipressin may be administered to the patient by intravenous (IV) injection.
- FIG. 1 hepatorenal syndrome Type 1 (FIRS-1)
- IV intravenous
- SCr serum creatinine
- ACLF Grade > 3 ACLF Grade 3
- the invention comprises a method of treating a patient with hepatorenal syndrome Type 1 (FIRS-1) comprising: administering a dose of terlipressin to a patient by intravenous (IV) injection, wherein administration occurs only if the patient has serum creatinine (SCr) ⁇ 5 mg/dl, the patient has an ACLF Grade ⁇ 3, or a combination thereof.
- the method may further include monitoring the patient for fluid overload during treatment with terlipressin; and reducing the terlipressin treatment if fluid overload develops.
- the terms “reducing the terlipressin treatment” and “reducing the terlipressin dose” may comprise lowering the terlipressin dose, interrupting the terlipressin dose, and/or not increasing the dose when the patient is previously prescribed or scheduled for an increased dose.
- Interrupting the terlipressin dose may include temporarily interrupting the dose until adverse events subside, until further notice, or until the patient has a serum creatinine (SCr) > 5 mg/dl.
- the method may further comprise measuring the SCr level in the patient.
- the patient’s ICU stay, non-ICU stay, and/or total length of hospital stay may be shortened.
- the terlipressin administration may be continued until there is a complete response or a partial response.
- a method of treating a patient with hepatorenal syndrome Type 1 comprises: administering a dose of terlipressin to a patient by intravenous (IV) injection; and managing fluid overload by reducing or discontinuing the administration of albumin, other fluids, and/or judicious use of diuretics.
- judicious use of diuretics means the use of an effective amount of diuretics.
- reducing the administration of albumin may comprise lowering the dose or interrupting the dose of albumin. If fluid overload persists, the method of treating may further comprise reducing or discontinuing terlipressin treatment.
- managing fluid overload may decrease mortality or the occurrence of adverse events in the patient or patient population receiving treatment according to the invention described herein.
- the method of treating a patient with hepatorenal syndrome Type 1 comprises: administering a dose of terlipressin to a patient by intravenous (IV) injection; and managing fluid overload by reducing or discontinuing the administration of albumin, other fluids, and/or judicious use of diuretics, wherein the patient additionally has respiratory failure, severe kidney disease, pulmonary edema, dyspnea, tachypnea, ischemia, or a combination thereof.
- a method of treating a patient with hepatorenal syndrome Type 1 includes administering a dose of terlipressin to a patient by intravenous (IV) injection, wherein the dose of terlipressin is not increased in the presence of fluid overload, pneumonia, bronchospasm, pulmonary edema, ongoing significant adverse reactions, preexisting severe coronary artery disease, or combinations thereof.
- a method of treating a patient with hepatorenal syndrome Type 1 includes administering a dose of terlipressin to a patient by intravenous (IV) injection, wherein the dose of terlipressin is reduced or discontinued in the presence of fluid overload, pneumonia, bronchospasm, pulmonary edema, ongoing significant adverse reactions, preexisting severe coronary artery disease, or combinations thereof.
- HRS-1 hepatorenal syndrome Type 1
- IV intravenous
- Ischemic events may occur following administration of terlipressin.
- the most common ischemia-associated adverse events may comprise included skin discoloration, cyanosis, intestinal ischemia, and combinations thereof.
- Serious ischemic events in patients treated with terlipressin with may comprise intestinal ischemia, vascular skin disorder, cyanosis, livedo reticularis, myocardial infarction, poor peripheral circulation, myocardial ischemia, or combinations thereof.
- Terlipressin should be used with caution in patients with a history of ischemic events and certain cardiac conditions.
- terlipressin dose should be reduced or permanently discontinued. Additional aspects of the disclosure relate to a method of treating a patient with hepatorenal syndrome Type 1 (HRS-1) comprising: administering a dose of terlipressin to a patient every 6 hours by intravenous (IV) bolus injection over 2 minutes, wherein the treatment of the patient with terlipressin is reduced or discontinued in the presence of ischemia.
- HRS-1 hepatorenal syndrome Type 1
- the invention comprises a method of treating a patient with hepatorenal syndrome Type 1 (HRS-1) comprising: administering a dose of terlipressin to a patient every 6 hours by intravenous (IV) bolus injection over 2 minutes, wherein the treatment of the patient with terlipressin is reduced or discontinued in the presence of skin, cardiac, vascular, or gastrointestinal ischemia, or combinations thereof in the patient.
- HRS-1 hepatorenal syndrome Type 1
- IV intravenous
- ischemic events may be used interchangeably.
- Yet other aspects of the disclosure relate to a method of treating a patient with hepatorenal syndrome Type 1 (HRS-1) comprising: administering a dose of terlipressin to a patient every 6 hours by intravenous (IV) bolus injection over 2 minutes, wherein the dose of terlipressin is not increased in the presence of fluid overload, pneumonia, bronchospasm, or pulmonary edema.
- HRS-1 hepatorenal syndrome Type 1
- HRS-1 hepatorenal syndrome Type 1
- IV intravenous
- a method of treating a patient with hepatorenal syndrome Type 1 includes: administering a dose of terlipressin to a patient every 6 hours by intravenous (IV) bolus injection over 2 minutes, wherein the treatment with terlipressin is immediately interrupted in the presence of treatment-emergent pulmonary edema, new onset or worsening pneumonia, or unresolved hepatic encephalopathy > Grade 3 with risk of aspiration.
- Further aspects of the disclosure relate to a method of increasing overall survival or a patient with hepatorenal syndrome Type 1 (HRS-1), the method comprising: measuring a serum creatinine (SCr) level in the patient; and administering a dose of terlipressin to the patient if the patient has serum creatinine (SCr) ⁇ 5 mg/dl. More aspects of the disclosure relate to a method of decreasing an overall ICU or hospital stay of a patient with hepatorenal syndrome Type 1 (HRS-1), the method comprising: measuring a serum creatinine (SCr) level in the patient; and administering a dose of terlipressin to the patient if the patient has SCr ⁇ 5 mg/dl.
- Additional aspects of the disclosure relate to a method of increasing a complete response of a patient with hepatorenal syndrome Type 1 (HRS-1), the method comprising: measuring a serum creatinine (SCr) level in the patient; administering a dose of terlipressin to a patient by intravenous (IV) injection if the patient’s SCr level is ⁇ 5 mg/dl; and continuing administration of terlipressin until the patient’s SCr level is £1.5 mg/dl.
- SCr serum creatinine
- IV intravenous
- Yet further aspects of the disclosure relate to a method of increasing a partial response of a patient with hepatorenal syndrome Type 1 (HRS-1 ), the method comprising: measuring a serum creatinine (SCr) level in the patient; administering a dose of terlipressin to a patient by intravenous (IV) injection if the patient’s SCr level is ⁇ 5 mg/dl; and continuing administration of terlipressin until the patient experiences greater than 20% improvement in serum creatinine.
- SCr serum creatinine
- IV intravenous
- FIG. 1 illustrates an exemplary embodiment of a terlipressin treatment protocol
- FIG. 2 illustrates an exemplary embodiment of a terlipressin treatment protocol
- FIG. 3 illustrates a set of unexpected results from an exemplary embodiment of a terlipressin treatment protocol
- FIG. 4 illustrates an exemplary embodiment of a terlipressin treatment protocol
- FIG. 5 is a graph showing 90-day survival of patients treated with and without terlipressin according to ACLF grade
- FIG. 6A shows the percentage of patients with renal failure at baseline and end of treatment for patients treated with terlipressin and placebo
- FIG. 6B shows the percentage of patients with respiratory failure at baseline and end of treatment for patients treated with terlipressin and placebo.
- FIG. 6C shows the percentage of patients with respiratory failure with ACLF Grade ⁇ 2 and ACLF Grade > 3 for patients treated with terlipressin and placebo.
- the principles and embodiments of the present disclosure relate to methods of improving a patient's renal condition involving a treatment protocol comprising terlipressin. Accordingly, various embodiments of the present disclosure provide methods of treating a patient with terlipressin or terlipressin and albumin.
- terlipressin may refer to terlipressin or salts, diacetate salts, hydrates, and/or free bases thereof.
- use of terlipressin may include terlipressin acetate or terlipressin diacetate pentahydrate.
- terlipressin may refer to any other suitable salts or hydrates thereof or any other biologically acceptable salts or hydrates thereof.
- reducing the terlipressin treatment” and “reducing the terlipressin dose” may comprise lowering the terlipressin dose, interrupting the terlipressin dose, and/or not increasing the dose when the patient is previously prescribed or scheduled for an increased dose.
- Interrupting the terlipressin dose may include temporarily interrupting the dose until adverse events subside, until further notice, or until the patient has a serum creatinine (SCr) > 5 mg/dl.
- the “mitigated population” or “subset of patients” includes HRS-1 patients with a baseline ACLF Grade 0-2, a baseline serum creatinine ⁇ 5 mg/dL, and/or a baseline MELD ⁇ 35.
- the mitigated population excludes patients with baseline ACLF Grade 3, baseline serum creatinine >5 mg/dL, and/or patients listed for transplant at baseline with a baseline MELD >35.
- the patient is evaluated to determine the particular disease and/or syndrome he or she may be suffering from, and beginning a treatment regimen for patients that will benefit from the administration of terlipressin.
- the patient has end stage liver disease complicated with acute kidney failure, such as FIRS, and is treated with terlipressin.
- end-stage liver disease may be cirrhosis of the liver or fulminant liver failure.
- the end-stage liver disease is complicated by impaired renal function.
- HRS-1 in decompensated cirrhosis is related to hemodynamic abnormalities.
- Terlipressin improves renal perfusion in HRS-1 by enhancing intravascular volume through splanchnic vasoconstriction.
- terlipressin may be more effective than placebo in albumin-treated patients with decompensated cirrhosis and HRS-1.
- An aspect of the present disclosure relates to a method of diagnosis of patients that show improved response to terlipressin treatment, as indicated by an increased probability of HRS reversal.
- the method of identifying an HRS-1 patient with an increased likelihood of responding to terlipressin treatment regimen comprises identifying a patient as having end stage live disease and impaired renal function, determining if the patient also exhibits at least two out of three criteria for SIRS, wherein the three response criteria include (1) a white blood cell count (WBC) that is less than 4,000 cells/mm 3 or greater than 12,000 cells/mm 3 , (2) a heart rate of greater than 90 beats per minute (BPM), and (3) an HC03 ⁇ 21 mmol/L, where HCCb is considered a surrogate measurement that approximates the response criteria of arterial partial pressure of carbon dioxide (PaC02) ⁇ 32 mmHg.
- a heart rate of >85 BPM and/or an HC03 ⁇ 23 mmol/L may be applied as the response criteria.
- An aspect of the present disclosure relates to terlipressin for use in the treatment of HRS-1 in a subject that is also exhibiting at least two of the following three response criteria:
- a white blood cell count (WBC) is less than 4,000 cells/mm 3 or greater than 12,000 cells/mm 3 ,
- HCCb is considered a surrogate measurement that approximates the response criteria of arterial partial pressure of carbon dioxide (PaC02) ⁇ 32 mmHg.
- one or more single dosages of terlipressin is administered to the subject, thereby treating the HRS-1.
- the terlipressin dosage is administered to the patient in the range of about 0.5 mg to about 2.0 mg every 4 to 6 hours, as a series of single doses, so that the patient receives a single dose in the range of about 0.5 mg to about 2.0 mg of terlipressin followed by another single dose 4 to 6 hours later.
- a patient may receive 4 to 6 doses over a 24 hour period, where each dose is in the range of about 0.5 mg to about 2.0 mg.
- the total dosage does not exceed 4.0 mg over a 24 hour period.
- FIG. 1 an exemplary embodiment of a method of treating a patient via an embodiment of a terlipressin treatment protocol.
- a patient who is initially identified as having end stage liver disease, for which treatment with a vasodilator may provide an improvement in renal function, is tested to determine the extent of the patient's cirrhosis and renal failure.
- a patient is initially identified as having end stage liver disease and impaired renal function.
- a patient may be suffering from cirrhosis of the liver or fulminant liver failure, where a patient identified with cirrhosis of the liver may have a Child-Pugh score of A, B, or C.
- a patient identified with cirrhosis of the liver that has a Child-Pugh score of B or C may be considered a viable candidate for terlipressin treatment.
- a patient identified with cirrhosis of the liver that has a Child-Pugh score of C may be considered a viable candidate for terlipressin treatment.
- Various complications of end- stage liver disease, and in particular cirrhosis are recognized and have a notably poor prognosis.
- a treatment protocol comprising dosages of terlipressin surprisingly provides reversal of one or more complicating factors, such as vasodilation, and reduces mortality from the associated complications within a 90 day window starting with treatment.
- the terlipressin treatment protocol comprises identifying a patient having end-stage liver disease and impaired renal function, where the identified patient may benefit from a treatment comprising administration of terlipressin, determining if the patient also exhibits at least two out of three response criteria, excluding the patient from administration of terlipressin if the patient exhibits uncontrolled infection, sepsis, or septic shock is excluded from the terlipressin treatment, and initiating terlipressin treatment by administering a daily dosage of terlipressin to the patient in an amount effective to produce an improvement in renal function, wherein an improvement in renal function is indicated by a reduction in SCr of at least 25% from baseline, reversal of HRS (defined as a decrease in SCr level to £1.5 mg/dl), and/or confirmed HRS reversal (defined as two serum creatinine values of £1.5 mg/dL at least 48 hours apart)).
- the patient is alive at day 90 after initiating terlipressin treatment.
- a patient that experiences HRS reversal, verified HRS reversal, and/or greater than 30% improvement in SCr after receiving terlipressin may have at least a 60%, 65%, or 70% likelihood of being alive at day 90.
- the patient is alive and transplant-free at day 90 after initiating terlipressin treatment.
- a patient that experiences HRS reversal, verified HRS reversal, and/or greater than 30% improvement in SCr after receiving terlipressin may have at least a 35%, 40%, or 45% likelihood of being alive and transplant-free at day 90.
- the terlipressin dosage may be in the range of about mg to about 10 mg, or 0.5 mg to about 5.0 mg, or 0.5 mg to about 2.0 mg, or 0.5 mg to about mg, or about 1.0 mg to about 2.0 mg per single administration.
- the injections may be administered intravenously as slow bolus injections over 2 minutes, where the dose may be repeated every four to six hours. If on day 4 of therapy (after a minimum of 10 doses), SCr had decreased, but by less than 30% from the baseline value, the dose may be increased to 2 mg every 6 hours ( ⁇ 30 min) (8 mg/day). The dose may not be increased if the subject had coronary artery disease; or in the clinical setting of circulatory overload, pulmonary edema, or treatment-refractory bronchospasm.
- the terms “circulatory overload” and “fluid overload” may be used interchangeably.
- terlipressin may be restarted at the same or lower dose (i.e. , 0.5 to 1 mg q6h).
- a patient that is not diagnosed with an end-stage liver disease and impairment of renal function is excluded from the terlipressin treatment.
- the patient is tested for three specific response criteria, where the criteria include a determination of (1 ) whether the white blood cell count (WBC) is less than 4,000 cells/mm 3 or greater than 12,000 cells/mm 3 ,
- the response criterion of a patient's core body temperature being less than 36° C. (96.8° F.) or greater than 38° C. (100.4° F.) is not measured or considered in determining if the patient has two or more response criteria.
- the response criteria may be SIRS criteria. In various embodiments, the criteria may be tested in any order.
- a patient is tested to determine if the patient's WBC is ⁇ 4,000 or >12,000 cells/mm 3 .
- the testing is specifically directed at determining if the patient's leukocytes are less than 4000 cells/mm 3 (4x10 9 cells/L) or greater than 12,000 cells/mm 3 (12x10 9 cells/L).
- a patient will be considered to meet the response criterion if the patient's WBC is ⁇ 5,000 or >12,000 cells/mm 3 .
- the patient is not tested for the presence of greater than 10% immature neutrophils (band forms).
- the testing method to determine the WBC may be any of the methods known in the art.
- the patient may still be diagnosed with SIRS if the patient meets the two other response criteria.
- a patient that has a WBC ⁇ 4,000 or >12,000 cells/mm 3 is considered to meet that response criterion.
- a patient that does not have a WBC outside the range of 4,000 to 12,000 cells/mm 3 is tested to determine if the patient's heart rate is >90 BPM. If the patient's heart rate is >90 BPM, the patient will be considered to meet that response criterion. In various embodiments, a patient with a heart rate of >85 BPM will be considered to meet that response criterion.
- the testing method to determine the patient's heart rate may be any of the methods known in the art.
- a patient that has a WBC outside the range of 5,000 to 12,000 cells/mm 3 is tested to determine if the patient's heart rate is >90 BPM. If the patient's heart rate is >90 BPM, the patient will be considered to meet that response criterion. In various embodiments, a patient with a heart rate of >85 BPM will be considered to meet that response criterion.
- a patient that does not exhibit both a WBC ⁇ 4,000 or >12,000 cells/mm 3 and a heart rate that is >90 BPM is considered to not qualify for two of the three response criteria, and therefore does not meet the requirements to be treated with terlipressin.
- a patient failing to meet at least two of the three response criteria is excluded from the terlipressin treatment.
- Such a patient may be treated instead with one or more other pharmacological agents such as nor-epinephrine, vasopressin, or a combination of midodrine and octreotide.
- any of the following may be used: N-acetylcysteine, misoprostol, and/or BQ123.
- TIPS transjugular intrahepatic portosystemic shunt
- a patient that has a WBC outside the range of 4,000 to 12,000 cells/mm 3 or a heart rate that is >90 BPM is tested to determine if the patient has >20 breaths per minute or an HC03 ⁇ 21 mmol/L. If the patient has >20 breaths per minute or an HC03 ⁇ 21 mmol/L, the patient will be considered to meet that response criterion. In various embodiments, a patient with an HC03 ⁇ 23 mmol/L will be considered to meet that response criterion.
- the testing method to determine the patient's breathing rate or HCO3 may be any of the methods known in the art.
- a patient that has a WBC outside the range of 5,000 to 12,000 cells/mm 3 is tested to determine if the patient has a breathing rate that is >20 breaths per minute or an HC03 ⁇ 21 mmol/L. If the patient has a breathing rate that is >20 breaths per minute or an HC03 ⁇ 21 mmol/L, the patient will be considered to meet that response criterion. In various embodiments, a patient with an HC03 ⁇ 23 mmol/L will be considered to meet that response criterion.
- the patient if the patient has a WBC outside the range of 4,000 to 12,000 cells/mm 3 and the patient has >20 breaths per minute or an HC03 ⁇ 21 mmol/L, the patient is considered to qualify for two of the three response criteria, and therefore meets the requirements to be treated with terlipressin unless otherwise excluded.
- the patient if the patient has a heart rate that is >90 BPM and the patient has a breathing rate that is >20 breaths per minute or an HC03 ⁇ 21 mmol/L, the patient is considered to qualify for two of the three response criteria, and therefore meets the requirements to be treated with terlipressin unless otherwise excluded.
- a patient that has a WBC outside the range of 4,000 to 12,000 cells/mm 3 , but does not have >20 breaths per minute or an HC03 ⁇ 21 mmol/L is tested to determine if the patient's heart rate is >90 BPM. If the patient's heart rate is >90 BPM, the patient will be considered to meet that response criterion. In various embodiments, a patient with a heart rate of >85 BPM will be considered to meet that response criterion.
- the patient in which the patient has a WBC outside the range of 5,000 to 12,000 cells/mm 3 , but the patient does not have >20 breaths per minute or an HC03 ⁇ 21 mmol/L, the patient is tested to determine if the patient's heart rate is >90 BPM. If the patient's heart rate is >90 BPM, the patient will be considered to meet that response criterion. In various embodiments, a patient with a heart rate of >85 BPM will be considered to meet that response criterion.
- the patient if the patient has a breathing rate that is >20 breaths per minute or an HC03 ⁇ 21 mmol/L a heart rate that is >90 BPM and the patient has a breathing rate that is >20 breaths per minute or an HC03 ⁇ 21 mmol/L, the patient is considered to qualify for two of the three response criteria, and therefore meets the requirements to be treated with terlipressin unless otherwise excluded.
- a patient that does not exhibit (1 ) a breathing rate that is >20 breaths per minute or an HC03 ⁇ 21 mmol/L and does not exhibit (2) a heart rate that is >90 BPM is considered to not qualify for at least two of the three response criteria, and therefore does not meet the requirements to be treated with terlipressin.
- a patient failing to meet at least two of the three response criteria is excluded from the terlipressin treatment.
- Optional alternative treatments for such a patient are described above.
- tests for the response criteria have be discussed in a particular order for the exemplary embodiment, the tests may be done in any particular order.
- temperature is not a response criterion because patient temperature may not provide an accurate indication of patient response to terlipressin.
- patient temperatures are excluded from the set of response criteria.
- a patient that has end stage liver disease with impaired renal function, and qualifies for at least two of the three response criteria is started on terlipressin.
- a patient with uncontrolled infection, sepsis, or septic shock is excluded from the terlipressin treatment.
- terlipressin is administered to the patient for one to four days.
- the patient is administered terlipressin for four days unless the patient experiences an adverse event.
- the terlipressin is administered to the patient as an IV drip.
- the terlipressin treatment protocol comprises administering a dosage of terlipressin in the range of about 0.1 mg to about 10 mg, or 0.5 mg to about 5.0 mg, or 0.5 mg to about 2.0 mg, or about 0.5 mg to about 1.0 mg, or about 1.0 mg to about 2.0 mg to the patient over about four hours to about six hours as an IV drip.
- the patient is administered terlipressin as an IV about every 4 to 6 hours for 1 to 4 days.
- the terlipressin may be administered for at least 4 days.
- the patient is administered terlipressin as a slow bolus over 2 minutes about every 4 to 6 hours for 1 to 4 days.
- the terlipressin may be administered for at least 4 days.
- the patient that is being administered the terlipressin is tested at least once during the one to four day period of administration to determine if the patient is responding to the terlipressin.
- the patient may be tested once prior to beginning the administration of the terlipressin to establish a baseline and once during the one to four days of terlipressin administration, or once prior to beginning the administration of the terlipressin to establish a baseline and once at the end of the four days of administration of the terlipressin.
- the patient's creatinine levels are measured to determine if there has been a reduction in the patient's serum creatinine, where a reduction in serum creatinine levels of about 1.0 mg/dL or greater, or in the range of about 1.0 mg/dL to about 2.0 mg/dL, or a reduction of about 1.7 mg/dL from the patient's initial baseline value indicates an improvement in renal function and that the patient is responding to the terlipressin.
- improvement in renal function is indicted by a decrease in serum creatinine level of about 25% or about 30% in the patient receiving terlipressin.
- a patient may have his or her serum creatinine levels measured once a day or once every other day for each of the four day period after administration of terlipressin has begun, wherein a measurement made on the first day of terlipressin administration may be recorded and used as the baseline creatinine level.
- the method may comprises testing the patient's SCr level during the 1 to 4 days of terlipressin administration and determining if the patient has a reduction in SCr level by the end of the 1 to 4 days of terlipressin administration.
- the serum creatinine levels may be measured by any of the methods known in the art, for example, the Jaffe reaction using alkaline picrate.
- the GFR may be measured directly by clearance studies of exogenous markers, such as inulin, iohexol, iothalamate, and Cr51-EDTA, or by estimated glomerular filtration rate (eGFR) using creatinine testing methods that are traceable to a reference method based on isotope dilution-mass spectrometry (IDMS).
- exogenous markers such as inulin, iohexol, iothalamate, and Cr51-EDTA
- eGFR estimated glomerular filtration rate
- IDMS isotope dilution-mass spectrometry
- a patient that shows a positive response to the administration of the terlipressin evidenced by a reduction in the patient's serum creatinine level is continued on the terlipressin at the dosage in the range of about 0.1 mg to about 10 mg, or 0.5 mg to about 5.0 mg, or 0.5 mg to about 2.0 mg, or about 0.5 mg to about 1.0 mg, or about 1.0 mg to about 2.0 mg.
- the dosage administered to the patient may be adjusted based upon the measured serum creatinine level(s).
- a patient being administered terlipressin may have their serum creatinine levels monitored for the entire time period that the patient is receiving terlipressin.
- the patient's serum creatinine level may be tested every day, or every other day, or every third day, or every fourth day, to confirm that the patient is still responding positively to the terlipressin treatment.
- the patient's terlipressin dosage may be increased from about 0.5 mg to about 1.0 mg to about 1.0 mg to about 2.0 mg after 2-3 days of terlipressin administration to the patient if there is ⁇ 1.5 mg/dL decrease in SCr during the first 2-3 days of treatment.
- the dosage may be repeated every four to six hours for a time period of one or more days until the patient shows recovery, or until the patient no longer shows improvement.
- the terlipressin may be administered to the patient for a time period in the range of about two days to about sixteen days, or for a time period in the range of about four days to about eight days. In various embodiments, the time period is in the range of about seven days. In various embodiments, the terlipressin treatment may be continued until there is a complete response. In various embodiments, the duration of treatment of a patient with terlipressin may be 1 to 28 days.
- a patient that does not show any improvement by the end of four days may have the terlipressin discontinued, where improvement is indicated by a decrease in serum creatinine levels over the one to four days the terlipressin is administered.
- the patient may be tested on the third or fourth day after starting treatment with the terlipressin to determine if there is a decrease in serum creatinine levels indicating a response to the treatment.
- a patient is provided 2 days of anti- infective therapy for documented or suspected infection before starting administration of terlipressin if an infection is suspected.
- a patient may be started on the terlipressin treatment protocol after the patient has been administered the anti-infective therapy.
- FIG. 2 illustrates an exemplary embodiment of a terlipressin treatment protocol.
- Principles and embodiments of the present disclosure also relate to providing terlipressin as an IV every four to six hours to patients that have been identified with HRS-1 and two or more of three specific response criteria.
- a patient is tested for (1 ) a white blood cell count (WBC) ⁇ 4 or >12 cells/pL; (2) a heart rate (HR)>90 beats per minute (bpm), and (3) HC0 3 ⁇ 21 mmol/L.
- WBC white blood cell count
- HR heart rate
- bpm beats per minute
- a non-SIRS patient is defined as subjects with ⁇ 2 of the response criteria described above.
- temperature is not used as a response criterion.
- terlipressin is administered to patients presenting with a particular set of symptoms to mitigate the vasoconstriction in the kidneys, and improve renal function as indicated by a reduction in serum creatinine levels of about 1.7 mg/dL from initial baseline.
- one or more patients that may be presenting with end-stage liver disease are tested to determine whether they are suffering from cirrhosis with ascites, and have serum levels of creatinine>133 pmol/l.
- a patient identified as having HRS is further tested and/or their medical history checked to determine if the initial serum levels of creatinine have doubled to greater than 226 pmol/l in less than 2 weeks indicating type 1 HRS.
- Patients having HRS-1 and at least two of three response criteria have surprisingly shown improved response to terlipressin treatment compared to non-SIRS HRS-1 patients, as indicated by reversal of the HRS indications.
- patients having HRS-1 , at least two of three response criteria, and not having uncontrolled infection, sepsis, or septic shock have surprisingly shown improved response to terlipressin treatment compared to non-SIRS HRS-1 patients.
- the HRS indications may include serum creatinine levels.
- the patients having HRS-1 and SIRS may experience HRS reversal, verified HRS reversal, or greater than 30% improvement in SCr after receiving terlipressin.
- the patent is alive at day 90 after initiating terlipressin treatment.
- a patient that experiences HRS reversal, verified HRS reversal, and/or greater than 30% improvement in SCr after receiving terlipressin may have at least a 60%, 65%, or 70% likelihood of being alive at day 90.
- the patient is alive and transplant-free at day 90 after initiating terlipressin treatment.
- a patient that experiences HRS reversal, verified HRS reversal, and/or greater than 30% improvement in SCr after receiving terlipressin may have at least a 35%, 40%, or 45% likelihood of being alive and transplant-free at day 90.
- the patient is tested to determine is the same patient is exhibiting at least two out of three criteria indicating SIRS, wherein the three criteria include a (1) WBC ⁇ 4 or >12 cells/pL; (2) HR>90 bpm, and (3) HC0 3 ⁇ 21 mmol/L.
- patients not identified as exhibiting at least two of the three response criteria in addition HRS-1 are excluded from the terlipressin treatment protocol.
- Patients having HRS-1 and exhibiting at least two of the three response criteria have surprisingly shown improved response to terlipressin treatment compared to non-SIRS HRS-1 patients, as indicated by reversal of the HRS indications, as shown in FIG. 3.
- patients that have been identified as having HRS-1 and exhibit at least two response criteria are tested to determine if they may also have an uncontrolled infection, sepsis, or septic shock, wherein patients identified as exhibiting an uncontrolled infection, sepsis, or septic shock are excluded from the terlipressin treatment protocol.
- patients that have HRS-1 have at least two of the three response criteria, and do not have an uncontrolled infection, sepsis, or septic shock are started on the terlipressin treatment.
- the terlipressin treatment is started within 48 hours of the initial diagnosis that the patient has both HRS-1 and at least two of three response criteria.
- the treatment protocol is started within 48 hours of the initial diagnosis, and treatment may be terminated once an uncontrolled infection, sepsis, or septic shock manifests or is determined.
- a baseline serum creatinine level may be determined for the patient prior to starting the administration of terlipressin to the patient; and the administration of terlipressin started within 2 days or within 3 days, or within 4 days of determining the baseline serum creatinine level.
- the patient may be tested at least once daily within four days after starting the administration of terlipressin to determine if the patient exhibits a decrease in the serum creatinine level compared to the previously determined baseline serum creatinine level.
- terlipressin treatment of the patient is started and the patient receives a dosage of terlipressin.
- the terlipressin may be administered to a patient as a slow infusion over 24 hours, wherein the dosage over the 24 hour period may be in the range of about 2.0 mg to about 12 mg. In various embodiments, the dosage over the 24 hour period may be in the range of about 2.0 mg to about 4.0 mg.
- the terlipressin is administered as a continuous intravenous (IV) drip lasting from about 4 hours to about 6 hours, and comprising a dosage of about 0.5 mg to about 2.0 mg.
- IV intravenous
- the terlipressin dosage may be a dosage of about 0.5 mg to about 2.0 mg administered intravenously every 4 to 6 hours as a slow bolus injection over 2 minutes.
- the dosage may be administered about every 4 hours, about every 5 hours, about every 6 hours, about every 7 hours, about every 8 hours, about every 9 hours, about every 10 hours, about every 11 hours, or about every 12 hours by slow IV bolus injection.
- the dosage may be administered about every 6 hours by slow IV bolus injection.
- the bolus injection may be given over about 1 minute, about 2 minutes, about 3 minutes, about 4 minutes, or about 5 minutes. In at least one example, the bolus injection may be given over about 2 minutes.
- the terlipressin is used to treat the patient exhibiting HRS-1 and at least two of the three response criteria.
- the patient is also tested to determine that the patient does not have an uncontrolled infection, sepsis, or septic shock before being using the terlipressin to treat the HRS-1 patient.
- the terlipressin dosage is given as a continuous IV feed.
- the terlipressin dosage is 1 mg administered intravenously every 6 hours as a slow bolus injection over 2 minutes.
- the terlipressin dosage is not given as a bolus.
- the terlipressin may be administered to the patient for up to 4 days, wherein the patient may be tested each day of the four days to determine whether the patient is responding to the terlipressin treatment.
- a response to the terlipressin treatment may be indicated by a change in the patient's serum creatinine levels, where indication may be a reduction in SCr of at least 25% from baseline.
- the terlipressin may be administered for at least 4 days.
- the amount of serum creatinine change is determined after 4 days of treatment with terlipressin, and the treatment with terlipressin continued if the serum creatinine level has improved.
- a sufficient improvement in serum creatinine levels after 4 days of treatment is indicated by a decrease of at least 1.0 mg/dL in serum creatinine level, or a decrease of about 1.7 mg/dL in serum creatinine level.
- the patient receives terlipressin for an additional 3 days to 8 days if improvement was exhibited over the previous 1 to 4 days.
- the patient receives terlipressin for an additional 3 days to 4 days if improvement was exhibited over the previous 1 to 4 days.
- the administration of terlipressin to the patient is continued for an additional 3 days to 12 days beyond the initial 4 days if the patient exhibits a decrease in the serum creatinine level.
- administration of terlipressin to the patient may be continued until at least one SCr value ⁇ 1.5 mg/dL is obtained.
- the duration of treatment may be extend to a maximum of 15 days or 16 days if HRS reversal was first achieved on days 13 or 14, respectively.
- the duration of treatment of a patient with terlipressin may be 1 to 28 days.
- a decrease in the serum creatinine level may be indicated by a reduction in SCr of at least 1 % or of at least 5% or at least 10% or at least 15% or at least 20% or at least 25% from baseline.
- the patient may have been administered albumin prior to beginning the terlipressin treatment protocol, and/or prior to the determination that the patient has HRS-1 , at least two of the three response criteria.
- albumin may be administered to a patient 7 days to 2 days before starting administration of terlipressin to the patient.
- the albumin treatment comprises administering 1 gram albumin per 1 kg of patient weight up to a maximum of 100 g per day of albumin to a patient.
- albumin may be administered in the range of about 20 g/day to about 50 g/day, where the albumin may be administered for the time period that the patient is administered terlipressin.
- a non-limiting embodiment of a method of treating HRS-1 patients exhibiting at least two of three response criteria with terlipressin comprises administering to a patient in need of such treatment a dosage of terlipressin in the range of 2.0 mg to 12.0 mg per day for 1 to 28 days, or in the range of 2.0 mg to 4.0 mg per day for 1 to 7 days, wherein the dosage may be administered as a continuous IV feed or as a slow bolus injection.
- Embodiments of the present disclosure also relate to treating patients with HRS-1 and meeting two or more response criteria with one dose of terlipressin every six hours, where the dose is in the range of about 0.5 mg to 2.0 mg, for 3 to 8 days to achieve reversal of the HRS-1.
- Embodiments of the present disclosure also relate to initiating terlipressin treatment within 48 hours of determining that a patient is presenting with HRS-1 and at least two of three response criteria, but without sepsis, septic shock, or uncontrolled infection.
- Another aspect of the present disclosure relates to a method of distributing a pharmaceutical product.
- the method of distributing comprises supplying terlipressin to a medical provider, where the medical provider may be responsible for treating a patient suffering from type 1 hepatorenal syndrome.
- the patient does not have overt sepsis, septic shock, or uncontrolled infection.
- the method includes providing a recommendation to the medical provider to treat the patient suffering from type 1 hepatorenal syndrome that does not have overt sepsis, septic shock, or uncontrolled infection and having at least two of (1 ) a white blood cell count (WBC) is less than 4,000 cells/mm 3 or greater than 12,000 cells/mm 3 , (2) a heart rate of greater than 90 beats per minute (BPM), or (3) an HC03 ⁇ 21 mmol/L, with terlipressin in an amount effective to reduce SCr.
- WBC white blood cell count
- BPM heart rate of greater than 90 beats per minute
- terlipressin in an amount effective to reduce SCr.
- the medical provider follows the recommendation and administers a treatment to the patient suffering from HRS-1 , but not overt sepsis, septic shock, or uncontrolled infection and having at least two of (1) a white blood cell count (WBC) is less than 4,000 cells/mm 3 or greater than 12,000 cells/mm 3 , (2) a heart rate of greater than 90 beats per minute (BPM), or (3) an HC03 ⁇ 21 mmol/L, with terlipressin in an amount effective to reduce SCr.
- WBC white blood cell count
- BPM heart rate of greater than 90 beats per minute
- terlipressin through its ability to reduce portal pressure, may decrease the extent of bacterial translocation across the gut wall of patients with decompensated cirrhosis, with consequent reduction in endotoxemia and decrease in the production of pro- inflammatory cytokines, hence making it easier for the patients to respond to the hemodynamic effects of terlipressin.
- FIG. 3 shows the unexpected results produced by an exemplary treatment protocol.
- An aspect of the present disclosure relates to methods of treating and/or reversing HRS-1. As shown in FIG. 4, an exemplary embodiment of a method of treating an adult patient with FIRS-1 via an embodiment of a terlipressin treatment protocol.
- a patient who is initially identified as having end stage liver disease, for which treatment with a vasodilator may provide an improvement in renal function, may be tested to determine the extent of the patient's cirrhosis and renal failure.
- the patient to be treated is an adult patient that has been diagnosed with FIRS-1.
- the method of treating an adult patient with type 1 hepatorenal syndrome includes assessing a baseline serum creatinine (SCr) level prior to administration of terlipressin to the patient, initiating dosing of about 0.5 mg to about 1 mg of terlipressin to the patient every 6 hours by IV for 1-3 days, assessing a serum creatinine level in the patient at day 4 ⁇ 1 day from initiating dosing; and administering a modified dosage of terlipressin based on a comparison of the assessed serum creatinine level at day 4 ⁇ 1 day and the baseline serum creatinine level.
- the method may further include continuing administration until 24 hours after two consecutive serum creatinine levels of ⁇ 1.5 mg/dL at least 2 hours apart for a maximum of 14 days.
- the terlipressin dosage may be in the range of about 0.1 mg to about 10 mg, about 0.5 mg to about 10 mg, or 0.5 mg to about 5.0 mg, or 0.5 mg to about 2.0 mg, or 0.5 mg to about 1.0 mg, about 0.85 mg to about 1.7 mg, or about 1.0 mg to about 2.0 mg per single administration.
- the terlipressin administered may be terlipressin acetate.
- the terlipressin acetate dosage may be administered to the patient in the range of about 0.5 mg to about 2.0 mg.
- the terlipressin acetate dosage may be about 0.5 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, or about 4 mg.
- the terlipressin may be prepared for injection as a white to off-white lyophilized powder in a single-dose vial for reconstitution at a dosage of 0.85 mg terlipressin (equivalent to 1 mg terlipressin acetate).
- the terlipressin acetate dosage may be given at an initial dose of about 0.5 mg or about 1 mg.
- dosing may be initiated with 1 mg terlipressin acetate.
- the terlipressin dosage may be modified after a period of time administering the initial dose. In at least one example, the modified dosage may be about 2 mg terlipressin acetate.
- the injections may be administered intravenously as slow bolus injections over 2 minutes, where the dose may be repeated every four to six hours. In one or more embodiments, the injections may be administered to the patient over about four hours to about six hours as an IV drip.
- an initial terlipressin dosage is administered to the patient in the range of about 0.5 mg to about 1.0 mg, every 4 to 6 hours, as a series of single doses, so that the patient receives a single dose in the range of about 0.5 mg to about 1.0 mg of terlipressin followed by another single dose 4 to 6 hours later.
- a patient may receive 4 to 6 doses over a 24 hour period, where each dose is in the range of about 0.5 mg to about 1.0 mg.
- the total dosage does not exceed 4.0 mg over a 24 hour period.
- the terlipressin dosage may be about 0.85 mg or about 1.0 mg terlipressin acetate.
- a baseline serum creatinine level may be measured before administration of terlipressin on day 1.
- an initial dose of terlipressin may be administered to the patient with HRS-1.
- the initial dose of terlipressin may about 0.5 mg to about 1.0 mg, and it may be administered every 6 hours for about 1-3 days.
- the initial dosage may be about 1.0 mg terlipressin acetate (i.e. 0.85 mg terlipressin).
- the serum creatinine level may be assessed and compared to the baseline level.
- the patient that is being administered the terlipressin is assessed at least once during the days 1 to 4 ⁇ 1 day of administration to determine if the patient is responding to the terlipressin.
- the patient may be tested once at the end of 3 or 4 days of administration of the terlipressin.
- the serum creatinine level may be continually assessed (e.g. daily) until administration is discontinued.
- the dosage administered to the patient may be adjusted based upon the measured serum creatinine level(s).
- a patient being administered terlipressin may have their serum creatinine levels monitored for the entire time period that the patient is receiving terlipressin.
- the patient's serum creatinine level may be tested every day, or every other day, or every third day, or every fourth day, to confirm that the patient is still responding positively to the terlipressin treatment.
- the serum creatinine levels may be measured by any of the methods known in the art, for example, the Jaffe reaction using alkaline picrate.
- the GFR may be measured directly by clearance studies of exogenous markers, such as inulin, iohexol, iothalamate, and Cr51-EDTA, or by estimated glomerular filtration rate (eGFR) using creatinine testing methods that are traceable to a reference method based on isotope dilution-mass spectrometry (IDMS).
- the patient's creatinine levels are assessed to determine if there has been a reduction in the patient's serum creatinine, where a reduction in serum creatinine levels of about 1.0 mg/dL or greater, or in the range of about 1.0 mg/dL to about 2.0 mg/dL, or a reduction of about 1.7 mg/dL from the patient's initial baseline value indicates an improvement in renal function and that the patient is responding to the terlipressin.
- the assessed serum creatinine level may be 30% or more less than the baseline serum creatinine level, may be between 1% and 29% less than the baseline serum creatinine level, or may be 0% or greater than the baseline serum creatinine level.
- a modified dosage of terlipressin may then be administered based on the comparison of the assessed serum creatinine level at day 4 ⁇ 1 day and the baseline serum creatinine level.
- the about 0.5 mg to about 1.0 mg dosage of terlipressin may be continued to be administered to the patient every 6 hours.
- the modified dosage may be the same as the initial dosage (e.g. 0.5 mg to 1.0 mg) if the assessed SCr level decreased by 30% or more from the baseline SCr level.
- the dosage of terlipressin may be increased to about 1.0 mg to about 2.0 mg every 6 hours.
- the modified dosage may be about 0.1 mg to about 2.0 mg of terlipressin every 6 hours ( ⁇ 30 min) (8 mg/day) if the assessed SCr level has decreased, but by less than 30% from the baseline level.
- the modified dosage may be The assessed dose may not be increased from the initial dose if the subject had coronary artery disease; or in the clinical setting of circulatory overload, pulmonary edema, or treatment-refractory bronchospasm.
- terlipressin may be restarted at the same or lower dose (i.e. , 0.5 to 1 mg q6h).
- the administration of terlipressin may be discontinued.
- the modified dosage may be a discontinuation of administering terlipressin if the assessed SCr level is at or above the baseline SCr level.
- administration of terlipressin may be continued until 24 hours after the patient achieves a second consecutive serum creatinine value of £ 1.5 mg/dL at least 2 hours apart or for a maximum of 14 days.
- the dosage may be repeated every four to six hours for a time period of one or more days until the patient shows recovery, or until the patient no longer shows improvement.
- the duration of treatment of a patient with terlipressin may be 1 to 14 days.
- the terlipressin may be administered for at least 4 days.
- the patient is administered terlipressin for up to 14 days unless the patient experiences an adverse event.
- the terlipressin may be administered for at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, or at least 14 days.
- the terlipressin may be administered to the patient for a time period in the range of about 2 days to about 14 days, or for a time period in the range of about 4 days to about 8 days. In various embodiments, the time period is in the range of about 7 days.
- the terlipressin treatment may be continued until there is a complete response.
- a treatment protocol comprising dosages of terlipressin surprisingly provides reversal of one or more complicating factors, such as vasodilation, and reduces mortality from the associated complications within a 90 day window starting with treatment.
- Treatment of the patient may include an improvement in renal function.
- An improvement in renal function is indicated by a reduction in SCr of at least 25% or 30% from baseline, reversal of HRS (defined as a decrease in SCr level to £1.5 mg/dl), and/or confirmed HRS reversal (defined as two serum creatinine values of £1.5 mg/dL at least 48 hours apart)).
- the patent is alive at day 90 after initiating terlipressin treatment.
- a patient that experiences HRS reversal, verified HRS reversal, and/or greater than 30% improvement in SCr after receiving terlipressin may have at least a 60%, 65%, or 70% likelihood of being alive at day 90.
- the patient is alive at day 90 post-liver transplant after initiating terlipressin treatment.
- a patient that experiences HRS reversal, verified HRS reversal, and/or greater than 30% improvement in SCr after receiving terlipressin may have at least a 35%, 40%, or 45% likelihood of being alive at day 90.
- the adult patient with HRS-1 also is SIRS positive.
- a patient with uncontrolled infection, sepsis, or septic shock is excluded from the terlipressin treatment.
- the patient is also up to a maximum of 100 g per day of albumin each day that the patient is treated with terlipressin.
- the patient may continue to be administered albumin after terlipressin has been discontinued.
- the percentage of patients who may achieve verified HRS reversal may be significantly higher with terlipressin than with placebo.
- the patients administered terlipressin may achieve two consecutive SCr values of 1.5 mg/dL or less at least 2 hours apart while receiving treatment by day 14 or discharge. This demonstrates a robust and clinically significant improvement in renal function.
- the patients administered terlipressin may achieve an absence of renal replacement therapy (RRT) for at least 10 days, which emphasizes the durability of this improvement in renal function.
- RRT renal replacement therapy
- the durability of HRS reversal with terlipressin may also persist to at least day 30 without the need for RRT.
- the patient administered terlipressin may achieve survival for at least 10 days, which establishes the effect of treatment on a key clinical outcome of initial survival.
- Terlipressin may be superior to placebo in inducing a response across all levels of baseline SCr, with the response rate to terlipressin inversely related to the baseline SCr.
- Renal replacement therapy poses particular challenges to patients with HRS-1 and advanced acute-on-chronic liver failure, and the lower rate of RRT and longer survival without RRT in the terlipressin group is clinically relevant.
- This significantly reduced need for RRT extending into the post-transplant period in the terlipressin group has important clinical implications, as post-transplant RRT is a significant predictor of post-transplant morbidity with worse graft survival mortality, and resource utilization.
- a method of increasing survival of a patient having HRS-1 and low MAP includes administering an effective dose of terlipressin to a patient in need thereof about every 6 hours by intravenous (IV) bolus injection over about 2 minutes, where the dose is sufficient to yield an increase in MAP and decrease in heart rate in the patient.
- IV intravenous
- a method of increasing survival of a patient having HRS-1 includes administering an effective dose of terlipressin to a patient in need thereof about every 6 hours by intravenous (IV) bolus injection over about 2 minutes, where the dose is sufficient to yield an increase in the diastolic, systolic and MAP, and decrease in heart rate in the patient.
- IV intravenous
- a method of increasing survival of a patient having HRS-1 includes administering an effective dose of about 0.5 mg to about 2 mg terlipressin acetate to a patient in need thereof about every 4 to 10 hours by intravenous (IV) bolus injection over about 1 to 5 minutes, where the dose is sufficient to yield an increase in MAP and decrease in heart rate in the patient.
- IV intravenous
- Terlipressin may cause adverse effects generally consistent with its mechanism of action (MOA) and class effects with the possibility of an increased risk of certain serious adverse event.
- MOA mechanism of action
- Patient selection is extremely important when employing terlipressin.
- Efficacy and safety outcomes in patients with a serum creatinine >5 mg/dL and/or a model end stage liver disease (MELD) score > 35 at the time of terlipressin initiation may be a tipping point for clinical outcomes.
- SCr > 5 mg/dL, MELD score > 35, and/or acute-on-chronic liver failure (ACLF) Grade > 3 may be a threshold of advanced disease presentation, decreased kidney function response, and increased adverse events.
- terlipressin in late- presenting HRS-1 or in advanced acute on chronic liver failure, where the likelihood of benefit is low.
- Use of terlipressin in patients with SCr > 5 mg/dL may be considered only when the anticipated benefit to the patient outweighs the potential risk.
- use of terlipressin in patients with at least about SCr> 5 mg/dL may be considered only when the anticipated benefit to the patient outweighs the potential risk.
- the adverse events may include ischemic or respiratory symptoms that may lead to serious or fatal outcomes.
- one of the possible respiratory symptoms is serious respiratory failure, which may be a major safety concern.
- the risk of respiratory failure may not be reliably predicted and managed. There may be multiple potential causes of respiratory failure.
- Other adverse events may be ischemia, pneumonia, or sepsis without a clear mechanism. The risk of fluid overload and associated albumin use may complicate the clinical presentation and management of the event.
- the management of adverse events, side effects, and undesirable symptoms for the current invention may include a variety of mitigation strategies.
- the method of the present invention comprises the mitigation strategy of actively managing fluid overload during therapy. Actively managing fluid overload may comprise reducing or discontinuing the administration of albumin, other fluids, and/or judicious use of diuretics. For clarity, reducing the administration of albumin may comprise lowering the dose or interrupting the dose of albumin. If fluid overload persists, the method of treating may further comprise reducing or discontinuing terlipressin treatment.
- Management of fluid overload by reducing or discontinuing the administration of albumin, other fluids, and/or judicious use of diuretics may also occur wherein the patient additionally has respiratory failure, severe kidney disease, pulmonary edema, dyspnea, tachypnea, ischemia, or a combination thereof.
- Actively managing fluid overload may comprise terlipressin dose alteration, for example, if symptoms persist. Actively managing fluid overload may also comprise terlipressin dose reduction, dose interruption, or dose discontinuation (i.e. , treatment discontinuation), if symptoms, side effects, or adverse events persist.
- the method of the present invention comprises the mitigation strategy of monitoring oxygen saturation during therapy. Monitoring oxygen saturation via pulse oximetry may identify patients at risk of developing serious respiratory adverse events.
- a mitigation strategy may be to stop or discontinue treatment in patients with serum creatinine > 5 mg/dl or patients with ACLF Grade > 3.
- Another mitigation strategy in the present invention is to stop or discontinue treatment in patients with a hepatic encephalopathy score > 3.
- Another mitigation strategy to use in the present invention is to exclude from treatment (i.e. , exclusion criteria) patients with serum creatinine > 5 mg/dl or a hepatic encephalopathy score > 3, and/or an ACLF Grade > 3.
- the present invention also includes an embodiment where only patients are treated (i.e., inclusion criteria) if they have a serum creatinine ⁇ 5 mg/dl, or a hepatic encephalopathy score ⁇ 3, and/or an ACLF Grade ⁇ 3.
- terlipressin may be administered to a patient with less than a critical level or threshold level of serum creatinine.
- the critical level or threshold level may be about 5 mg/dl.
- terlipressin may be administered to a patient if the patient has a serum creatinine level of ⁇ 5 mg/dl.
- the duration of terlipressin treatment may be about 6 days to about 7 days in patients with presenting SCr ⁇ 5 mg/dL as compared to about 6 days to about 11 days in patients with a presenting SCr > 5 mg/dL and treated with terlipressin. There may be no significant difference between the groups in the proportion of patients who receive antibiotics or albumin.
- a patient with a serum creatinine level of ⁇ [00169]
- 5 mg/dl and administered a dose of terlipressin may have a decreased likelihood of adverse events, an increased overall survival, a decreased overall ICU, non-ICU, or hospital stay, increased likelihood of complete response, and/or an increased likelihood of a partial response as compared to a patient with a serum creatinine level of > 5 mg/dl administered terlipressin.
- a complete response may be when the patient’s SCr level has decreased to £1.5 mg/dl.
- terlipressin may be continued to be administered to the patient until the patient’s serum creatinine level is £1.5 mg/dl.
- terlipressin may be continued to be administered to the patient until 24 hours after two consecutive measured SCr levels of £1.5 mg/dl at least 2 hours apart.
- a partial response may be when the patient’s SCr level has decreased > 20%, or preferably > 30%, but is >1.5 mg/dL.
- terlipressin may be continued to be administered to the patient until the patient’s serum creatinine level has improved by greater than 20%.
- Higher presenting SCr may be linked to poorer efficacy in patients with HRS-1. For example, patients with SCr >5 mg/dL may be significantly more likely to develop adverse events compared to those with a presenting SCr ⁇ 5 mg/dL when administered terlipressin.
- a complete response may be achieved in about 50% to about 60% of patients with presenting SCr ⁇ 5 mg/dL as compared to about 10% to about 20% in patients with presenting SCr >5 mg/dL when administered terlipressin.
- a partial response may be achieved in about 50% to about 60% of patients with presenting SCr ⁇ 5 mg/dL as compared to about 15% to about 25% in patients with presenting SCr >5 mg/dL when administered terlipressin.
- patients with presenting SCr > 5 mg/dL may be more likely to develop fluid overload or pulmonary edema (about 20% to about 30%) and multi-organ failure (about 25% to about 35%) compared to patients with a SCr ⁇ 5 mg/dL (about 10% to about 20% and about 5% to about 10%, respectively) when administered terlipressin.
- Overall survival may be significantly better in patients with presenting SCr ⁇ 5 mg/dL than in patients with presenting SCr >5 mg/dL when administered terlipressin.
- patients with SCr ⁇ 5 may have a significantly shorter ICU stay of about 0.5 to about 1.5 days as compared to about 5 days to about 10 days for patients with presenting SCr >5 mg/dL when administered terlipressin.
- patients with SCr ⁇ 5 may have a significantly shorter non-ICU stay of about 20 days to about 25 days as compared to about 30 days to about 40 days for patients with presenting SCr >5 mg/dL when administered terlipressin.
- patients with SCr ⁇ 5 may have a significantly shorter total length of hospital stay of about 20 days to about 25 days as compared to about 40 days to about 45 days for patients with presenting SCr >5 mg/dL when administered terlipressin.
- a further mitigation strategy in the present invention is to stabilize patients with respiratory events.
- the present invention may further comprise managing fluid overload and pneumonia prior to treatment.
- the mitigation strategies that may be used as part of the present invention may result in reduced adverse events, a reduced risk of mortality, a reduced incidence of mortality, and combinations thereof. Reduced risk of mortality or reduced incidence of mortality may include overall survival (e.g., measured as alive at Day 90 after beginning treatment).
- Higher baseline MELD scores may be linked to poorer efficacy (e.g. poor survival) in patients with HRS-1.
- patients with a baseline MELD score of greater than 35 may be significantly more likely to develop adverse events compared to those with a baseline MELD score of less than 35 when administered terlipressin.
- Patients may be excluded from treatment if the patient is listed for liver transplant with a MELD score >35.
- a method of treating a patient with HRS-1 by administering a dose of terlipressin to the patient by IV injection when the patient has a baseline model end stage liver disease (MELD) score of less than 35.
- MELD model end stage liver disease
- the patient is listed for transplant at baseline and has a baseline MELD ⁇ 35.
- the patient is not listed for transplant at baseline and has MELD score ⁇ 35 or > 35.
- the administration of terlipressin to this subset of patients may lead to increasing overall survival of the patient, decreasing an overall ICU or hospital stay of the patient, increasing a complete response of the patient, and/or increasing a partial response of the patient.
- the overall survival at day 90 of a patient with a baseline MELD score ⁇ 35 treated with terlipressin may be increased by about 5% to 50%, about 5% to 15%, about 10% to 20%, about 25% to 35%, about 30% to 40%, about 35% to 45%, or about 40% to 50% as compared to placebo and/or as compared to a patient with a baseline MELD score > 35 treated with terlipressin.
- the transplant-free survival at day 90 of the patient with a baseline MELD score ⁇ 35 treated with terlipressin may be increased by about 5% to 50%, about 5% to 15%, about 10% to 20%, about 25% to 35%, about 30% to 40%, about 35% to 45%, or about 40% to 50% as compared to placebo and/or as compared to a patient with a baseline MELD score > 35 treated with terlipressin.
- the patient with a MELD score ⁇ 35 may also have severe kidney disease, pulmonary edema, dyspnea, or a combination thereof.
- the method may further include acquiring the baseline MELD score of the patient, acquiring a serum creatinine (SCr) level in the patient prior to administering the dose of terlipressin to determine a baseline SCr level, and/or determining the patient’s acute-on-chronic liver failure (ACLF) grade.
- the terlipressin may not be administered if the baseline SCr is > 5 mg/dl and/or ACLF Grade is > 3.
- the method may include discontinuing administration or reducing the dose of terlipressin in patients with SCr > 5 mg/dl and/or an ACLF Grade > 3.
- a dose of terlipressin may be administered to the patient if the patient’s baseline MELD score is ⁇ 35 and the baseline SCr level is ⁇ 5 mg/dl. Patients with a baseline MELD score of less than 35 may further be monitored for a SCr level of greater than 5 mg/dl and or an ACLF grade of greater than or equal to 3 for discontinuation of the terlipressin administration.
- the patient is listed for transplant at baseline and has a baseline MELD ⁇ 35. In other examples, the patient is not listed for transplant at baseline and has MELD score ⁇ 35 or > 35.
- administering terlipressin to patients with a baseline MELD score of ⁇ 35 may decrease the patient’s risk of mortality (i.e. increase survival).
- the patient may be listed for transplant and have a MELD score of ⁇ 35.
- treatment of patients on the transplant list at baseline with a baseline MELD score of ⁇ 35 may further aid in not compromising a patient’s place on a transplant list.
- the patient may have a reduced risk of their place on a transplant list being compromised or impacted due to the administration of terlipressin.
- a patient on the transplant list with a MELD score of > 35 may be high on the transplant list and therefore may have a faster treatment time by waiting for the liver transplant rather than be treated with terlipressin. Therefore, not treating patients listed for a liver transplant with a baseline MELD score >35 may allow the patient to maintain their spot on the transplant list and receive a transplant quicker than if they were first treated with terlipressin. In at least one embodiment, the patient may only be treated if the patient belongs to a patient population that has median waiting time from listing to transplant of about 5.6 months or greater.
- the patient may be excluded from treatment if the patient belongs to a patient population that has median waiting time from listing to transplant of 0.23 months (approximately 7 days) or less.
- the patient’s ICU stay, non- ICU stay, and/or total length of hospital stay may be shortened due to the patient having a baseline MELD score ⁇ 35, a baseline SCr level of ⁇ 5 mg/dl, and/or an SCLF grade of ⁇ 3.
- the terlipressin administration is continued until there is a complete response or a partial response.
- discontinuing administration or reducing the dose of terlipressin occurs in patients with respiratory failure.
- administering terlipressin to patients with a baseline MELD score of ⁇ 35 may reduce the likelihood of the patient having respiratory failure as compared to patients with a baseline MELD score of > 35.
- the dose of terlipressin administered may be 0.5 mg to about 2 mg terlipressin acetate and may be administered every 4 to 10 hours by IV bolus injection over about 1 to 5 minutes. In at least one example, the terlipressin may be administered every 6 hours by IV bolus injection over 2 minutes.
- the method may further include monitoring the patient’s oxygen saturation during treatment with the terlipressin.
- the monitoring of the oxygen saturation may decrease the occurrence of adverse events.
- a method of treating an HRS patient may include obtaining a baseline oxygenation level (Sp0 ) via pulse oximetry, administering a dose of terlipressin to the patient by IV injection if the patient is not experiencing hypoxia, and monitoring the patient’s Sp0 2 during treatment with the terlipressin.
- the patient’s SpC may be obtained at baseline prior to the first dose of terlipressin and then may be monitored at least 3 times a day, at least 4 times a day, at least 5 times a day, at least 6 times a day, or continuously during administration of terlipressin.
- the patient’s oxygen saturation (SpC ) may be monitored for hypoxia.
- An SpC value of ⁇ 90% may be indicative of some degree of hypoxia.
- Fraction of inspired oxygen (F1O2) may also be monitored as an indication of pulmonary function.
- F1O2 3 0.36 may be an indication of compromised pulmonary function.
- the method may further include discontinuing administration or reducing the dose of terlipressin if hypoxia is detected.
- the method may further include monitoring the patient for fluid overload during treatment with the terlipressin.
- the terlipressin dose may then be reduced or discontinued if fluid overload develops.
- Diuretics may also be administered to the patient if fluid overload develops.
- the method may further include measuring the SCr level in the patient during administration of terlipressin.
- the administration may then be continued until the patient’s SCr level is £1.5 mg/dl or until the patient experiences greater than 20% improvement in SCr. In some examples, administration is continued until the patient experiences greater than 30% improvement in serum creatinine.
- Also provided herein is a method of treating a patient with FIRS-1 by narrowing the population of eligible patients for treatment to a mitigated population to reduce the risks selected from the group consisting of respiratory failure, serious adverse events, death, and combinations thereof and then administering a dose of terlipressin to the patient of the mitigated population by IV injection.
- the mitigated population excludes patients with baseline ACLF Grade 3, baseline serum creatinine >5 mg/dL, and/or patients listed for transplant at baseline with a baseline MELD >35. It was surprising that this mitigated population had improved survival, lower incidence of respiratory failure, and lower pre-transplant mortality as compared to an overall population treated with terlipressin.
- HRS-1 patients having a baseline ACLF Grade 0-2, baseline SCr ⁇ 5 mg/dL, and/or be listed for transplant at baseline with a baseline MELD ⁇ 35 may favorably impact the incidence of liver transplantation and minimize the risk that a patient listed for liver transplant will be precluded from receiving a transplant due to a potential adverse effect of terlipressin.
- Treating this subset of HRS patients leads to a higher rate of verified HRS reversal, lower incidence of renal replacement therapy (RRT), and favorable RRT-free survival with terlipressin compared with placebo.
- RRT renal replacement therapy
- this subset of treated patients may have a reduction in risks compared with the overall population, including lower incidence of respiratory failure, overall mortality, and pre-transplant mortality.
- the overall survival, verified HRS reversal, HRS reversal, durability of HRS reversal, HRS reversal in SIRS subgroup, and/or verified HRS reversal without HRS recurrence by day 30 of a patient in the mitigated population treated with terlipressin may be increased by about 5% to 50%, including about 5% to 15%, about 10% to 20%, about 25% to 35%, or about 30% to 40% as compared to the overall population treated with terlipressin.
- the overall survival, verified HRS reversal, HRS reversal, durability of HRS reversal, HRS reversal in SIRS subgroup, and/or verified HRS reversal without HRS recurrence by day 30 of a patient in the mitigated population treated with terlipressin may be increased by about 5% to 100%, including about 5% to 15%, about 10% to 20%, about 25% to 35%, about 30% to 40%, about 35% to 45%, about 40% to 50%, about 50% to 60%, about 60% to 70%, about 70% to 80%, about 80% to 90%, or 90% to 100% as compared to the overall population or the mitigated population given placebo.
- patients in the mitigated population treated with terlipressin may have an increased likelihood of survival without RRT by day 14, day 30, or day 60 as compared to patients in the overall population treated with terlipressin.
- patients in the mitigated population treated with terlipressin may have an about 2% to about 20%, about 5% to 15%, or about 10% to 20% increase in the likelihood of survival without RRT by day 14, day 30, or day 60 as compared to patients in the overall population treated with terlipressin.
- patients in the mitigated population treated with terlipressin may have an increased likelihood of survival without RRT by day 14, day 30, day 60, or day 90 as compared to patients in the overall population treated with placebo or the mitigated population treated with placebo.
- patients in the mitigated population treated with terlipressin may have an about 2% to about 40%, about 5% to 10%, about 10% to 20%, about 20% to 30%, or about 30% to 40% increase in the likelihood of survival without RRT by day 14, day 30, day 60, or day 90 as compared to patients in the overall population treated with placebo or the mitigated population treated with placebo.
- REVERSE placebo-controlled, double-blind study
- the objective of the study was to determine the efficacy and safety of intravenous terlipressin compared with placebo in the treatment of adult patients with HRS typel receiving intravenous albumin.
- ICA International Club of Ascites
- Exclusion criteria were intended to product a patient sample limited to individuals with functional renal impairment secondary to cirrhosis and ascites, who could safely be administered terlipressin and who could be expected to survive through the active study period.
- exclusion criteria was an exclusion criterion for patients with systemic inflammatory response syndrome (SIRS), defined as the presence of 2 or more of the following findings: (1) temperature>38° C. or ⁇ 36° C.; (2) heart rate>90/min; (3) respiratory rate of >20/min or a PaCC of ⁇ 32 mm Hg; (4) white blood cell count of >12,000 cells/pL or ⁇ 4,000/g L. This was based on the concern of enrolling patients with uncontrolled infection.
- SIRS systemic inflammatory response syndrome
- HRS type 1 allows for patients with ongoing bacterial infection, but not sepsis or uncontrolled infection, to be considered as having HRS type 1 (as opposed to renal dysfunction associated with infection) (Salixo F, Gerbes A, Gines P, Wong F, Arroyo V.,
- HRS type 1 The patients selected for treatment clinically met the criteria for HRS type 1 , where ICA criteria for HRS type 1 allows for patients with ongoing bacterial infection, but not sepsis, to be considered as having HRS type 1 , as opposed to renal dysfunction associated with infection. A diagnosis of HRS was not made where the patient remained with obvious manifestations of uncontrolled infection despite antibiotic treatment.
- Patients in the active treatment group received terlipressin 1 mg intravenously every 6 hours as a slow bolus injection over 2 minutes. Criteria for dose increases, study discontinuation, treatment resumption and treatment completion during the active study period were provided for.
- the dosing regimen for patients in the placebo (6 mL lyophilized mannitol solution) group was identical to the terlipressin regimen. The follow up period began after the end of study treatment and concluded 90 days after the start of study treatment. Survival, renal replacement therapy, and transplantation were assessed.
- the SIRS subgroup of patients in this study was defined as any subject with 32 of 3 criteria available from the study database which included: (1 ) WBC ⁇ 4 or >12 cells/pL; (2) HR>90 bpm and (3) HC03 ⁇ 21 mmol/L.
- the latter criterion represented an approximation of the SIRS criterion PaC02 of ⁇ 32 mm Hg.
- This approximation was derived from the observed HCCb in subjects with HRS in whom a PaC02 value was available and the calculated HCCb in subjects with decompensated liver disease and PaC02 of ⁇ 32 mm Hg.
- the non-SIRS subgroup was defined as subjects with ⁇ 2 criteria described above. Terlipressin response was analyzed in the SIRS and non-SIRS subgroups to determine whether SIRS status had any effect on terlipressin efficacy.
- reversal of HRS is indicated by a decrease in SCr level to £1.5 mg/dl, and confirmed reversal of HRS is defined as two SCr values of £1.5 mg/dL at least 48 hours apart.
- a randomized, placebo-controlled, double-blind study (“CONFIRM”) was conducted to evaluate the efficacy of terlipressin in HRS type 1.
- the objective of the study was to characterize the efficacy and safety of terlipressin plus albumin versus albumin alone for the treatment of HRS-1 in patients with well-defined HRS-1.
- the study used the similar inclusion and exclusion criteria as described in Example 1.
- HRS-1 was defined based on modified prior criteria outlined by the International Club of Ascites (ICA), as rapidly deteriorating renal function to SCr >2.25 mg/dL, with actual or projected doubling of SCr within 2 weeks, without improvement in renal function ( ⁇ 20% decrease in SCr 48 hours after both diuretic withdrawal and albumin-fluid challenge) in adult patients with cirrhosis and ascites.
- Subjects were randomized 2:1 to terlipressin (1 mg IV every 6 hours) or placebo, plus albumin in both groups. Treatment was continued to Day 14 unless the following occurred: verified HRS reversal (VHRSR), renal replacement therapy (RRT), liver transplantation (LT) or SCr at or above baseline (BL) at Day 4.
- VHRSR the primary endpoint
- HRS reversal was a decrease in SCr to ⁇ 1.5 mg/dL.
- Secondary end points included HRS reversal (any SCr value 1.5 mg/dL or less during treatment), HRS reversal without RRT by day 30, HRS reversal in patients with systemic inflammatory response syndrome, and verified HRS reversal without recurrence by day 30.
- the patients were at least 18 years of age, with cirrhosis, ascites, and rapidly progressive renal failure, with a SCr doubling to at least 2.25 mg/dL within 14 days.
- Major exclusion criteria included SCr of greater than 7.0 mg/dL, one or more large-volume paracenteses of 4 L or more within 2 days of randomization, evidence of parenchymal renal diseases or obstructive uropathy, or presence of sepsis and/or uncontrolled bacterial infection.
- Patients with severe cardiovascular disease or recent (within 4 weeks) renal replacement therapy (RRT) were excluded.
- 300 subjects were enrolled in the study. Of the 300 subjects, 199 were randomized to terlipressin and 101 to placebo (albumin alone). Patients were stratified by qualifying SCr (less than 3.4 mg/dL or 3.4 mg/dL or greater) and pre-enrollment large-volume paracentesis (at least one single event of 4 L or greater, or less than 4 L within 3 to 14 days prior to randomization).
- One hundred forty-five patients (72.9%) in the terlipressin group and 72 (71.3%) in the placebo group had received prior midodrine and octreotide.
- Demographic and BL clinical characteristics were similar between treatment groups.
- the two treatment groups had similar average age, weight, height, sex distribution, ethnicity distribution, race distribution, presence of alcoholic hepatitis, baseline serum creatinine, large volume paracentesis (LVP) randomization strata, baseline model end stage liver disease (MELD) score, baseline Child-Pugh score, baseline white blood cell count, baseline bilirubin, baseline mean arterial pressure (MAP), baseline heart rate, baseline blood urea nitrogen (BUN), baseline bicarbonate (HCO3) or carbon Dioxide (CO2), baseline temperature, baseline respiratory rate, baseline acute on chronic liver failure (ACLF) grade, baseline chronic liver failure-sepsis organ failure assessment (CLIF-SOFA) score and presence of prior conditions/treatments such as esophageal variceal hemorrhage (EVFI) banding, pneumonia, urinary tract infection (UTI), spontaneous bacterial peritonitis (SBP), and receipt of albumin.
- a baseline SCr value was assessed before the patients received the assigned treatment. Patients received blinded assigned treatment (terlipressin or placebo) 1 mg administered intravenously over 2 minutes every 6 hours ( ⁇ 30 minutes). In keeping with current guidelines, it was strongly recommended that albumin (1 g/kg to a maximum of 100 g, on day 1 and 20 to 40 g/day thereafter) be administered to all subjects. If SCr decreased ⁇ 30% from the baseline value on Day 4, after a minimum of 10 doses of study drug, dose increase to 2 mg every 6 hours ( ⁇ 30 minutes) (8 mg/day) was mandated, except in subjects with coronary artery disease or in the setting of circulatory overload, pulmonary edema, or bronchospasm. Dose resumption was permitted after interruption for adverse events except for cardiac or mesenteric ischemia, for which treatment was permanently discontinued.
- the primary efficacy end point was the incidence of verified FIRS reversal, defined as the percentage of patients with two consecutive SCr values no greater than 1.5 mg/dL at least 2 hours apart, while remaining alive without RRT for at least 10 days after achieving verified FIRS reversal, while excluding SCr values after RRT, transjugular intrahepatic portosystemic shunt, liver transplant, or open-label vasopressor from primary end point analysis.
- 58 patients (29.1%) treated with terlipressin achieved verified FIRS reversal versus 16 (15.8%) treated with placebo (P 0.01).
- 31.7% of patients treated with terlipressin achieved HRS reversal without RRT by day 30 versus 15.8% (P 0.003) treated with placebo.
- SIRS systemic inflammatory response syndrome
- Table 3 shows transplant-free survival up to 90 days for subjects with HRS reversal and/or greater than 30% improvement in serum creatinine (SCr) compared to subjects with no HRS reversal and no more than 30% improvement in SCr in the SIRS subgroup of the intent-to-treat population.
- SCr serum creatinine
- the median time to first RRT was 6.0 days in the terlipressin group and 5.5 days in the placebo group.
- the transplant-free survival estimate up to Day 90 was higher in the terlipressin group than the placebo group for subjects with SIRS at baseline (Table 5).
- the overall survival estimate up to Day 90 was slightly higher in the terlipressin group than the placebo group for subjects with SIRS at baseline.
- SIRS subgroup overall survival of subjects out to 90 days was analyzed to compare differences between subjects who achieved verified HRS reversal or >30% improvement in serum creatinine and those who did not).
- the survival estimate was higher in responders than nonresponders.
- the RRT-free survival estimate up to Day 90 was higher in the terlipressin group than the placebo group for subjects with SIRS at baseline.
- SIRS subjects in the terlipressin group had a shorter mean length of stay in the ICU (6.3 days) than in the placebo group (12.1 days).
- FIGS. 6A-6B there was an increased incidence of respiratory failure in those patients who received terlipressin, but not in those who received placebo.
- the incidence of respiratory failure was based on CLIF- SOFA score definition of respiratory failure. Therefore, this study assessed in patients with HRS1 whether the presence of severe or grade 3 ACLF according to the EASL- CLIF system at baseline was a risk factor for the development of respiratory failure with terlipressin use.
- HRS-1 was defined as rapidly rising serum creatinine (SCr) to >2.25mg/dl_ in ⁇ 14 days without response to volume challenge or evidence of structural renal disease.
- FIG. 5 is a graph showing 90-day survival of patients treated with and without terlipressin according to ACLF grade. Patients with an ACLF grade of 3 and treated with terlipressin had a lower likelihood of survival than patients with an ACLF grade of 0-2 and treated with terlipressin or patients treated with placebo regardless of ACLF grade.
- FIG. 6C shows the percent of patients with respiratory failure among those treated with terlipressin was similar to placebo for patients with an ACLF grade of 0-2. The percent of patients with respiratory failure in patients treated with terlipressin with an ACLF score of 3 was much higher than placebo. The rate of respiratory failure in FIG. 6C was based on reporting of respiratory failure during the study by the investigator.
- Table 8 provides the odds ratio for additional baseline parameters as predictors of respiratory failure with terlipressin use.
- the mitigated population is at a similar risk for undergoing RRT as the overall population as evidenced by the proportion of subjects who received RRT up to Day 90 (Table 13). In these subjects, RRT-free survival remained numerically favorable in the terlipressin group compared with the placebo group. Table 13. Subjects Alive Without RRT Though Day 90 in the Overall Population and the Mitigated Population in CONFIRM
- the risk mitigation strategy preserved the beneficial effects of terlipressin as demonstrated in the overall CONFIRM study population (i.e. , statistical significance for primary endpoint, lower incidence of RRT, and favorable RRT-free survival with terlipressin compared with placebo).
- the mitigated population there was also a clinically meaningful reduction in risks compared with the overall population, including lower incidence of respiratory failure, overall mortality, and pre-transplant mortality. Therefore, the mitigated population represents a population where the benefits of terlipressin treatment outweigh the risks in this rare complication of liver disease associated with a high medical need and no current FDA-approved or proven pharmacological treatments.
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CN202280040420.5A CN117425488A (en) | 2021-06-07 | 2022-06-07 | Methods of treating patients suffering from type 1 hepatorenal syndrome |
AU2022288996A AU2022288996A1 (en) | 2021-06-07 | 2022-06-07 | Method of treating patients with hepatorenal syndrome type 1 |
KR1020237040067A KR20240019089A (en) | 2021-06-07 | 2022-06-07 | Treatment methods for patients with hepatorenal syndrome type 1 |
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