Method of treating patients with hepatorenal syndrome type 1

• US 10,335,452 B2
• Filed: 10/22/2015
• Issued: 07/02/2019
• Est. Priority Date: 10/24/2014
• Status: Active Grant

• Current Assignee: Mallinckrodt Hospital Products IP Ltd. (Mallinckrodt plc)
• Original Assignee: Mallinckrodt Hospital Products IP Ltd. (Mallinckrodt plc)
• Inventors: Jamil, Khurram, Pappas, Stephen Chris, Potenziano, Jim
• Primary Examiner(s): Cordero Garcia, Marcela M
• Assistant Examiner(s): Lee, Jia-Hai
• Application Number:
  US14/920,392
• Publication Number:
  US 20160113994A1
• Time in Patent Office: 1,349 Days
• CPC Class Codes: A61B 5/0205 Simultaneously evaluating both cardiovascular conditions and different types of body conditions, e.g. heart and respiratory condition
• CPC Class Codes: A61B 5/14542 for measuring blood gases A61B5/14551 takes precedence
• CPC Class Codes: A61K 38/095 Oxytocins; Vasopressins; Related peptides
• CPC Class Codes: A61K 38/38 Albumins
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61M 27/002 Implant devices for drainage of body fluids from one part of the body to another intraocular A61F9/00781; middle ear A61F11/202
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/00 Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 5/10 of the posterior pituitary hormones, e.g. oxytocin, ADH
• CPC Class Codes: A61P 5/38 of the suprarenal hormones
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: G01N 15/10 Investigating individual particles
• CPC Class Codes: G01N 2015/016 White blood cells
• CPC Class Codes: G01N 2015/1024 Counting particles by non-optical means
• CPC Class Codes: G01N 33/4925 measuring blood gas content, e.g. O2, CO2 , HCO3

Abstract

The principles and embodiments of the present disclosure relate to methods for using terlipressin to treat a patient having impaired renal function associated with liver disease. A patient identified as suffering from HRS-1 is tested to determine if the patient meets at least two out of three criteria, wherein the three criteria include a WBC<4 or >12 cells/μL; HR>90 bpm; and any one of HCO₃<21 mmol/L or PaCO₂<32 mmHg or >20 breaths per minute. If the patient meets at least two of the criteria, he or she is administered terlipressin in an amount effective to produce a reduction in serum creatinine of at least 1.0 mg/dL.

Claims

1. A method of treating type 1 hepatorenal syndrome (HRS-1), the method comprising:

identifying a plurality of patients as having HRS-1;

determining that a first patient of the plurality exhibits at least two of the following three criteria for Systemic Inflammatory Response Syndrome (SIRS);

(i) a white blood cell count (WBC) less than 4,000 cells/mm³ or greater than 12,000 cells/mm³,

(ii) a heart rate of greater than 90 beats per minute (BPM), and

(iii) either a partial pressure of carbon dioxide in the blood (PaCO₂)<

32 mmHg or a blood bicarbonate (HCO₃) level<

23 mmol/L;

determining that the first patient does not have overt sepsis, septic shock, or uncontrolled infection;

determining that, because the first patient exhibits at least two of the three criteria and does not have overt sepsis, septic shock, or uncontrolled infection, the HRS-1 of the first patient is likely to respond to treatment with terlipressin;

administering to the first patient an amount of terlipressin effective to treat HRS-1 in the first patient;

determining that a second patient of the plurality exhibits only one or none of the three criteria or has overt sepsis, septic shock, or uncontrolled infection;

determining that, because the second patient does not exhibit at least two of the three criteria or has overt sepsis, septic shock, or uncontrolled infection, the HRS-1 of the second patient is unlikely to respond to treatment with terlipressin;

excluding the second patient from treatment with terlipressin determining that a third patient of the plurality has overt sepsis, septic shock, or uncontrolled infection; and

excluding the third patient from treatment with terlipressin.

2. The method of claim 1, wherein a treatment other than terlipressin is administered to the second patient.

3. The method of claim 1, wherein criterion (iii) is a HCO3 level<

23 mmol/L.

4. The method of claim 1, wherein criterion (iii) is a HCO3 level<

21 mmol/L.

5. The method of claim 1, wherein the amount of terlipressin administered to the first patient is in the range of 2.0 mg to 12.0 mg per day for 1 to 28 days.

6. The method of claim 5, wherein the amount of terlipressin administered to the first patient is in the range of about 0.5 mg to about 2.0 mg every 4 to 6 hours.

7. The method of claim 1, comprising determining if the first patient has a reduction in serum creatinine level during the initial 1 to 4 days of terlipressin administration.

8. The method of claim 7, comprising discontinuing administration of terlipressin to the first patient if the first patient does not show a reduction in serum creatinine level during the initial 1 to 4 days of terlipressin administration.

9. The method of claim 7, comprising continuing administration of terlipressin to the first patient for an additional 3 to 12 days if the first patient shows a reduction in serum creatinine level during the initial 1 to 4 days of terlipressin administration.

10. The method of claim 1, wherein administration of terlipressin to the first patient produces a decrease in serum creatinine level to ≤

1.5 mg/dl.

11. The method of claim 1, comprising treating the first patient with up to a maximum of 100 g per day of albumin for each day of the time period that the first patient is administered terlipressin.

12. The method of claim 1, wherein administering terlipressin to the first patient provides reversal of one or more complicating factors.

13. The method of claim 12, wherein one or more of the complicating factors is splanchnic vasodilation.

14. The method of claim 12, wherein reversal of one or more complicating factors reduces mortality from an associated complication within a 90 day window starting with administering the terlipressin.

15. A method of increasing the effectiveness of terlipressin for the treatment of impaired renal function associated with liver disease, comprising:

identifying a plurality of patients with end-stage liver disease and impaired renal function;

testing the plurality of patients to determine whether each meets each of the following three criteria (i)-(iii);

(i) a white blood cell count either less than 4,000 cells/mm³ or greater than 12,000 cells/mm³,

(ii) a heart rate of greater than 90 beats per minute, and

(iii) either (a) a partial pressure of carbon dioxide in the blood (PaCO₂) of <

32 mmHg or (b) a blood bicarbonate HCO₃ level of <

23 mmol/L or (c) tachypnea with more than 20 breaths per minute;

determining that a first patient of the plurality meets at least two of the three criteria;

determining that the first patient does not have overt sepsis, septic shock, or uncontrolled infection;

determining that, because the first patient meets at least two of the three criteria and does not have overt sepsis, septic shock, or uncontrolled infection, the first patient'"'"'s renal function is more likely to improve upon treatment with terlipressin than if the first patient exhibited only one or none of the three criteria;

administering to the first patient an amount of terlipressin effective to improve the first patient'"'"'s renal function;

determining that a second patient of the plurality meets only one or none of the three criteria or has overt sepsis, septic shock, or uncontrolled infection;

determining that, because the second patient does not meet at least two of the three criteria or has overt sepsis, septic shock, or uncontrolled infection, the second patient'"'"'s renal function is less likely to respond to treatment with terlipressin than if the second patient exhibited at least two of the three criteria; and

excluding the second patient from treatment with terlipressin.

16. The method of claim 15, wherein, during treatment with terlipressin, the first patient is tested to determine if the first patient'"'"'s renal function is improved compared to prior to treatment with terlipressin.

17. The method of claim 15, wherein a treatment other than terlipressin is administered to the second patient.

18. The method of claim 15, wherein criterion (iii) is a HCO3 level<

23 mmol/L.

19. The method of claim 15, wherein criterion (iii) is a HCO3 level<

21 mmol/L.

20. The method of claim 15, comprising determining that a third patient of the plurality has overt sepsis, septic shock, or uncontrolled infection, and excluding the third patient from treatment with terlipressin because of the presence of overt sepsis, septic shock, or uncontrolled infection.

21. The method of claim 15, comprising determining that the plurality of patients have cirrhosis of the liver with a Child-Pugh score of B or C.

22. The method of claim 15, wherein the dosage of terlipressin administered to the first patient over a 4 hour to 6 hour period is in the range of about 0.5 mg to about 2.0 mg.

23. The method of claim 15, wherein the terlipressin is administered to the first patient as a continuous IV drip.

24. The method of claim 15, wherein the dosage of terlipressin administered to the first patient does not exceed 4.0 mg over each 24 hour period of administration.

25. The method of claim 15, comprising determining a baseline serum creatinine level for the first patient within 2 days prior to starting the administration of terlipressin to the first patient and testing the first patient at least once within four days after starting the administration of terlipressin to determine if the first patient'"'"'s serum creatinine level has decreased compared to the baseline level.

26. The method of claim 25, wherein the administration of terlipressin to the first patient is continued if testing the first patient'"'"'s serum creatinine level after starting the administration of terlipressin shows that the first patient'"'"'s serum creatinine level has decreased compared to the baseline level, and the administration is discontinued if the first patient'"'"'s serum creatinine level has not decreased compared to the baseline level.

27. The method of claim 26, wherein the first patient'"'"'s serum creatinine level is shown to have decreased compared to the baseline level, and then administration of terlipressin to the first patient is continued for an additional 3 days to 8 days.

28. The method of claim 15, wherein, following treatment with terlipressin, the first patient'"'"'s serum creatinine level is tested and found to be ≤

1.5 mg/dl.