Bile acid recycling inhibitors for treatment of pediatric cholestatic liver diseases

• US 10,512,657 B2
• Filed: 04/25/2016
• Issued: 12/24/2019
• Est. Priority Date: 10/28/2011
• Status: Active Grant

• Current Assignee: Shire Human Genetic Therapies, Inc. (Shire plc)
• Original Assignee: Lumena Pharmaceuticals LLC (Shire plc)
• Inventors: Gedulin, Bronislava, Grey, Michael, O'Donnell, Niall
• Primary Examiner(s): Pagonakis, Anna
• Application Number:
  US15/137,323
• Publication Number:
  US 20160310518A1
• Time in Patent Office: 1,338 Days
• Field of Search: None
• CPC Class Codes: A61K 31/155 Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
• CPC Class Codes: A61K 31/38 having sulfur as a ring hetero atom
• CPC Class Codes: A61K 31/41 having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
• CPC Class Codes: A61K 31/4436 containing a heterocyclic ring having sulfur as a ring hetero atom
• CPC Class Codes: A61K 31/495 having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazinesA61K31/48 takes precedence ; with three nitrogen atoms A61K31/53
• CPC Class Codes: A61K 31/4965 Non-condensed pyrazines
• CPC Class Codes: A61K 31/4985 Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
• CPC Class Codes: A61K 31/4995 Pyrazines or piperazines forming part of bridged ring systems
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 31/554 having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
• CPC Class Codes: A61K 31/7042 Compounds having saccharide radicals and heterocyclic rings
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61K 9/0056 Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
• CPC Class Codes: A61K 9/1611 Inorganic compounds
• CPC Class Codes: A61K 9/1617 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/1623 Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
• CPC Class Codes: A61K 9/1635 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/2009 Inorganic compounds
• CPC Class Codes: A61K 9/2013 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/2018 : Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• CPC Class Codes: A61K 9/2027 : obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/2054 : Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/2059 : Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
• CPC Class Codes: A61K 9/2081 : with microcapsules or coated microparticles according to A61K9/50
• CPC Class Codes: A61P 1/10 : Laxatives
• CPC Class Codes: A61P 1/14 : Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• CPC Class Codes: A61P 1/16 : for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 1/18 : for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 13/02 : of urine or of the urinary tract, e.g. urine acidifiers
• CPC Class Codes: A61P 17/04 : Antipruritics
• CPC Class Codes: A61P 3/06 : Antihyperlipidemics
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: C07D 281/10 : condensed with one six-membered ring
• CPC Class Codes: C07D 337/08 : condensed with one six-membered ring
• CPC Class Codes: C07D 409/10 : linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 487/08 : Bridged systems
• CPC Class Codes: C07H 15/26 : Acyclic or carbocyclic radicals, substituted by hetero rings

Abstract

Provided herein are methods of treating or ameliorating a pediatric cholestatic liver disease by non-systemically administering to an individual in need thereof a therapeutically effective amount of a pediatric formulation comprising an Apical Sodium-dependent Bile Acid Transporter Inhibitor (ASBTI) or a pharmaceutically acceptable salt thereof. Also provided are methods for treating or ameliorating a pediatric liver disease, decreasing the levels of serum bile acids or hepatic bile acids, treating or ameliorating pruritis, reducing liver enzymes, or reducing bilirubin comprising non-systemically administering to an individual in need thereof a therapeutically effective amount of a pediatric formulation comprising an ASBTI or a pharmaceutically acceptable salt thereof.

Claims

1. A method for treating or ameliorating pediatric progressive familial intrahepatic cholestasis type 2 (PFIC2) in a pediatric subject comprising administering to the pediatric subject an Apical Sodium-dependent Bile Acid Transporter Inhibitor (ASBTI), the ASBTI is

4. The method of claim 1, wherein the method comprises reducing xanthoma, serum lipoprotein X, liver enzymes, bilirubin, intraenterocyte bile acids/salts, or necrosis and/or damage to hepatocellular architecture.

7. The method of claim 1, wherein the ASBTI is administered in an amount between about 10 μ

g/kg/day and about 300 μ

g/kg/day.

8. The method of claim 1, wherein the ASBTI is administered in an amount between about 14 μ

g/kg/day to about 280 μ

g/kg/day.

9. The method of claim 1, wherein the ASBTI is administered in an amount between about 14 μ

g/kg/day to about 140 μ

g/kg/day.

11. The method of claim 1, wherein the progressive familial intrahepatic cholestasis type 2 (PFIC2) is characterized by one or more symptoms selected from jaundice, pruritis, cirrhosis, hypercholemia, neonatal respiratory distress syndrome, lung pneumonia, increased serum concentration of bile acids, increased hepatic concentration of bile acids, increased serum concentration of bilirubin, hepatocellular injury, liver scarring, liver failure, hepatomegaly, xanthomas, malabsorption, splenomegaly, diarrhea, pancreatitis, hepatocellular necrosis, giant cell formation, hepatocellular carcinoma, gastrointestinal bleeding, portal hypertension, hearing loss, fatigue, loss of appetite, anorexia, peculiar smell, dark urine, light stools, steatorrhea, failure to thrive, and renal failure.

12. The method of claim 1, wherein the pediatric patient is between 6 months to 12 years old.

13. The method of claim 1, wherein less than 10% of the ASBTI is systemically absorbed.

15. The method of claim 1, wherein the ASBTI is effective for decreasing at least 30% of serum and/or hepatic bile acid levels in the pediatric subject as compared to bile acid levels prior to administration of the ASBTI.

16. The method of claim 1, wherein the ASBTI is effective for decreasing at least 40% of serum and/or hepatic bile acid levels in the pediatric subject as compared to bile acid levels prior to administration of the ASBTI.

17. The method of claim 1, wherein the ASBTI is effective for decreasing at least 50% of serum and/or hepatic bile acid levels in the pediatric subject as compared to bile acid levels prior to administration of the ASBTI.

2. A method for treating or ameliorating pruritis in a pediatric subject suffering from progressive familial intrahepatic cholestasis type 2 (PFIC2) comprising administering to the pediatric subject an Apical Sodium-dependent Bile Acid Transporter Inhibitor (ASBTI), the ASBTI is

3. A method for treating or ameliorating pediatric progressive familial intrahepatic cholestasis type 2 (PFIC2) in a pediatric subject comprising administering to the pediatric subject a pharmaceutical composition comprising an Apical Sodium-dependent Bile Acid Transporter Inhibitor (ASBTI), the ASBTI is

5. The method of claim 3, wherein the composition is a pediatric dosage form.

6. The method of claim 5, wherein the pediatric dosage form is selected from a solution, syrup, suspension, elixir, powder for reconstitution as suspension or solution, dispersible/effervescent tablet, chewable tablet, gummy candy, lollipop, freezer pops, troches, oral thin strips, orally disintegrating tablet, sachet, soft gelatin capsule, and sprinkle oral powder or granules.

10. The method of claim 5, wherein the pediatric dosage form comprises between 0.1 to 20 mg of the ASBTI.

14. The method of claim 3, wherein the composition further comprises a bile acid sequestrant or binder.