CN118139623A

CN118139623A - Methods of administering apical sodium-dependent cholic acid transporter inhibitors (ASBTIs)

Info

Publication number: CN118139623A
Application number: CN202280071134.5A
Authority: CN
Inventors: 克里斯多福·皮茲
Original assignee: Mirum Pharmaceuticals Inc
Current assignee: Mirum Pharmaceuticals Inc
Priority date: 2021-10-26
Filing date: 2022-10-25
Publication date: 2024-06-04

Abstract

The present invention relates generally to methods of reducing, minimizing, preventing, ameliorating or eliminating one or more side effects associated with administration of sodium-apical dependent bile acid transporter inhibitors (ASBTIs). The invention also relates to a method of treating cholestatic liver disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of ASBTI prior to ingestion of food.

Description

Methods of administering apical sodium-dependent cholic acid transporter inhibitors (ASBTIs)

Cross reference to related applications

The present application claims priority from U.S. provisional application No. 63/271,916 to application No. 2021, 10, 26, 2021, 11, 17, 63/280,470, and 63/354,424 to application No. 2022, 6, 22, the disclosures of which are incorporated herein by reference in their entirety.

Technical Field

The present invention relates generally to methods of reducing, minimizing, preventing, ameliorating or eliminating one or more side effects associated with administration of an apical sodium-dependent bile acid transporter inhibitor (ASBTI) in an individual in need thereof by administering to the individual a therapeutically effective amount of ASBTI prior to ingestion of food. The invention also relates to a method of treating cholestatic liver disease in an individual comprising administering to the individual a therapeutically effective amount of ASBTI prior to ingestion of food and/or in a fasted state.

Background

Hypercholesteremia (Hypercholemia) and cholestatic liver disease are liver diseases associated with impaired bile secretion (i.e., cholestasis), with intracellular accumulation of bile acids/salts in liver cells, and often secondary thereto. Hypercholesteremia is characterized by elevated serum concentrations of cholic acid or bile salts. Cholestasis can be categorized in clinical pathology into two major categories of obstructive (often extrahepatic) cholestasis and non-obstructive (or intrahepatic) cholestasis. Non-obstructive intrahepatic cholestasis can be further categorized into two major subgroups of primary intrahepatic cholestasis due to constitutive defective bile secretion and secondary intrahepatic cholestasis due to hepatocyte damage. Primary intrahepatic cholestasis includes diseases such as benign recurrent intrahepatic cholestasis, which are mainly adult forms with similar clinical symptoms, and Progressive Familial Intrahepatic Cholestasis (PFIC) types 1, 2 and 3, which are diseases affecting children.

Children's cholestatic liver disease affects a small proportion of children, but annual therapy results in significant health care costs. Currently, many pediatric cholestatic liver diseases require invasive and costly treatments such as liver transplantation, surgery, and the like. There is no effective and less invasive treatment suitable for the pediatric population with minimal adverse effects on the gastrointestinal tract upon administration.

In recent years, apical sodium-dependent bile acid transporter inhibitors (ASBTIs) have evolved into an important novel class of therapeutic agents capable of reducing serum and/or hepatobiliary acids and thus reducing cholestasis. There is a further need to reduce the adverse effects of ASBTI and/or to develop methods of treating cholestasis and cholestatic liver disease with reduced adverse effects.

Disclosure of Invention

Various non-limiting aspects and embodiments of the invention are described below.

In one aspect, the invention provides a method of reducing, minimizing, preventing, ameliorating or eliminating one or more side effects associated with administration of a sodium-apical dependent bile acid transporter inhibitor (ASBTI) in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of ASBTI prior to ingestion of food.

In certain embodiments, the one or more side effects associated with administration of ASBTI are reduced, minimized, prevented, ameliorated, or eliminated as compared to side effects when ASBTI is administered after ingestion of food, concurrently with food, or in combination with food.

In another aspect, the invention provides a method of improving Gastrointestinal (GI) tolerance of an ASBTI in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an ASBTI prior to ingestion of food.

In some embodiments, the improvement in GI tolerance comprises reducing, minimizing, preventing, ameliorating, or eliminating one or more GI adverse events.

In some embodiments, the improvement in GI tolerance comprises one or more of reduction, minimization, prevention, amelioration, or elimination of diarrhea, loose stool (loose stools), nausea, abdominal pain, and anorectal discomfort.

In some embodiments, the GI tolerance is improved compared to the GI tolerance when ASBTI is administered at the time of a meal or immediately after food intake.

In some embodiments, the GI tolerance is improved by at least 10% as compared to the GI tolerance when ASBTI is administered at the time of a meal or immediately after food intake.

In some embodiments, the GI tolerance is improved by at least 20% as compared to the GI tolerance when ASBTI is administered at the time of a meal or immediately after food intake.

In some embodiments, the GI tolerance is improved by at least 50% as compared to the GI tolerance when ASBTI is administered at the time of a meal or immediately after food intake.

In one aspect, the invention provides a method of treating cholestatic liver disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of ASBTI prior to ingestion of food, wherein the subject experiences a reduction in frequency and/or severity of one or more side effects associated with administration of ASBTI.

In certain embodiments, the frequency and/or severity of side effects is reduced compared to side effects when ASBTI is administered after ingestion of food, concurrently with food, or in combination with food.

In certain embodiments, the cholestatic liver disease is a pediatric cholestatic liver disease. In certain embodiments, the cholestatic liver disease is an adult cholestatic liver disease. In certain embodiments, the cholestatic liver disease is non-obstructive biliary stasis, extrahepatic biliary stasis, intrahepatic biliary stasis, primary intrahepatic biliary stasis, secondary intrahepatic biliary stasis, progressive familial intrahepatic biliary stasis (PFIC), PFIC type 1, PFIC type 2, PFIC type 3, benign recurrent intrahepatic biliary stasis (BRIC), BRIC type 1, BRIC type 2, BRIC type 3, total venous nutrition-related biliary stasis, paraneoplastic biliary stasis, stokes Syndrome (Stauffer Syndrome), intrahepatic pregnancy bile stasis, contraceptive-related biliary stasis, drug-related biliary stasis, infection-related biliary stasis, durbin-Jiang Sener Syndrome (Dubin-Johnson Syndrome), primary Biliary Cirrhosis (PBC), primary Sclerosing Cholangitis (PSC), cholelithiasis, alagekol Syndrome (Alagille Syndrome), biliary closure, post-Ge Xishu biliary closure (post-Kasai biliary atresia), post-implantation biliary closure, post-implantation liver injury, or related liver injury. In certain embodiments, the cholestatic liver disease is arga Ji Ouzeng syndrome, PFIC, BRIC, PSC, PBC, or biliary tract occlusion.

In certain embodiments, the ASBTI is administered to an individual in a fasted state. In certain embodiments, the ASBTI is administered less than about 60 minutes prior to ingestion of food. In certain embodiments, the ASBTI is administered less than about 30 minutes prior to ingestion of food. In certain embodiments, the ASBTI is administered immediately prior to ingestion of food. In certain embodiments, the ASBTI is administered at least 4 hours after the last meal.

In certain embodiments, the ASBTI is administered once daily. In certain embodiments, the ASBTI is administered twice daily.

In certain embodiments, the ASBTI is administered in an amount of about 0.1mg to about 100mg per dose. In certain embodiments, the ASBTI is administered in an amount of about 10mg to about 100mg per dose. In certain embodiments, the ASBTI is administered in an amount of about 20mg to about 80mg per dose. In certain embodiments, the ASBTI is administered in an amount of about 100 ug/kg/day to 1400 ug/kg/day. In certain embodiments, the ASBTI is administered in an amount of about 400 ug/kg/day to 800 ug/kg/day.

In certain embodiments, the ASBTI is selected from

/> Or a pharmaceutically acceptable salt thereof. In certain embodiments, the ASBTI is

In certain embodiments, the ASBTI is Fu Lixi bat or a pharmaceutically acceptable salt thereof. In certain embodiments, the ASBTI is Fu Lixi bart potassium.

In certain embodiments, the individual does not ingest food about 0.5 to about 16 hours before ASBTI administration.

In certain embodiments, the individual is a pediatric individual. In certain embodiments, the pediatric individual is 0 to 18 years old.

In certain embodiments, the ASBTI is administered orally.

In certain embodiments, less than 10% of the ASBTIs is systemically absorbed. In certain embodiments, less than 30% of the ASBTIs is systemically absorbed.

Drawings

Fig. 1 depicts study designs, drugs (mrx= Ma Lali sibat, vlx= Fu Lixi bat), dosages, and meal time/fasted time lines according to certain embodiments of the present disclosure. * Fasted food begins at > 10 to 12 hours prior to MRX administration. ╪ patients 1:1 were randomly grouped into two cohorts and continuously fasted and then dosed at the meal time or fasted and then fasted at the meal time.

Fig. 2 is a pie chart showing the proportion of healthy participants experiencing Gastrointestinal (GI) therapy-emergent Adverse Events (AEs) at meal time versus ASBTI administration in the fasted state for each of the three studies.

Figure 3 shows the effect of Ma Lali cilazabat (MRX) on fecal cholic acid (fBA) excretion in dogs: study medication, and dosing/meal time schedules.

Fig. 4 is a bar graph of the effect of Ma Lali cilazabat (MRX) on fecal cholic acid (fBA) in dogs: change in fBA excretion from pre-treatment to day 7.

Detailed Description

Detailed embodiments of the present invention are disclosed herein; however, it is to be understood that the disclosed embodiments are merely illustrative of the invention, which can be embodied in various forms. Furthermore, each of the examples given in connection with the various embodiments of the invention is intended to be illustrative, and not limiting. Therefore, specific structural and functional details disclosed herein are not to be interpreted as limiting, but merely as a representative basis for teaching one skilled in the art to variously employ the present invention.

Cholic acid/bile salts play a key role in activating digestive enzymes and dissolving fat and fat-soluble vitamins and are involved in liver, biliary tract and intestinal tract diseases. Cholic acid is synthesized in the liver through multi-step, multi-organ pathways. The hydroxyl group is newly added to a specific site on the steroid structure, the double bond of the cholesterol B ring is reduced, and the hydrocarbon chain is shortened by three carbon atoms resulting in a carboxyl group at the end of the chain. The most common cholic acid is cholic acid and chenodeoxycholic acid (chenodeoxycholic acid) ("primary cholic acid"). Before leaving the hepatocytes and forming bile, the bile acids are bound to glycine (to produce glycocholic acid or glycochenodeoxycholic acid (glycochenodeoxycholic acid)) or taurine (to produce taurocholic acid or taurochenodeoxycholic acid (taurochenodeoxycholic acid)). The binding of cholic acid is known as bile salts and its amphipathic nature makes it a cleaner more effective than cholic acid. Bile salts are found in bile instead of cholic acid.

Bile salts are secreted by hepatocytes into the tubules to form bile. The tubules drain into the right and left hepatic ducts and bile flows to the gall bladder. Bile is released from the gall bladder and travels to the duodenum where it promotes metabolism and degradation of fat. Bile salts are resorbed in the terminal ileum and transported back to the liver via the portal vein. Bile salts often undergo multiple intestinal hepatic cycles prior to excretion via the stool. A small proportion of bile salts may be resorbed in the proximal intestine by passive or carrier-mediated transport processes. Most bile salts are recovered in the remote ileum via a bile acid transporter at a sodium-dependent apical position, known as the apical sodium-dependent bile acid transporter (ASBT). On the basal surface of intestinal epithelial cells, a truncated form of ASBT involves transfer of the cholic acid/bile salt carrier into the portal circulation. Completion of the intestinal liver circulation occurs at the underside surface of hepatocytes through a transport process mediated primarily by sodium-dependent bile acid transport proteins. The transport of intestinal cholic acid plays a key role in the intestinal hepatic circulation of bile salts. Molecular analysis of this process has recently led to important advances in understanding the biology, physiology and pathology of intestinal cholic acid transport.

In the intestinal lumen, the cholic acid concentration varies, with most of the resorption occurring in the remote intestinal tract. Described herein are certain compositions and methods for controlling the concentration of cholic acid in the intestinal lumen, thereby controlling hepatic cell damage due to cholic acid accumulation in the liver and administration in a fasted state to achieve minimal adverse gastrointestinal effects.

The presently disclosed objects are based, at least in part, on the following findings: the unexpected administration of ASBTI to an individual in need thereof prior to ingestion of food results in a reduction, minimization, prevention, amelioration, and/or elimination of one or more side effects associated with the administration of ASBTI.

Class of cholestatic liver diseases

As used herein, "cholestasis" is meant to include diseases or symptoms that include impaired bile formation and/or bile flow. As used herein, "cholestatic liver disease" means liver disease associated with cholestasis. Cholestatic liver disease is often associated with jaundice, fatigue and itching. Biomarkers for cholestatic liver disease include elevated serum bile acid concentration, elevated serum Alkaline Phosphatase (AP), elevated gamma-glutamyl-trans-peptidase, elevated binding hyperbilirubinemia (hyperbilirubinemia), and elevated serum cholesterol.

Cholestatic liver disease can be clinically and pathologically classified into two major categories of obstructive (often extrahepatic) cholestatic and non-obstructive (or intrahepatic) cholestatic. In the former, cholestasis occurs when bile flow is mechanically blocked, such as by gall stones or tumors, or as in extrahepatic biliary locking.

The latter group, with non-obstructive intrahepatic cholestasis, falls into two major subgroups. In the first subgroup, cholestasis is caused when the process of bile secretion and modification or the process of synthesis of components of bile is secondary to such severe hepatocyte damage that nonspecific impairment of many functions, including those favoring bile formation, can be expected. In the second subgroup, the putative cause of hepatocyte damage cannot be identified. When one of the steps of bile secretion or modification, or synthesis of components of bile, is constitutively damaged, cholestasis appears to result in such patients. Such cholestasis is considered as primary.

Accordingly, provided herein are methods and compositions for stimulating the proliferation and/or regeneration of epithelium and/or an enhancement of adaptive processes in the intestinal lining in an individual suffering from hypercholesteremia and/or cholestatic liver disease. In some such embodiments, the method comprises increasing the concentration of cholic acid and/or GLP-2 in the intestinal lumen.

Increased levels of cholic acid, and increased levels of AP (alkaline phosphatase), LAP (leukocyte alkaline phosphatase), ygt (gamma-glutamyl transpeptidase), and 5' -nucleotidase are biochemical markers of cholestasis and cholestasis liver disease. Accordingly, provided herein are methods and compositions for stimulating the promotion of epithelial proliferation and/or regeneration and/or adaptation processes of the intestinal lining in the intestines of individuals suffering from hypercholesteremia and elevated levels of AP (alkaline phosphatase), LAP (leukocyte alkaline phosphatase), gamma GT (gamma-glutamyl transpeptidase or GGT) and/or 5' -nucleotidase. In some such embodiments, the method comprises increasing the concentration of cholic acid in the intestinal lumen. Further provided herein are methods and compositions for reducing hypercholesteremia, and elevated levels of AP (alkaline phosphatase), LAP (leukocyte alkaline phosphatase), ygt (gamma-glutamyl transpeptidase), and 5' -nucleotidase, comprising reducing overall serum cholic acid loading by excreting cholic acid in feces.

Itching is often associated with hypercholesteremia and cholestatic liver disease. Itching has been proposed to originate from the action of bile salts on peripheral pain afferent nerves. The degree of itching varies from individual to individual (i.e., some individuals are more sensitive to elevated levels of cholic acid/salt).

Administration of agents that reduce serum bile acid concentrations has been shown to reduce itching in certain individuals. Accordingly, provided herein are methods and compositions for stimulating the proliferation and/or regeneration of epithelium and/or an adaptive process of the intestinal lining in the intestines of individuals suffering from pruritus. In some such embodiments, the method comprises increasing the concentration of cholic acid in the intestinal lumen. Further provided herein are methods and compositions for treating itching comprising reducing overall serum cholic acid loading by excreting cholic acid in feces.

Another symptom of hypercholesteremia and cholestatic liver disease is an increase in serum concentration of bound bilirubin. The elevated serum concentration of bound bilirubin results in jaundice and dark urine. The magnitude of the increase is not diagnostically critical, as there is no established relationship between the serum content of bound bilirubin and the severity of hypercholesteremia and cholestatic liver disease. The combined bilirubin concentration rarely exceeds 30mg/dL. Accordingly, provided herein are methods and compositions for stimulating the proliferation and/or regeneration of epithelium and/or an adaptive process of intestinal lining in the intestines of individuals having an elevated serum concentration of binding bilirubin. In some such embodiments, the method comprises increasing the concentration of cholic acid in the intestinal lumen. Further provided herein are methods and compositions for treating elevated serum concentrations of bound bilirubin, comprising reducing overall serum cholic acid loading by excreting cholic acid in the stool.

Increased serum concentrations of unbound bilirubin are also considered a diagnosis of hypercholesteremia and cholestatic liver disease. Serum bilirubin is partially and covalently bound to albumin (delta bilirubin or bile proteins (biliprotein)). This fraction may account for a significant proportion of bilirubin in patients with cholestatic jaundice. The presence of large amounts of delta bilirubin is indicative of long-standing cholestasis. Delta bilirubin in spinal cord blood or neonatal blood is indicative of prenatal cholestasis/cholestatic liver disease. Accordingly, provided herein are improved methods and compositions for stimulating epithelial proliferation and/or regeneration and/or adaptive processes of intestinal lining in the intestines of individuals having elevated serum concentrations of unbound bilirubin or delta bilirubin. In some such embodiments, the method comprises increasing the concentration of cholic acid in the intestinal lumen. Further provided herein are methods and compositions for treating elevated serum concentrations of unbound bilirubin and delta bilirubin, comprising reducing overall serum cholic acid loading by excreting cholic acid in feces.

Cholestasis and cholestasis liver disease cause hypercholesteremia. During metabolic cholestasis, hepatocytes retain bile salts. Bile salts flow back from hepatocytes into the serum, which results in an increase in the concentration of bile salts in the peripheral circulation. Furthermore, absorption of bile salts into the liver in portal blood is inefficient, which results in bile salts spilling into the peripheral circulation. Accordingly, provided herein are methods and compositions for stimulating epithelial proliferation and/or regeneration and/or enhancement of an adaptive process of the intestinal lining in the intestines of an individual suffering from hypercholesteremia. In some such embodiments, the method comprises increasing the concentration of cholic acid in the intestinal lumen. Further provided herein are methods and compositions for treating hypercholesteremia comprising reducing overall serum cholic acid loading by excreting cholic acid in the stool.

Hyperlipidemia is a characteristic of some, but not all, cholestatic diseases. Serum cholesterol is elevated in cholestasis due to a reduction in circulating bile salts that contribute to metabolism and degradation of cholesterol. Cholesterol retention is associated with an increase in membrane cholesterol content and a decrease in membrane fluidity and membrane function. Furthermore, since bile salts are metabolites of cholesterol, a decrease in cholesterol metabolism results in a decrease in bile acid/salt synthesis. Serum cholesterol observed in children with cholestasis is in the range of about 1,000mg/dL to about 4,000 mg/dL. Accordingly, provided herein are improved methods and compositions for stimulating epithelial proliferation and/or regeneration and/or adaptive processes of the intestinal lining in the intestines of individuals suffering from hyperlipidemia. In some such embodiments, the method comprises increasing the concentration of cholic acid in the intestinal lumen. Further provided herein are methods and compositions for treating hyperlipidemia comprising reducing overall serum cholic acid loading by excreting cholic acid in feces.

In individuals with hypercholesteremia and cholestatic liver disease, xanthomas develop due to deposition of excessive circulating cholesterol into the dermis. The development of xanthomas is more characteristic of obstructive cholestasis than hepatocellular cholestasis. Planar xanthomas occur first around the eyes and then in folds of the palm and sole, followed by the neck. Nodular xanthomas are associated with chronic and long-term cholestasis. Accordingly, provided herein are methods and compositions for stimulating the proliferation and/or regeneration of epithelium and/or an adaptive process of the intestinal lining in the intestines of a subject suffering from a xanthoma. In some such embodiments, the method comprises increasing the concentration of cholic acid in the intestinal lumen. Further provided herein are methods and compositions for treating xanthomas comprising reducing overall serum cholic acid loading by excreting cholic acid in the stool.

In children with chronic cholestasis, one of the major consequences of hypercholesteremia and cholestatic liver disease is growth retardation. Growth retardation is a consequence of reduced delivery of bile salts to the intestine, which contributes to inefficient digestion and absorption of fat, and reduced absorption of vitamins (malabsorption of vitamins E, D, K and a in cholestasis). In addition, delivery of fat into the colon can lead to colonic secretion and diarrhea. Treatment of growth retardation involves dietary replacement and supplementation of long chain triglycerides, medium chain triglycerides and vitamins. Ursodeoxycholic acid, which is used to treat some cholestatic conditions, does not form mixed micelles and has no effect on fat absorption. Accordingly, provided herein are methods and compositions for stimulating epithelial proliferation and/or regeneration and/or enhancement of the adaptive process of the intestinal lining in the intestines of an individual suffering from growth retardation (e.g., a child). In some such embodiments, the method comprises increasing the concentration of cholic acid in the intestinal lumen. Further provided herein are methods and compositions for treating growth retardation comprising reducing overall serum cholic acid loading by excreting cholic acid in feces.

Primary Biliary Cirrhosis (PBC)

Primary biliary cirrhosis is an autoimmune disease of the liver characterized by destruction of the bile duct. Damage to the bile duct results in bile accumulation in the liver (i.e., cholestasis). Stagnation of bile in the liver damages liver tissue and can lead to scarring (scarring), fibrosis and cirrhosis. PBCs typically appear in adulthood (e.g., 40 years and older). Individuals with PBC often experience fatigue, itching, and/or jaundice. PBC is diagnosed if the individual has an elevated AP concentration for at least 6 months, an elevated ygt content, anti-granulial antibodies (AMA) (> 1:40) in serum, and bright red (florid) bile duct lesions. Serum ALT and serum AST and binding bilirubin may also be elevated, but these are not considered diagnostic. The cholestasis associated with PBC is treated or ameliorated by administration of ursodeoxycholic acid (UDCA or Xiong Erchun). Corticosteroids such as prine Lai Song (prednisone) and budesonide and immunosuppressants such as azathioprine (azathioprine), cyclosporin a, methotrexate, chlorambucil (chlorambucil) and mycophenolate mofetil have been used to treat cholestasis associated with PBC. Su Linda grams (Sulindac), bezafibrate (bezafibrate), tamoxifen (tamoxifen) and lamivudine (lamivudine) have been shown to treat or ameliorate cholestasis associated with PBC.

Progressive Familial Intrahepatic Cholestasis (PFIC)

PFIC is a rare genetic disorder that causes progressive liver disease that often leads to liver failure. In humans with PFIC, liver cells are less able to secrete bile. The accumulation of bile produced causes liver disease in afflicted individuals. Signs and symptoms of PFIC typically begin in infancy. Patients experience severe itching, jaundice, inability to grow at the desired rate (growth retardation) and gradual loss of liver function (liver failure). In the united states and europe, the disease is expected to affect one of every 50,000 to 100,000 births. Six types of PFICs have been identified genetically, all of which are similarly characterized by impaired bile flow and progressive liver disease.

PFIC 1

PFIC 1 (also known as bayer disease (Byler disease) or FICl deficiency) is associated with a mutation in the ATP8B1 gene (also designated FICl). This gene, which encodes a P-type atpase, is located on human chromosome 18 and is also mutated in the milder phenotype, benign recurrent intrahepatic cholestasis type 1 (BRIO) and in the familial cholestasis of agliflora (GREENLAND). FICl proteins are located on the tubular membrane of hepatocytes but are expressed in the liver primarily in cholangiocytes. P-type atpase appears to be an aminophospholipid transporter responsible for maintaining enrichment of phosphatidylserine and phosphatidylethanolamine on the inner leaflet of plasma membrane compared to the outer leaflet. The asymmetric distribution of lipids in the membrane bilayer plays a protective role against high bile salt concentrations in the tubule lumen. Abnormal protein function can indirectly interfere with biliary secretion of cholic acid. Abnormal secretion of bile acids/salts leads to overload (overload) of hepatocellular bile acids.

PFIC 1 is typically present in infants (e.g., 6 to 18 months of age). Infants may show signs of itching, jaundice, abdominal distension, diarrhea, malnutrition and constrictive stature (shortened stature). Biochemically, individuals with PFIC 1 have elevated serum transglutaminase, elevated bilirubin, elevated serum cholic acid content, and low levels of γgt. The individual may also have liver fibrosis. Individuals with PFIC 1 typically do not have biliary tract proliferation. Most individuals with PFIC 1 will develop end-stage liver disease by 10 years of age. No medical treatment has proven beneficial for long-term treatment of PFIC 1. To reduce extrahepatic symptoms (e.g., malnutrition and growth retardation), children often administer medium chain triglycerides and fat-soluble vitamins. Xiong Erchun have not been shown to be effective in individuals with PFIC 1.

PFIC 2

PFIC 2 (also known as bayer syndrome or BSEP deficiency) is associated with a mutation in the ABCB11 gene (also designated BSEP). The ABCB11 gene encodes the ATP-dependent small tube Bile Salt Export Pump (BSEP) of the human liver and is located on chromosome 2 in humans. BSEP protein (which is expressed at the hepatic cell tubule membrane) is the primary output of primary bile acids/salts against extreme concentration gradients. This mutation of the protein causes the biliary bile salt secretion described in afflicted patients to decrease, resulting in reduced bile flow and accumulation of bile salts inside the hepatocytes, causing sustained severe hepatocellular damage.

PFIC 2 is typically present in infants (e.g., 6 to 18 months of age). The infant may show signs of itching. Biochemically, individuals with PFIC 2 have elevated serum transglutaminase, elevated bilirubin, elevated serum cholic acid content, and low levels of γgt. The subject may also have portal inflammation and cytomegalohepatitis. In addition, individuals often develop hepatocellular carcinoma. No medical treatment has proven beneficial for long-term treatment of PFIC 2. To reduce extrahepatic symptoms (e.g., malnutrition and growth retardation), children often administer medium chain triglycerides and fat-soluble vitamins. The PFIC 2 patient population represents about 60% of the PFIC population.

PFIC 3

PFIC 3 (also known as MDR3 defect) is caused by a gene defect in the ABCB4 gene (also designated MDR 3) located on chromosome 7. Class III multidrug resistance (MDR 3) P-glycoprotein (P-gp) is a phospholipid translocator involved in the secretion of biliary tract phospholipids (phosphatidylcholine) in the tubular membrane of hepatocytes. PFIC 3 is caused by the toxicity of bile, where the detergent bile salts are not inactivated by phospholipids, resulting in damage to the bile canaliculi and biliary epithelium.

PFIC 3 is also present in childhood. In contrast to PFIC 1 and PFIC 2, individuals have elevated γgt content. Individuals also suffer from portal inflammation, fibrosis, cirrhosis, and large-scale biliary proliferation. Individuals can also develop liver and gall lithiasis. Xiong Erchun have been effective in treating or ameliorating PFIC 3.

Benign Recurrent Intrahepatic Cholestasis (BRIC)

BRIC 1

BRIC1 is caused by a genetic defect in the FICl protein in the tubular membrane of hepatocytes. BRIC1 is generally associated with normal serum cholesterol and elevated levels of gamma-glutamyl transpeptidase. Residual FICl expression and function are associated with BRICl. Although cholestasis or recurrent episodes of cholestasis liver disease, most patients do not progress to chronic liver disease. During the seizure, the patient suffered from severe jaundice and had itching, steatorrhea (steatorrhea), and weight loss. Some patients also have kidney stones, pancreatitis, and diabetes.

BRIC 2

BRIC2 is caused by mutations in ABCB11, resulting in defective BSEP expression and/or function in the tubular membrane of hepatocytes.

BRIC 3

BRIC3 is associated with defective expression and/or function of MDR3 in the tubular membrane of hepatocytes. Patients with MDR3 deficiency typically exhibit elevated serum gamma-glutamyl transpeptidase levels in the presence of normal or slightly elevated cholic acid levels.

Dubin-Jiang Sener's syndrome (DJS)

DJS is characterized by combined hyperbilirubinemia due to hereditary dysfunction of MRP 2. Liver function remains in afflicted patients. Several different mutations are associated with this disorder, resulting in complete absence of immunohistochemically detectable MRP2 or protein maturation and impaired classification in afflicted patients.

Acquired cholestatic disease

Primary Biliary Cirrhosis (PBC)

PBC is a chronic inflammatory liver condition that slowly progresses to end-stage liver failure in the majority of afflicted patients. In PBC, the inflammatory process affects mainly the small bile ducts.

Primary Sclerosing Cholangitis (PSC)

PSC is a chronic inflammatory liver condition that slowly progresses to end-stage liver failure in the vast majority of afflicted patients. In PSC inflammation, fibrosis and blockage of large and medium-sized intrahepatic ducts are dominant.

PSC is characterized by progressive cholestasis. Cholestasis can often lead to severe itching, which significantly detracts from quality of life.

Intrahepatic Cholestasis of Pregnancy (ICP)

ICP is characterized by the occurrence of transient cholestasis or cholestatic liver disease in pregnant females when circulating levels of estrogen are high, usually in the end of gestation (THIRD TRIMESTER). ICP is associated with itching of varying severity and biochemical cholestasis or cholestatic liver disease and becomes a risk factor for premature birth and intrauterine fetal death. Genetic predisposition has been suspected based on strong regional clusters, higher prevalence of female family members of ICP patients, and susceptibility of ICP patients to develop intrahepatic cholestasis or cholestatic liver disease under other enzymatic challenges such as oral contraception. The heterogeneous status of MDR3 gene defects may represent a genetic predisposition.

Cholelithiasis disease

Cholelithiasis is one of the most common and expensive diseases of all digestive tract and has an prevalence of up to 17% in caucasian females. Cholesterol-containing gallstones are the primary form of gallstones and supersaturation of bile with cholesterol is thus a prerequisite for gallstone formation. The ABCB4 mutation may be involved in the pathogenesis of cholesterol gallstone disease.

Drug-induced cholestasis

Drug inhibition of BSEP function is an important mechanism of drug-induced cholestasis, leading to liver accumulation of bile salts and subsequent hepatocyte damage. Several drugs are associated with BSEP inhibition. Most of these drugs (e.g. rifampin, cyclosporine, glibenclamide or troglitazone, etc.) directly inhibit ATP-dependent taurocholate transport in a competitive manner, whereas estrogen and progesterone metabolites indirectly trans-inhibit BSEP after secretion into bile canaliculi via Mrp 2. Alternatively, drug-mediated stimulation of MRP2 may promote cholestasis or cholestatic liver disease by altering the bile composition.

Total venous nutrition-related cholestasis

TPNAC is one of the most severe clinical situations in which cholestasis or cholestatic liver disease occurs rapidly and is highly associated with early death. The growth of infants (who are usually premature and who have undergone intestinal resection) is dependent on TPN and frequently develops cholestasis or cholestasis liver disease, which typically progresses rapidly to fibrosis, cirrhosis and portal hypertension 6 months before birth. The extent of cholestasis or cholestasis liver disease in these infants and the chance of survival are related to the number of septicemia episodes that may be initiated by recurrent bacterial translocation across their intestinal mucosa. Although there is also cholestatic effect from intravenous formation in these infants, sepsis mediators are likely to be responsible for the greatest extent of liver function changes.

Total venous nutrition-related cholestasis

Alaski European syndrome (ALGS)

Alaskov syndrome is a genetic disorder that images liver and other organs. ALGS are also known as symptomatic intrahepatic bile duct deficiency or hepatic arterial hypoplasia. ALGS is a rare genetic disorder in which bile ducts are abnormally stenosed, dysplastic, and reduced in number, which leads to bile accumulation in the liver and ultimately to progressive liver disease. ALGS is chromosomal dominant, which is caused by mutations in JAG1 (> 90% of cases) or NOTCH 2. The estimated incidence of ALGS in the united states and europe is one example of every 30,000 or 50,000 births. In patients with ALGS, multiple organ systems can be affected by mutations, including the liver, heart, kidneys, and central nervous system. The accumulation of cholic acid prevents the liver from working properly to eliminate waste from the blood stream and results in progressive liver disease, which ultimately requires liver transplantation in 15% to 47% of patients. Signs and symptoms due to liver damage in ALGS may include jaundice, itching and xanthoma, and reduced growth. Itching experienced by patients with ALGS is among the most severe of any chronic liver disease and occurs in most afflicted children to the third year after birth.

ALGS often occurs during infancy (e.g., 6 to 18 months of age) to childhood (e.g., 3 to 5 years of age) and may stabilize after 10 years of age. Symptoms may include chronic progressive cholestasis, reduced catheter (ductopenia), jaundice, itching, xanthoma, congenital heart problems, intrahepatic bile duct deficiency, linear dysplasia, hormonal resistance, posterior embryotoxin (posterior embryotoxon), ai Kesheng verd (Axenfeld) abnormality, retinitis pigmentosa, pupil abnormality, heart murmur, atrial septal defect, ventricular septal defect, open arterial catheter (patent ductus arteriosus), and falozenda (Tetralogy of Fallot). Individuals diagnosed with alageur syndrome have been treated with Xiong Erchun, hydroxyzine, pin cholic amine (cholestyramine), rifampin, and phenobarbital. Individuals with Alaskohm syndrome are further administered high doses of vitamin complex (multivitamins) due to a reduced ability to absorb fat-soluble vitamins.

Biliary tract occlusion

Biliary locking is a life threatening condition in infants in which the bile duct inside or outside the liver does not have a normal opening. In the case of biliary tract occlusion, bile is trapped, accumulates, and damages the liver. The damage results in scarring, loss of liver tissue, and cirrhosis. Without treatment, the liver eventually fails and the infant requires liver transplantation to survive. Two types of biliary tract occlusion are fetal and perinatal infants. Fetal biliary locking occurs when an infant is in the uterus. Biliary locking in perinatal infants is more common and does not manifest until 2 to 4 weeks after birth.

Ge Xishu posterior biliary tract occlusion

Biliary tract occlusion is treated with a procedure known as Ge Xi (Kasai) surgery or liver transplantation. Ge Xishou surgery is generally the first treatment for biliary closure. During Ge Xishou surgery, the child surgeon removes the infant's damaged bile duct and brings the intestinal circuit out in place of it. Although the gexi procedure can restore bile flow and correct many of the problems caused by biliary locking, the procedure does not cure biliary locking. If Ge Xishou is unsuccessful, infants typically need to undergo liver transplantation within 1 to 2 years. Even after successful surgery, most infants with biliary closure develop cirrhosis slowly over the years and require liver transplantation in adulthood. Possible complications after Ge Xishou surgery include ascites, bacterial cholangitis, portal hypertension and itching.

Biliary tract occlusion after liver transplantation

If occlusion is complete, liver transplantation is the only option. While liver transplantation is generally successful in treating biliary locking, liver transplantation can have complications such as organ rejection. Furthermore, donor livers may not be available. Furthermore, in some patients, liver transplantation may be unsuccessful in curing biliary closure.

Xanthoma (yellow tumor)

Xanthomas are skin disorders associated with cholestatic liver disease, in which some fat accumulates below the surface of the skin. Cholestasis results in several disturbances of lipid metabolism leading to the formation of abnormal lipid particles called lipoprotein X in the blood. Lipoprotein X is a cell formed by refluxing bile lipids from the liver into the blood and not bound to LDL receptors to deliver cholesterol to the whole body like normal LDL. Lipoprotein X increases liver cholesterol production by five times and prevents normal removal of lipoprotein particles from the blood by the liver.

General definition

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a method" includes one or more methods, and/or steps of the type described herein and/or apparent to those having skill in the art upon reading this disclosure.

As used herein, the term "baseline" or "pre-dosing baseline" refers to information collected at the beginning of a study or an initial known value for comparison with subsequent data. A baseline is an initial measurement of a measurable condition taken at an early point in time and used for comparison over time to find changes in the measurable condition. For example, the concentration of serum cholic acid in the patient prior to drug administration (baseline) and after drug administration. Baseline is an observation or value representing a normal or onset level of measurable quality for comparison with a value representing a response to an intervention or environmental stimulus. Baseline is the time "zero" before participants in the study receive experimental agents or interventions or negative controls. For example, "baseline" may in some cases refer to 1) a state of a measurable amount just prior to the start of a clinical study or 2) a state of a measurable amount just prior to changing a dose or composition administered to a patient from a first dose or composition to a second dose or composition.

As used herein, the terms "content" and "concentration" are used interchangeably. For example, "high serum bilirubin levels" may be alternatively the phrase "high serum bilirubin levels".

As used herein, the term "normalized" or "normal range" indicates an age-specific value (i.e., normal or normalized value) within a range corresponding to a healthy individual. For example, the phrase "serum bilirubin concentration is normalized within three weeks" means that the serum bilirubin concentration falls within a range known in the art to correspond to a range of healthy individuals within three weeks (i.e., within a normal range, rather than, for example, an elevated range). In various embodiments, the normalized serum bilirubin concentration is from about 0.1mg/dL to about 1.2mg/dL. In various embodiments, the normalized serum bile acid concentration is from about 0 μmol/L to about 25 μmol/L.

As used herein, the terms "ITCHRO (OBS)" and "ITCHRO" (or "ITCHRO (Pt)") are used interchangeably, wherein the ITCHRO (OBS) scale is defined as measuring the severity of itching in children less than 18 years old and the ITCHRO scale is used to measure the severity of itching in adults at least 18 years old. Thus, where the ITCHRO (OBS) scale is mentioned in relation to adult patients, the ITCHRO scale is the indicated scale. Similarly, whenever the ITCHRO scale is mentioned with respect to pediatric patients, the ITCHRO (OBS) scale is typically the indicated scale (allowing older children to report their own score as ITCHRO score the ITCHRO (OBS) scale is in the range of 0 to 4 and the ITCHRO scale is in the range of 0 to 10.

As used herein, the term "bile acids" includes the steroids (and/or carboxylate anions thereof) found in bile of animals (e.g., humans) and salts thereof, including (as illustrated by non-limiting examples) cholic acid, cholate, deoxycholic acid, deoxycholate, hyodeoxycholic acid, hyodeoxycholate, glycocholic acid, glycocholate, taurocholate, chenodeoxycholic acid (chenodeoxycholic acid), ursodeoxycholic acid, xiong Erchun, tauroursodeoxycholic acid (tauroursodeoxycholic acid), gan Anxiong deoxycholic acid (glycoursodeoxycholic acid), 7-B-methylcholic acid, methyllithocholic acid, chenodeoxycholate (chenodeoxycholate), lithocholic acid salts, and the like. The taurocholate and/or taurocholate salt is referred to herein as TCA. Any reference to cholic acid as used herein includes reference to cholic acid, one and only one cholic acid, one or more cholic acids, or at least one cholic acid. Thus, unless otherwise indicated, the terms "cholic acid", "bile salt", "cholic acid/salt", "cholic acid", "bile salt" and "cholic acid/salt" are used interchangeably herein. Any reference to cholic acid as used herein includes reference to cholic acid or a salt thereof. Furthermore, pharmaceutically acceptable cholate is optionally used as "cholic acid" as described herein, e.g. cholic acid/salt bound to an amino acid (e.g. glycine or taurine). Other cholate esters include, for example, substituted or unsubstituted alkyl esters, substituted or unsubstituted heteroalkyl esters, substituted or unsubstituted aryl esters, substituted or unsubstituted heteroaryl esters, and the like. For example, the term "cholic acid" includes cholic acid bound to glycine or taurine, respectively: glycocholate and taurocholate (and salts thereof). Any reference to cholic acid described herein includes reference to the same compound, either naturally or synthetically prepared. Furthermore, it is to be understood that any singular reference to a component (cholic acid or otherwise) as used herein includes reference to one and only one, one or more, or at least one such component. Similarly, any multiple references to components used herein include references to one and only one, one or more, or at least one such component unless noted otherwise.

The terms "subject", "patient", "participant (participant)" or "individual (index)" are used interchangeably herein and refer to, for example, mammals and non-mammals suffering from the disorders described herein. Examples of mammals include, but are not limited to, any member of the mammalian class: humans, non-human primates (e.g., chimpanzees, etc.), and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, pigs, etc.; domestic animals such as rabbits, dogs, cats, etc.; laboratory animals, including rodents, such as rats, mice, and guinea pigs. Examples of non-mammals include, but are not limited to, birds, fish, and the like. In one embodiment of the methods and compositions provided herein, the mammal is a human.

As used herein, the term "about" includes any value within 10% of the stated value.

As used herein, the term "composition" includes disclosure of compositions and compositions administered in methods as described herein. Furthermore, in some embodiments, the compositions of the present invention are or comprise "formulations" (i.e., an oral dosage form or rectal dosage form as described herein).

As used herein, the term "treating" and other grammatical equivalents include reducing, inhibiting or reducing symptoms, reducing or inhibiting the severity of a disease or condition symptom, reducing the incidence of a disease or condition symptom, reducing or inhibiting the recurrence of a disease or condition symptom, delaying the onset of a disease or condition symptom, delaying the recurrence of a disease or condition symptom, alleviating or ameliorating a disease or condition symptom, ameliorating the underlying cause of a symptom, inhibiting the development of a disease or condition, alleviating a disease or condition, causing regression of a disease or condition, alleviating a condition caused by a disease or condition, or preventing a symptom of a disease or condition. The term further includes achieving a therapeutic benefit. Therapeutic benefit means that one or more of the underlying condition being treated is eliminated or ameliorated, and/or the physiological symptoms associated with the underlying condition is eliminated or ameliorated such that an improvement is observed in the patient.

As used herein, the term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of at least one agent (e.g., a therapeutically active agent) administered to achieve a desired result in an individual or subject, e.g., to alleviate one or more symptoms of a disease or disorder being treated to some extent. In some cases, the result is a reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. In certain instances, an "effective amount" for therapeutic use is an amount required to provide a clinically significant reduction in disease of a composition comprising an agent as described herein. In any individual case, any suitable technique, such as dose escalation studies, etc., is used to determine a suitable "effective" amount. In some embodiments, a "therapeutically effective amount" or "effective amount" of an ASBTI refers to a sufficient amount of an ASBTI to treat cholestasis or cholestatic liver disease in a subject/diagnostic.

As used herein, the term "administer" (administer/ADMINISTERING/adminisration) or the like refers to a method that can be used to achieve delivery of an agent or composition to a desired site of biological action. Such methods include, but are not limited to, oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion), topical and rectal administration. Administration techniques optionally used with the reagents and methods described herein are described in sources such as Goodman and Ji Erman (Gilman), the pharmacological foundation of therapeutics (The Pharmacological Basis of Therapeutics), the latest edition; pangamon (Pergamon); and Remington, pharmaceutical science (Pharmaceutical Sciences) (latest edition), microphone Publishing co., pennsylvania, easton, pa, all of which are incorporated herein by reference in their entirety for all purposes. In certain embodiments, the agents and compositions described herein are administered orally.

The term "ASBT inhibitor" refers to a compound that inhibits apical sodium-dependent bile transport or any restorative bile salt transport. The term apical sodium-dependent bile transporter (ASBT) may be used interchangeably with the term Ileal Bile Acid Transporter (IBAT).

The phrase "pharmaceutically acceptable" as used in connection with the compositions of the present invention refers to the molecular entities and other ingredients of such compositions that are physiologically tolerable and do not normally produce adverse reactions when administered to a mammal (e.g., a human). Preferably, as used herein, the term "pharmaceutically acceptable" means approved by a regulatory agency of the federal or a state government or listed in the U.S. pharmacopeia or in other generally recognized pharmacopeia for use in mammals, and more particularly in humans.

In various embodiments, pharmaceutically acceptable salts described herein include (by way of non-limiting example) nitrates, chlorides, bromides, phosphates, sulfates, acetates, hexafluorophosphates, citrates, gluconate, benzoates, propionates, butyrates, subsalicylates (subsalicylate), maleates, laurates, maleates, fumarates, succinates, tartrates, stilbenesulfonates (amsonate), pamoate, p-toluenesulfonates, methanesulfonates, and the like. Furthermore, pharmaceutically acceptable salts include, by way of non-limiting example, alkaline earth metal salts (e.g., calcium or magnesium), alkali metal salts (e.g., sodium-dependent or potassium), ammonium salts, and the like.

As used herein, the term "fasted state" is defined as a state in which the individual has completely digested and absorbed the last meal, and the individual's insulin content is at a low or baseline level. In some embodiments, a fasted state is defined as a state in which an individual 18 years old or older does not consume any food for at least 4 hours. In some embodiments, the fasted state is defined as a state in which the individual is not consuming any food for at least 2 hours. In some embodiments, the fasted state is defined as a state about 30 minutes prior to a meal.

As used herein, fasted patients are defined as patients who have not consumed any food, i.e., have fasted at least 4 hours prior to administration of ASBTI (for individuals 18 years or older) or at least 2 hours prior to administration of ASBTI (for pediatric individuals) and at least 30 minutes after administration of ASBTI. The ASBTI is optionally administered with water during the fasting period, and water may be allowed ad libitum.

As used herein, tolerability refers to the extent to which a patient can tolerate the adverse effects of a drug. In certain embodiments, gastrointestinal (GI) tolerance refers to the extent to which a patient may tolerate adverse GI effects. In some embodiments, the improvement in GI tolerance comprises reducing, minimizing, preventing, ameliorating, or eliminating one or more GI adverse effects.

Cholic acid

Bile contains water, electrolytes, and many organic molecules including cholic acid, cholesterol, phospholipids, and bilirubin. Bile is secreted from the liver and stored in the gallbladder, and upon gallbladder contraction, bile enters the intestine through the bile duct due to ingestion of fatty meal. Cholic acid/salt is critical for digestion and absorption of fat and fat-soluble vitamins in the small intestine. Adult humans produce 400 to 800mL of bile per day. Secretion of bile can be considered to occur in two phases. Initially, hepatocytes secrete bile into the tubules, from where it flows into the bile duct and such hepatobiliary juice contains a large amount of bile acids, cholesterol and other organic molecules. Then, as bile flows through the bile duct, it is modified by the addition of aqueous bicarbonate-rich secretions from the catheter epithelial cells. Bile is concentrated, typically five times, during storage in the gallbladder.

During fasting, bile flow is minimal and a substantial portion thereof is diverted into the gallbladder for concentration. When chyme (chyme) from the meal enters the small intestine, acids and partially digested fats and proteins stimulate the secretion of cholecystokinin and secretin, both of which are important for bile secretion and flow. Cholecystokinin (gallbladder=gallbladder and kinin=movement) is a hormone that stimulates contraction of the gallbladder and common bile duct, resulting in the delivery of bile into the intestine. The most effective stimulus for the release of cholecystokinin is the presence of fat in the duodenum. Secretin is a hormone secreted in response to acids in the duodenum, and it mimics cholangiocytes to secrete bicarbonate and water, which expands bile volume and increases its outflow into the intestine.

Cholic acid/salt is a derivative of cholesterol. Cholesterol ingested as part of the diet or derived from liver synthesis is converted to bile acids/salts in hepatocytes. Examples of such bile acids/salts include cholic acid and chenodeoxycholic acid, which are then bound to amino acids (e.g. glycine or taurine etc.) to produce a bound form that is actively secreted into the tubules (cannaliculi). The most abundant bile salts in humans are cholate and deoxycholate, and they are typically combined with glycine or taurine to produce glycocholate or taurocholate, respectively.

Free cholesterol is hardly soluble in aqueous solutions, however, in bile it becomes soluble due to the presence of bile acids/salts and lipids. Liver synthesis of cholic acid/salt accounts for most of the cholesterol breakdown in humans. In humans, about 500mg of cholesterol per day is converted to bile acids/salts and eliminated in bile. Thus, secretion into bile is the primary route for cholesterol elimination. A large amount of bile acid/salt is secreted into the intestine daily, but only a relatively small amount is lost from the human body. This is because about 95% of the bile acids/salts delivered to the duodenum are absorbed back into the blood in the ileum by a process known as "intestinal liver recirculation".

Venous blood from the ileum enters directly into the portal vein and thus passes through the sinuses of the liver. Hepatocytes extract bile acids/salts from sinus blood very efficiently and rarely escape the healthy liver into the systemic circulation. Cholic acid/salt is then transported through the hepatocytes for re-secretion into the tubules. The net effect of this intestinal liver recirculation is to reuse each bile salt molecule about 20 times (often twice or three times) during a single digestion period. Bile biosynthesis represents the major metabolic fate of cholesterol, accounting for more than half of the cholesterol consumed by average adults during metabolism at about 800 mg/day. In contrast, steroid hormone biosynthesis consumes only about 50mg of cholesterol per day. Much more than 400mg of bile salts are required per day and secreted into the intestine, and this is achieved by recycling the bile salts. Most of the bile salts secreted into the upper region of the small intestine are absorbed along with their emulsified dietary lipids at the lower end of the small intestine. It is separated from dietary lipids and returned to the liver for reuse. Thus, recirculation allows for secretion of 20 to 30g of bile salts into the small intestine per day.

Cholic acid/salts are amphoteric in that the cholesterol-derived moiety contains both hydrophobic (fat-soluble) and polar (hydrophilic) moieties while the amino acid conjugate is generally polar and hydrophilic. This amphoteric nature allows cholic acid/salt to perform two important functions: emulsification of lipid aggregates and dissolution and transport of lipids in an aqueous environment. The bile acids/salts have a detergent action on the particles of dietary fat, which results in breakdown or emulsification of the fat globules. Emulsification is important because it greatly increases the surface area of fat that can be digested by lipases that cannot enter the inside of the lipid droplets. Furthermore, bile acids/salts are lipid carriers and are capable of dissolving many lipids by forming micelles and are critical for the transport and absorption of fat-soluble vitamins.

As used herein, the term "non-systemic" or "minimal absorption" refers to low systemic bioavailability and/or absorption of the administered compound. In some embodiments, the non-systemic compound is a compound that is not substantially absorbed systemically. In some embodiments, the ASBTI compositions described herein deliver ASBTI to the remote ileum, colon, and/or rectum and are non-systemic (e.g., a substantial portion of the ASBTI is not absorbed systemically). In some embodiments, systemic absorption of a non-systemic compound is <0.1%, <0.3%, <0.5%, <0.6%, <0.7%, <0.8%, <0.9%, <1%, <1.5%, <2%, <3% or <5% of the administered dose (wt% or mole%). In some embodiments, systemic absorption of the non-systemic compound is <10% of the administered dose. In some embodiments, systemic absorption of the non-systemic compound is <15% of the administered dose. In some embodiments, systemic absorption of the non-systemic compound is <25% of the administered dose. In an alternative approach, a non-systemic ASBTI is a compound that has a lower systemic bioavailability relative to the systemic bioavailability of a systemic ASBTI (e.g., compounds 100A, 100C). In some embodiments, the bioavailability of a non-systemic ASBTI described herein is <30%, <40%, <50%, <60% or <70% of the bioavailability of a systemic ASBTI (e.g., compounds 100A, 100C).

In another alternative method, the compositions described herein are formulated to systemically deliver <10% of the administered dose of ASBTI. In some embodiments, the compositions described herein are formulated to systemically deliver <20% of the administered dose of ASBTI. In some embodiments, the compositions described herein are formulated to systemically deliver <30% of the administered dose of ASBTI. In some embodiments, the compositions described herein are formulated to systemically deliver <40% of the administered dose of ASBTI. In some embodiments, the compositions described herein are formulated to systemically deliver <50% of the administered dose of ASBTI. In some embodiments, the compositions described herein are formulated to systemically deliver <60% of the administered dose of ASBTI. In some embodiments, the compositions described herein are formulated to systemically deliver <70% of the administered dose of ASBTI. In some embodiments, systemic absorption is measured in any suitable manner, including total circulation, amount cleared after administration, and the like.

ASBT inhibitors

In various embodiments of the methods of the invention, an ASBT inhibitor is administered to an individual. ASBT inhibitors (ASBTIs) reduce or inhibit bile acid circulation in the remote Gastrointestinal (GI) tract, including the remote ileum, colon and/or rectum. Inhibition of apical sodium-dependent cholic acid transport interrupts the intestinal-hepatic circulation of cholic acid and results in more cholic acid being excreted in the stool, resulting in a systemic reduction of cholic acid content, thereby reducing cholic acid-mediated liver damage and related effects and complications. In certain embodiments, the ASBTI is systemic absorption. In certain embodiments, the ASBTI is non-systemic absorption. In some embodiments, ASBTIs described herein are modified or substituted to be non-systemic.

In certain embodiments, the compounds described herein have one or more chiral centers. Thus, all stereoisomers are contemplated herein. In various embodiments, the compounds described herein are present in optically active or racemic forms. It is to be understood that the compounds of the present invention include racemic, optically active, regio-and stereoisomeric forms, or combinations thereof, which possess the therapeutically useful properties described herein. The preparation of the optically active form is accomplished in any suitable manner, including (as illustrated by non-limiting examples) resolution of the racemic form by use of recrystallization techniques, by synthesis from optically active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase. In some embodiments, a mixture of one or more isomers is used as the therapeutic compound described herein. In certain embodiments, the compounds described herein have one or more chiral centers. Such compounds are prepared by any means, including enantioselective synthesis and/or isolation of mixtures of enantiomers and/or diastereomers. Resolution of the compounds and their isomers is achieved by any means including, by way of non-limiting example, chemical processes, enzymatic processes, fractional crystallization, distillation, chromatography, and the like.

In some embodiments, the ASBTI is

(Chloro Ma Lali cilazalide, LUM-001, SHP625, chloro Ma Xiba dtex (lopixibat chloride)) or an alternative pharmaceutically acceptable salt thereof.

In some embodiments, the ASBTI is

(Fu Lixi Bart, (2R, 3R,4S,5R, 6R) -4-benzyloxy-6- {3- [3- ((3S, 4R, 5R) -3-butyl-7-dimethylamino-3-ethyl-4-hydroxy-1, 1-dioxo-2, 3,4, 5-tetrahydro-1H-benzo [ b ] thiepin (thiepin) -5-yl) -phenyl ] -ureido } -3, 5-dihydroxy-tetrahydro-pyran-2-ylmethyl) hydrogen sulfate) or a pharmaceutically acceptable salt thereof.

In some embodiments, the ASBTI is

(LUM-002; SHP626; SAR548304; fu Lixi bar potassium) or an alternative pharmaceutically acceptable salt thereof.

In various embodiments, the ASBTI is(Aldersibat; AZD8294; WHO10706; AR-H064974; SCHEMBL946468; A4250;1, 1-dioxo-3, 3-dibutyl-5-phenyl-7-methylthio-8- (N- { (R) -a- [ N- ((S) -1-carboxypropyl) carbamoyl ] -4-hydroxybenzyl } carbamoylmethoxy) -2,3,4, 5-tetrahydro-1, 2, 5-benzothiadiazine) or a pharmaceutically acceptable salt thereof.

In some embodiments, the ASBTI is

(Ibrutinib; 2- [ [ (2R) -2- [ [2- [ (3, 3-dibutyl-7-methylsulfanyl-1, 1-dioxo-5-phenyl-2, 4-dihydro-1λ6, 5-benzothiazepan-8-yl) oxy ] acetyl ] amino ] -2-phenylacetyl ] amino ] acetic acid) or a pharmaceutically acceptable salt thereof.

In some embodiments, the ASBTI is(GSK 2330672; li Naixi Bart (linerixibat); 3- ((((3R, 5R) -3-butyl-3-ethyl-7- (methyloxy) -1, 1-dioxo-5-phenyl-2, 3,4, 5-tetrahydro-1, 4-benzothiazepin-8-yl) methyl) amino) glutaric acid) or a pharmaceutically acceptable salt thereof.

In some embodiments, ASBTI used in the methods or compositions of the invention is Ma Lali sibatt (e.g., in the form of chloro Ma Lali sibatt), fu Lixi bat (e.g., in the form of Fu Lixi bat potassium), or adesibatt (a 4250), or a pharmaceutically acceptable salt thereof.

In some embodiments, the ASBTI used in the methods or compositions of the invention is Ma Lali sibat or a pharmaceutically acceptable salt thereof.

In some embodiments, the ASBTI used in the methods or compositions of the invention is Fu Lixi bat or a pharmaceutically acceptable salt thereof.

In some embodiments, the ASBTI used in the methods or compositions of the invention is aldrich or a pharmaceutically acceptable salt thereof.

In some embodiments, the ASBTI used in the methods or compositions of the invention is ibrutinib or a pharmaceutically acceptable salt thereof.

In some embodiments, the ASBTI used in the methods or compositions of the invention is GSK2330672 or a pharmaceutically acceptable salt thereof.

In some embodiments, the ASBTI may comprise a mixture of different ASBTIs; for example, the ASBTI may be a composition comprising Ma Lali cilobate, fu Lixi bat, aldrich bat, GSK2330672, ibrutinib, or various combinations thereof.

Methods for treating cholestasis and minimizing adverse gastrointestinal effects

Provided herein is a method for treating cholestasis in an individual having liver disease. The method comprises administering to a subject in need of treatment a apical sodium-dependent bile acid transporter inhibitor (ASBTI). The ASBTI is Ma Lali cilazabat or voricobat or a pharmaceutically acceptable salt thereof. The ASBTI is administered in an amount of about 100 μg/kg/day to about 1400 μg/kg/day.

Provided herein is a method for treating cholestatic liver disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of ASBTI prior to ingestion of food, wherein the subject experiences a reduction in frequency and/or severity of one or more side effects associated with administration of ASBTI. The method comprises administering ASBTI to an individual in need of treatment prior to ingestion of food. In certain embodiments, the ASBTI is Ma Lali cilazabat or voricobat, or a pharmaceutically acceptable salt thereof. The ASBTI is administered in an amount of about 100 μg/kg/day to about 1400 μg/kg/day.

Provided herein is a method of reducing, minimizing, preventing, ameliorating, or eliminating one or more side effects associated with the administration of ASBTI in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of ASBTI prior to ingestion of food. In certain embodiments, the one or more side effects associated with administration of ASBTI are reduced, minimized, prevented, ameliorated, or eliminated as compared to side effects when ASBTI is administered after ingestion of food, concurrently with food, or in combination with food.

In certain embodiments, the one or more side effects are diarrhea, runny stool, nausea, gastrointestinal pain, abdominal pain, cramping (cramping), anorectal discomfort, or a combination thereof.

In certain embodiments, the ASBTI is administered to an individual in a fasted state. In certain embodiments, the ASBTI is administered less than about 1 minute, less than about 5 minutes, less than about 10 minutes, less than about 15 minutes, less than about 20 minutes, less than about 30 minutes, or less than about 60 minutes prior to ingestion of food. In certain embodiments, ABSTI is administered immediately prior to ingestion of the food.

In various embodiments, the liver disease is cholestatic liver disease. In some embodiments, the liver disease is PFIC, ALGS, PSC, biliary closure, intrahepatic cholestasis of pregnancy, PBC, any of the above, or various combinations thereof.

In certain embodiments, the cholestatic liver disease is Progressive Familial Intrahepatic Cholestasis (PFIC), PFIC type 1, PFIC type 2, PFIC type 3, ala Ji Ouzeng syndrome, dubin-Jiang Sener syndrome, biliary tract closure, ge Xishu postbiliary tract closure, posthepatic graft cholestasis, post-hepatic graft related liver disease, intestinal failure related liver disease, cholic-mediated liver injury, pediatric primary sclerosing cholangitis, MRP2 deficiency syndrome, neonatal sclerosing cholangitis, pediatric obstructive cholestasis, pediatric non-obstructive cholestasis, pediatric extrahepatic cholestasis, pediatric intrahepatic cholestasis, pediatric primary intrahepatic cholestasis, pediatric secondary intrahepatic cholestasis, benign Recurrent Intrahepatic Cholestasis (BRIC), type BRIP, BRIC type 2, BRIC type 3, total intravenous nutrition related cholestasis, paraneoplastic cholestasis, stokes syndrome, drug related cholestasis, infection related cholestasis, or cholic disease. In some embodiments, the cholestatic liver disease is a pediatric form of liver disease. In some embodiments, the subject has Intrahepatic Cholestasis (ICP).

In certain embodiments, the cholestatic liver disease is characterized by one or more symptoms selected from the group consisting of: jaundice, itching, cirrhosis, hypercholesteremia, neonatal respiratory distress syndrome, pneumonia, increased serum concentration of cholic acid, increased liver concentration of cholic acid, increased serum concentration of bilirubin, hepatocyte injury, liver scarring, liver failure, hepatomegaly, xanthoma, malabsorption, splenomegaly, diarrhea, pancreatitis, hepatocyte necrosis, giant cell formation, hepatocellular carcinoma, gastrointestinal bleeding, portal hypertension, hearing loss, fatigue, anorexia, abnormal odor, oliguria redness, fecal light color, steatorrhea, growth retardation, and/or renal failure.

In various embodiments, the liver disease is PFIC 2 and the individual has a non-truncated mutation of the ABCB11 gene. In various embodiments, the non-truncated mutation of the ABCB11 gene is a missense mutation. In various embodiments, the missense mutation may be selected from one of those listed in Bai En (Byrne) et al, ABCB11 damage bile salt export pump handling and function or pre-disruption messenger RNA splicing, and single nucleotide polymorphism (Missense Mutations and Single Nucleotide Polymorphisms in ABCB11 Impair Bile Salt Export Pump Processing and Function or Disrupt Pre-Messanger RNA Splicing)", liver disease science (Hepatology), 49:553-567 (2009), which is incorporated herein by reference in its entirety for all purposes.

In various embodiments, the subject has a disorder associated with, caused by, or in part caused by a BSEP deficiency. In certain embodiments, the disorder associated with, caused by, or caused in part by BSEP deficiency is neonatal hepatitis, primary Biliary Cirrhosis (PBC), primary Sclerosing Cholangitis (PSC), PFIC 2, benign Recurrent Intrahepatic Cholestasis (BRIC), intrahepatic Cholestasis of Pregnancy (ICP), drug-induced cholestasis, oral contraceptive-induced cholestasis, biliary locking, or a combination thereof.

In various embodiments, the patient is a pediatric patient aged 0,1, 2, 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or under 18 years old. In certain embodiments, the pediatric individual is a neonate, premature neonate, infant, toddler, preschool child (preschooler), school-age child (school-age child), pre-pubertal child (pre-pubescent child), post-pubertal child (post-pubescent child), adolescent, or adolescent under 18 years of age. In some embodiments, the pediatric individual is a neonate, premature neonate, infant, preschool child, or preschool child. In some embodiments, the pediatric individual is a neonate, premature neonate, infant, toddler, or preschool child. In some embodiments, the pediatric individual is a neonate, premature neonate, infant, or young child. In some embodiments, the pediatric individual is a neonate, premature neonate, or infant. In some embodiments, the pediatric individual is a neonate. In some embodiments, the pediatric individual is an infant. In some embodiments, the pediatric individual is a child. In various embodiments, the pediatric patient has PFIC 2, PFIC 1, or ALGS. In some embodiments, the patient is an adult aged 18, 20, 30, 40, 50, 60, or 70 years old. In some patients, the adult patient has PSC. In some embodiments, the pediatric patient has any pediatric cholestatic condition that results in less than normal growth, height, or weight.

In certain embodiments, the methods of the invention comprise non-systemic administration of a therapeutically effective amount of ASBTI. In certain embodiments, the method comprises contacting the gastrointestinal tract (including the remote ileum and/or colon and/or rectum) of an individual in need thereof with an ASBTI. In various embodiments, the methods of the invention result in a reduction in intestinal cholic acid, or a reduction in damage to hepatocytes or intestinal structures caused by cholestasis or cholestatic liver disease.

In various embodiments, the methods of the invention comprise delivering a therapeutically effective amount of any of the ASBTIs described herein to the ileum or colon of an individual.

In various embodiments, the methods of the invention comprise reducing damage to hepatocytes or intestinal structures or cells from cholestatic or cholestatic liver disease comprising administering a therapeutically effective amount of ASBTI. In certain embodiments, the methods of the invention comprise reducing intestinal bile acid/bile salts by administering to an individual in need thereof a therapeutically effective amount of ASBTI.

In some embodiments, the methods of the invention can inhibit bile salt circulation after administration of any of the compounds described herein to a subject. In some embodiments, the ASBTIs described herein are systemically absorbed after administration. In some embodiments, the ASBTIs described herein are not absorbed systemically. In some embodiments, ASBTI herein is orally administered to a subject. In some embodiments, the ASBTIs described herein are delivered and/or released in the individual's remote ileum.

In various embodiments, contacting the subject's remote ileum with ASBTI (e.g., any of the ASBTIs described herein) inhibits bile acid reabsorption and increases the concentration of bile acids/salts near L cells in the remote ileum and/or colon and/or rectum, thereby reducing intestinal cholic acid, reducing serum and/or hepatobiliary acid content, reducing overall serum cholic acid loading, and/or reducing damage to the ileal structure caused by cholestasis or cholestasis liver disease. Without being limited to any particular theory, lowering serum and/or hepatic cholate levels ameliorates hypercholesteremia and/or cholestatic disease.

Administration of the compounds described herein may be accomplished in any suitable manner, including (as illustrated by way of non-limiting example) by oral, enteral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal routes of administration. Any of the compounds or compositions described herein may be administered in a method or formulation suitable for treating a neonate or infant. Any of the compounds or compositions described herein can be administered in an oral formulation (e.g., solid or liquid) to treat a neonate or infant. Any of the compounds or compositions described herein can be administered with the food prior to or after ingestion of the food.

In certain embodiments, a compound described herein or a composition comprising a compound described herein is administered for prophylactic and/or therapeutic treatment. In therapeutic applications, the composition is administered to an individual already suffering from a disease or disorder in an amount sufficient to cure or at least partially arrest the symptoms of the disease or disorder. In each case, the amount effective for this use is based on the severity and course of the disease or disorder, past therapy, the health status, weight, and response of the individual to the drug, and the discretion of the attending physician.

In prophylactic applications, a compound described herein or a composition containing a compound described herein may be administered to an individual susceptible to or otherwise at risk of a particular disease, disorder or condition. In certain embodiments of such use, the precise amount of compound administered depends on the health state, weight, etc. of the individual. Furthermore, in some cases, when a compound or composition described herein is administered to an individual, an effective amount for such use is based on the severity and course of the disease, disorder or condition, past therapy, the health status and response of the individual to the drug, and the discretion of the attendant physician.

In certain embodiments of the methods of the invention, wherein the subject's condition is not improved at the discretion of the physician after administration of a selected dose of a compound or composition described herein, the administration of the compound or composition described herein is optionally administered frequently, i.e., for a longer period of time (including the entire subject's lifetime) in order to ameliorate or otherwise control or limit the symptoms of the subject's condition, disease, or disorder.

In certain embodiments of the methods of the invention, the effective amount of the administered agent varies depending on one or more of a number of factors, such as the particular compound, the disease or disorder and severity thereof, the identity (e.g., body weight) of the individual or host in need of treatment, etc., and is determined based on the particular circumstances surrounding the case, including, for example, the particular agent administered, the route of administration, the disorder being treated, and the individual or host being treated. In some embodiments, the doses administered include those up to the maximum tolerated dose. In some embodiments, the doses administered include those up to the maximum tolerable dose for the neonate or infant.

In various embodiments of the methods of the invention, the desired dose is conveniently presented in a single dose or multiple doses administered simultaneously (or over a short period of time) or at suitable intervals (e.g., in two, three, four or more sub-doses per day). In various embodiments, a single dose of ASBTI is administered every 6 hours, every 12 hours, every 24 hours, every 48 hours, every 72 hours, every 96 hours, every 5 days, every 6 days, or weekly. In some embodiments, the total single dose of ASBTI is within the ranges described below.

In various embodiments of the methods of the invention, optionally, the ASBTI is administered continuously at the discretion of the physician in cases where the patient's status does improve; or the dose of administered drug is temporarily reduced or temporarily suspended for a certain period of time (i.e. "drug holiday"). The length of the drug holiday optionally varies between 2 days and 1 year, including, by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days. Dose reduction during drug holidays includes 10% to 100% of the original dose, including (by way of example only) 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100% of the original dose. In some embodiments, the total single dose of ASBTI is within the ranges described below.

Once an improvement in the patient's condition has occurred, a maintenance dose is administered as necessary. Subsequently, the dose or frequency or both administered is reduced to the extent that the improved disease, disorder or condition is retained. In some embodiments, the patient is in need of long-term intermittent treatment at any recurrence of symptoms.

In some cases, there are many variables for individual treatment regimens, and a large number of deviations from these recommended values are considered to be within the ranges described herein. The dosages described herein optionally vary depending upon a number of variables, such as, by way of non-limiting example, the activity of the compound used, the disease or condition to be treated, the mode of administration, the needs of the individual, the severity of the disease or condition being treated, and the judgment of the practitioner.

Toxicity and therapeutic efficacy of such treatment regimens are optionally determined by pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, determination of LD ₅₀ (the dose lethal to 50% of the population) and ED ₅₀ (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and can be expressed as the ratio between LD ₅₀ and ED ₅₀. Compounds exhibiting a high therapeutic index are preferred. In certain embodiments, data obtained from cell culture assays and animal studies are used in formulating a range of dosage for use in humans. In certain embodiments, the dosage of a compound described herein is within a circulating concentration range that includes ED ₅₀ with minimal toxicity. The dosage is optionally varied within this range, depending upon the dosage form used and the route of administration used.

In certain embodiments, the composition used or administered comprises an absorption inhibitor, a carrier, and one or more of a cholesterol absorption inhibitor, an enteroendocrine peptide, a peptidase inhibitor, a diffusant (SPREADING AGENT), and a wetting agent.

In some embodiments of the methods of the invention, the compositions for preparing an oral dosage form or for oral administration comprise an absorption inhibitor, an orally suitable carrier, optionally a cholesterol absorption inhibitor, optionally an enteroendocrine peptide, optionally a peptidase inhibitor, optionally a diffusant, and optionally a wetting agent. In certain embodiments, the orally administered composition evokes an anorectal response. In particular embodiments, the anorectal response is an increase in secretion of one or more enteroendocrine peptides by cells in the colon and/or rectum (e.g., in the L cells, the epithelial layer of the colon, the ileum, the rectum, or a combination thereof). In some embodiments, the anorectal reaction continues for at least 1, 2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours. In other embodiments, the anorectal reaction is for a period of time between 24 hours and 48 hours, while in other embodiments, the anorectal reaction is for a period of time longer than 48 hours.

Dosage of

In various embodiments, the ASBTI is Ma Lali cilazabat or voricobat, or a pharmaceutically acceptable salt thereof.

In various embodiments, the ASBTI is administered to an individual prior to ingestion of food.

In various embodiments, the efficacy and safety of ASBTI administration to a patient is monitored by determining the serum content of 7α -hydroxy-4-cholesten-3-one (7αc4), sBA concentration, the ratio of 7αc4 to sBA (7αc4: sBA), serum binding bilirubin concentration, serum autotaxin (autotaxin) concentration, serum bilirubin concentration, serum total cholesterol concentration, serum LDL-C concentration, serum ALT concentration, serum AST concentration, or a combination thereof. In various embodiments, the efficacy of ASBTI administration is determined by monitoring the ITCHRO (OBS) score, HRQoL (e.g., pedsQL) score, CSS score, xanthoma score, height Z score, weight Z score, or various combinations thereof, reported by the observer. In various embodiments, the methods include monitoring the serum content of 7α -hydroxy-4-cholesten-3-one (7αc4), sBA concentrations, the ratio of 7αc4 to sBA (7αc4: sBA), serum-bound bilirubin concentrations, serum total cholesterol concentrations, serum LDL-C concentrations, serum autotaxin concentrations, serum bilirubin concentrations, serum ALT concentrations, serum AST concentrations, or combinations thereof. In various embodiments, the method includes monitoring an itch report result (ITCHRO (OBS)) score, a weight Z score, an HRQoL (e.g., pedsQL) score, a xanthoma score, a CSS score, a height Z score, or various combinations thereof, reported by the observer.

In some embodiments, the ASBTI is administered at a dose of about or at least about 0.5μg/kg、1μg/kg、2μg/kg、3μg/kg、4μg/kg、5μg/kg、6μg/kg、7μg/kg、8μg/kg、9μg/kg、10μg/kg、15μg/kg、20μg/kg、25μg/kg、30μg/kg、35μg/kg、40μg/kg、45μg/kg、50μg/kg、55μg/kg、60μg/kg、65μg/kg、70μg/kg、75μg/kg、80μg/kg、85μg/kg、90μg/kg、100μg/kg、140μg/kg、150μg/kg、200μg/kg、240μg/kg、250μg/kg、280μg/kg、300μg/kg、360μg/kg、380μg/kg、400μg/kg、500μg/kg、560μg/kg、600μg/kg、700μg/kg、800μg/kg、880μg/kg、900μg/kg、1,000μg/kg、1,100μg/kg、1,200μg/kg、1,300μg/kg、1,400μg/kg、1500μg/kg、1,600μg/kg、1,700μg/kg、1,800μg/kg、1,900μg/kg or 2,000 μg/kg. In various embodiments, the ASBTI is administered at a dose of no more than about 1μg/kg、2μg/kg、3μg/kg、4μg/kg、5μg/kg、6μg/kg、7μg/kg、8μg/kg、9μg/kg、10μg/kg、15μg/kg、20μg/kg、25μg/kg、30μg/kg、35μg/kg、40μg/kg、45μg/kg、50μg/kg、55μg/kg、60μg/kg、65μg/kg、70μg/kg、75μg/kg、80μg/kg、85μg/kg、90μg/kg、100μg/kg、140μg/kg、150μg/kg、200μg/kg、240μg/kg、250μg/kg、280μg/kg、300μg/kg、360μg/kg、380μg/kg、400μg/kg、500μg/kg、560μg/kg、600μg/kg、700μg/kg、800μg/kg、880μg/kg、900μg/kg、1,000μg/kg、1,100μg/kg、1,200μg/kg、1,300μg/kg、1,400μg/kg、1,500μg/kg、1,600μg/kg、1,700μg/kg、1,800μg/kg、1,900μg/kg、2,000、 or 2,100 μg/kg. In various embodiments, the ASBTI is administered at a dose of about or at least about 0.5 mg/day, 1 mg/day, 2 mg/day, 3 mg/day, 4 mg/day, 5 mg/day, 6 mg/day, 7 mg/day, 8 mg/day, 9 mg/day, 10 mg/day, 11 mg/day, 12 mg/day, 13 mg/day, 14 mg/day, 15 mg/day, 16 mg/day, 17 mg/day, 18 mg/day, 19 mg/day, 20 mg/day, 30 mg/day, 40 mg/day, 50 mg/day, 60 mg/day, 70 mg/day, 80 mg/day, 90 mg/day, 100 mg/day, 150 mg/day, 200 mg/day, 300 mg/day, 500 mg/day, 600 mg/day, 700 mg/day, 800 mg/day, 900 mg/day, 1000 mg/day. In various embodiments, the ASBTI is administered at a dose of no greater than about 1 mg/day, 2 mg/day, 3 mg/day, 4 mg/day, 5 mg/day, 6 mg/day, 7 mg/day, 8 mg/day, 9 mg/day, 10 mg/day, 11 mg/day, 12 mg/day, 13 mg/day, 14 mg/day, 15 mg/day, 16 mg/day, 17 mg/day, 18 mg/day, 19 mg/day, 20 mg/day, 30 mg/day, 40 mg/day, 50 mg/day, 60 mg/day, 70 mg/day, 80 mg/day, 90 mg/day, 100 mg/day, 150 mg/day, 200 mg/day, 300 mg/day, 500 mg/day, 600 mg/day, 700 mg/day, 800 mg/day, 900 mg/day, 1,000 mg/day, 1,100 mg/day.

In some embodiments, the ASBTI is administered at a dose of about 140 μg/kg/day to about 1400 μg/kg/day. In various embodiments, the ASBTI is provided in an amount of about or at least about 0.5 μg/kg/day, 1 μg/kg/day, 2 μg/kg/day, 3 μg/kg/day, 4 μg/kg/day, 5 μg/kg/day, 6 μg/kg/day, 7 μg/kg/day, 8 μg/kg/day, 9 μg/kg/day, 10 μg/kg/day, 15 μg/kg/day, 20 μg/kg/day, 25 μg/kg/day, 30 μg/kg/day, 35 μg/kg/day, 40 μg/kg/day, 45 μg/kg/day, 50 μg/kg/day, 100 μg/kg/day, 140 μg/kg/day, 150 μg/kg/day, 200 μg/kg/day, 240 μg/kg/day, 280 μg/kg/day, 300 μg/kg/day, 250 μg/kg/day, 280 μg/kg/day, 300 μg/kg/day, 360 μg/kg/day, 380 μg/kg/day, 400 μg/kg/day, 500 μg/kg/day, 560 μg/kg/day, 600 μg/kg/day, 700 μg/kg/day, 800 μg/kg/day, 880 μg/kg, 900 μg/kg/day, 1,000 μg/kg/day, 1,100 μg/kg/day, 1,200 μg/kg/day, or 1,300 μg/kg/day. In various embodiments, the ASBTI is used in an amount of no more than about 1 μg/kg/day, 2 μg/kg/day, 3 μg/kg/day, 4 μg/kg/day, 5 μg/kg/day, 6 μg/kg/day, 7 μg/kg/day, 8 μg/kg/day, 9 μg/kg/day, 10 μg/kg/day, 15 μg/kg/day, 20 μg/kg/day, 25 μg/kg/day, 30 μg/kg/day, 35 μg/kg/day, 40 μg/kg/day, 45 μg/kg/day, 50 μg/kg/day, 100 μg/kg/day, 140 μg/kg/day, 150 μg/kg/day, 200 μg/kg/day, 240 μg/kg/day, 280 μg/kg/day, 300 μg/kg/day, 250 μg/kg/day, 280 μg/kg/day, 300 μg/kg/day, 360 μg/kg/day, 380 μg/kg/day, 400 μg/kg/day, 500 μg/kg/day, 560 μg/kg/day, 600 μg/kg/day, 700 μg/kg/day, 800 μg/kg/day, 880 μg/kg/day, 900 μg/kg/day, 1,000 μg/kg/day, 1,100 μg/kg/day, 1,200 μg/kg/day, 1,300 μg/kg/day, or 1,400 μg/kg/day. In various embodiments, the ASBTI is provided in an amount of about 0.5 μg/kg/day to about 500 μg/kg/day, about 0.5 μg/kg/day to about 250 μg/kg/day, about 1 μg/kg/day to about 100 μg/kg/day, about 10 μg/kg/day to about 50 μg/kg/day, about 10 μg/kg/day to about 100 μg/kg/day, about 0.5 μg/kg/day to about 2000 μg/kg/day, about 280 μg/kg/day to about 1400 μg/kg/day, about 420 μg/kg/day to about 1400 μg/kg/day, About 250 to about 550. Mu.g/kg/day, about 560. Mu.g/kg/day to about 1400. Mu.g/kg/day, about 700. Mu.g/kg/day to about 1400. Mu.g/kg/day, about 560. Mu.g/kg/day to about 1200. Mu.g/kg/day, about 700. Mu.g/kg/day to about 1200. Mu.g/kg/day, about 560. Mu.g/kg/day to about 1000. Mu.g/kg/day, about 700. Mu.g/kg/day to about 1000. Mu.g/kg/day, about 800. Mu.g/kg/day to about 1000. Mu.g/kg/day, about 200. Mu.g/kg/day to about 600. Mu.g/kg/day, About 300 μg/kg/day to about 600 μg/kg/day, about 400 μg/kg/day to about 500 μg/kg/day, about 400 μg/kg/day to about 600 μg/kg/day, about 400 μg/kg/day to about 700 μg/kg/day, about 400 μg/kg/day to about 800 μg/kg/day, about 500 μg/kg/day to about 800 μg/day, about 500 μg/kg/day to about 900 μg/kg/day, about 600 μg/kg/day to about 900 μg/kg/day, about 700 μg/kg/day to about 900 μg/kg/day, About 200 μg/kg/day to about 600 μg/kg/day, about 800 μg/kg/day to about 900 μg/kg/day, about 100 μg/kg/day to about 1500 μg/kg/day, about 300 μg/kg/day to about 2,000 μg/kg/day, or from about 400 μg/kg/day to about 2000 μg/kg/day.

In various embodiments, the ASBTI is administered at a dose of about 30 μg/kg to about 1400 μg/kg/dose. In some embodiments, the ASBTI is administered at a dosage of about 0.5 μg/kg to about 2000 μg/kg/agent, about 0.5 μg/kg to about 1500 μg/kg/agent, about 100 μg/kg to about 700 μg/kg/agent, about 5 μg/kg to about 100 μg/kg/agent, about 10 μg/kg to about 500 μg/kg/agent, about 50 μg/kg to about 1400 μg/kg/agent, about 300 μg/kg to about 2,000 μg/kg/agent, about 60 μg/kg to about 1200 μg/kg/agent, about 70 μg/kg to about 1000 μg/kg/agent, about 70 μg/kg to about 700 μg/kg/agent, about 80 μg/kg to about 1000 μg/kg/agent, about 80 μg/kg to about 800 μg/kg/agent, about 100 μg/kg to about 500 μg/kg/agent, about 100 μg/kg to about 600 μg/kg/agent, about 150 μg/kg to about 400 μg/kg/agent, about 400 μg/kg to about 400 μg/kg/agent.

In some embodiments, the ASBTI is administered at a dose of about 0.5 mg/day to about 550 mg/day. In various embodiments, the ASBTI is administered at a dosage of about 1 mg/day to about 500 mg/day, about 1 mg/day to about 300 mg/day, about 1 mg/day to about 200 mg/day, about 2 mg/day to about 300 mg/day, about 2 mg/day to about 200 mg/day, about 4 mg/day to about 300 mg/day, about 4 mg/day to about 200 mg/day, about 4 mg/day to about 150 mg/day, about 5 mg/day to about 100 mg/day, about 5 mg/day to about 80 mg/day, about 5 mg/day to about 50 mg/day, about 5 mg/day to about 40 mg/day, about 5 mg/day to about 30 mg/day, about 5 mg/day to about 20 mg/day, about 5 mg/day to about 15 mg/day, about 10 mg/day to about 100 mg/day, about 10 mg/day to about 80 mg/day, about 10 mg/day to about 50 mg/day, about 10mg to about 40 mg/day, about 20mg to about 20 mg/day, about 20 mg/day to about 40 mg/day, about 20 mg/day to about 20 mg/day, about 20 mg/day to about 40 mg/day.

In some embodiments, the ASBTI is administered in an amount of about 200 μg/kg to about 400 μg/kg/dose twice daily (BID). In some embodiments, the ASBTI is administered in an amount of about 280 μg/kg/day to about 1400 μg/kg/day. In some embodiments, the ASBTI is administered in an amount of about 400 μg/kg/day to about 800 μg/kg/day. In some embodiments, the ASBTI is administered in an amount of about 20 mg/day to about 50 mg/day. In some embodiments, the ASBTI is administered in an amount of about 5 mg/day to about 15 mg/day. In some embodiments, the ASBTI is administered in an amount of about 560 μg/kg/day to about 1,400 μg/kg/day. In some embodiments, the ASBTI is administered in an amount of about 700 μg/kg/day to about 1,400 μg/kg/day. In some embodiments, the ASBTI is administered in an amount of about 400 μg/kg/day to about 800 μg/kg/day. In some embodiments, the ASBTI is administered in an amount of about 700 μg/kg/day to about 900 μg/kg/day. In some embodiments, the ASBTI is administered in an amount of about 560 μg/kg/day to about 1400 μg/kg/day. In some embodiments, the ASBTI is administered in an amount of 700 μg/kg/day to about 1400 μg/kg/day. In some embodiments, the ASBTI is administered in an amount of about 200 μg/kg/day to about 600 μg/kg/day. In some embodiments, the ASBTI is administered in an amount of about 400 μg/kg/day to about 600 μg/kg/day.

In various embodiments, the dose of ASBTI is a first dose. In various embodiments, the dose of ASBTI is a second dose. In some embodiments, the second dose is greater than the first dose. In some embodiments, the second dose is about or at least about 1.5, 2, 3, 4,5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, or 100 times (times/fold) greater than the first dose. In some embodiments, the second dose is no more than about 1.5, 2, 3, 4,5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, or 150 times greater (times/fold) than the first dose.

In various embodiments, the ASBTI is administered once daily (QD) at one of the above doses or within one of the above dose ranges. In various embodiments, the ASBTI is administered at one of the above doses or within one of the above dose ranges twice daily (BID). In various embodiments, the ASBTI dose is administered daily, every other day, twice weekly, or once weekly.

In various embodiments, the ASBTI is administered periodically for a period of about or at least about 1,2,3,4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 48, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, or 800 weeks. In various embodiments, the ASBTI is administered for no more than about 1,2,3,4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 48, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, or 1000 weeks. In various embodiments, the ASBTI is administered periodically for a period of about or at least about 0.5, 1, 1.5, 2,3,4, 5, 6, 7, 8, 9, or 10 years. In various embodiments, the ASBTI is administered periodically for a period of time of no more than about 0.5, 1, 1.5, 2,3,4, 5, 6, 7, 8, 9, 10, or 15 years.

Reduction of symptoms of cholestatic liver disease or change in disease-related laboratory measurements

In the various embodiments of the method of the present invention described above, administration of ASBTI results in a reduction in symptoms of cholestatic liver disease or a change in a disease-related laboratory metric (i.e., improvement in the patient's condition) maintained for about or at least about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 6 months, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 1, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7,8, 9 or 10 years. In various embodiments, the decrease in symptoms or change in disease-related laboratory measures includes a decrease in sBA concentration, an increase in serum 7αc4 concentration, an increase in 7αc4: sBA ratio, an increase in fBA excretion, a decrease in itching, a decrease in serum total cholesterol concentration, a decrease in serum LDL-C cholesterol concentration, a decrease in ALT content, an increase in quality of life scale score associated with fatigue, a decrease in xanthoma score, a decrease in serum autotaxin concentration, an increase in growth, or a combination thereof. In various embodiments, the reduction in symptoms or the change in disease-related laboratory measurements is measured relative to a baseline level. That is, the reduction in symptoms or the change in the disease-related laboratory metric is determined relative to a measurement of the change in the symptoms or the disease-related laboratory metric prior to: 1) altering the dose of ASBTI administered to an individual, 2) altering the dosing regimen followed by the patient, 3) initiating administration of ASBTI, or 4) any other variety of changes made in order to reduce the change in symptoms or disease-related laboratory metrics in the patient. In various embodiments, the reduction in symptoms or the change in disease-related laboratory measurements is a statistically significant reduction.

In the context of a variety of embodiments of the present invention, the decrease in symptoms of cholestatic liver disease or change in the disease-associated laboratory metric is determined to be a progressive decrease in symptoms or change in the disease-associated laboratory metric for about or at least about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 6 months, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks, 1 year, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 2 years, 2.5 years, 3 years, 3.5 years, 4 years, 4.5 years, 5 years, 5.5 years, 6 years, 6.5 years, 7 years, 8 years, 9 years or 10 years.

In some embodiments, the patient is a pediatric patient and the reduction in symptoms or change in disease-related laboratory metrics includes an increase or improvement in growth. In some embodiments, the increase in growth is relative to a baseline determination. In various embodiments, the increase in growth is measured as an increase in height Z-score or weight Z-score. In various embodiments, the increase in height Z-score or weight Z-score is statistically significant. In various embodiments, the height Z-score, the weight Z-score, or both are increased by at least 0.1、0.11、0.12、0.13、0.14、0.15、0.16、0.17、0.18、0.19、0.2、0.21、0.22、0.23、0.24、0.25、0.26、0.27、0.28、0.29、0.3、0.31、0.32、0.33、0.34、0.35、0.36、0.37、0.38、0.39、0.4、0.41、0.42、0.43、0.44、0.45、0.46、0.47、0.48、0.49、0.5、0.51、0.52、0.53、0.54、0.55、0.56、0.57、0.58、0.59、0.6、0.7、0.8 or 0.9 relative to baseline. In some embodiments, the height Z-score, the weight Z-score, or both are progressively increased during the administration of the ASBTI for a period of time of about or at least about 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 48, 50, 60, 70, or 72 weeks.

In various embodiments, the administration of ASBTI results in an increase in serum 7αc4 concentration. In various embodiments, the serum 7αc4 concentration is increased relative to baseline by about or at least about 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, or 500 times (times/fold). In various embodiments, the serum 7αc4 concentration is increased by about or at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, 1,000%, or 10,000% relative to baseline.

In various embodiments, administration of the ASBTI results in an increase in 7αc4: sBA ratio relative to baseline of about or at least about 1.25、1.5、1.75、2、2.5、3、4、5、6、7、8、9、10、15、20、30、40、50、75、100、150、200、300、500、750、1,000、2,000、3,000、4,000、5,000 or 10,000 fold.

In various embodiments, administration of the ASBTI results in increased fBA excretion. In some embodiments, administration of the ASBTI results in an increase in fBA excretion of about or at least about 100%, 110%, 115%, 120%, 130%, 150%, 200%, 250%, 275%, 300%, 400%, 500%, 600%, 700%, 800%, 1,000%, 5,000%, 10,000%, or 15,000% from baseline. In various embodiments, fBA excretion is increased relative to baseline by about or at least about 1, 1.5, 2,3, 4,5, 6,7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100 fold (fold/time). In some embodiments, fBA excretion is increased relative to baseline by about or at least about 100 μmol, 150 μmol, 200 μmol, 250 μmol, 300 μmol, 400 μmol, 500 μmol, 600 μmol, 700 μmol, 800 μmol, 900 μmol, 1,000 μmol, or 1,500 μmol. In various embodiments, the administration of ASBTI results in a dose-dependent increase in fBA excretion such that administration of a higher dose of ASBTI results in a correspondingly higher degree of fBA excretion. In various embodiments, the ASBTI is administered at a dose sufficient to cause at least about or about 1,2, 3, 4,5, 6,7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100 fold (fold/time) increase in cholic acid secretion relative to baseline.

In various embodiments, administration of the ASBTI results in a sBA concentration decrease from baseline of about or at least about 5%, 10%, 15%, 20%, 25%, 30%, 31%, 35%, 40%, 45%, 50%, 55%, 57%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%.

In some embodiments, the administration of ASBTI results in a reduction in the severity of itching. In various embodiments, the severity of itching is determined using an ITCHRO (OBS) score, ITCHRO score, CSS score, or a combination thereof. In various embodiments, the administration of ASBTI results in a decrease in ITCHRO (OBS) score from baseline of about or at least about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.25, 2.5, or 3 according to a scale of 1 to 4. In various embodiments, administration of the ASBTI results in a ITCHRO score reduction of about or at least about 0.1, 0.2, 0.3, 0.4, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, or 10 on a scale of 1 to 10. In various embodiments, the administration of ASBTI results in a reduction of ITCHRO (OBS) score, ITCHRO score, or both to zero. In various embodiments, the administration of ASBTI results in a reduction of ITCHRO (OBS) score or ITCHRO score to 1.0 or less. In various embodiments, administration of the ASBTI results in a reduction in CSS score relative to baseline of about or at least about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.25, 2.5, or 3. In various embodiments, the administration of the ASBTI results in a reduction of the CSS score to zero. In various embodiments, the administration of the ASBTI results in a reduction in CSS score, ITCHRO (OBS) score, ITCHRO score, or a combination thereof by about or at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% relative to baseline. In various embodiments, a reduced value of CSS score, ITCHRO (OBS) score, ITCHRO score, or a combination thereof relative to baseline is observed on 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the days.

In some embodiments, patients with a higher baseline ITCHRO (OBS) score demonstrate a greater reduction in symptoms or a change in disease-related laboratory metrics as compared to patients with a lower baseline ITCHRO (OBS) score. In some embodiments, a patient having a baseline ITCHRO (OBS) score of at least 2,3, or 4, or a ITCHRO score of at least 4, 5, 6, 7, 8, 9, or 10, has a greater reduction in symptoms or a change in disease-related laboratory metric from baseline as compared to a lower reduction in patients having a lower baseline pruritus severity score. In various embodiments, patients with PSC and a baseline ITCHRO score of at least 4 demonstrate a greater reduction in symptoms or change in disease-related laboratory metrics compared to patients with a baseline ITCHRO score of less than 4. In various embodiments, the method comprises predicting that if the patient's baseline ITCHRO score is at least 4, then the patient will have a greater reduction in symptoms or a change in disease-related laboratory metric as compared to a patient having a baseline ITCHRO score of less than 4. In various embodiments, the lower reduction is about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, or 60% of the greater reduction. In various embodiments, after the first administration of the ASBTI at the first dose or at the second dose, the difference (i.e., between greater reduction and lesser reduction) in the reduction of symptoms or change in disease-related laboratory measurements between a patient having a ITCHRO score of at least 4 at baseline and a patient having a ITCHRO score of less than 4 at baseline is determined to be about or at least about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 6 months, 25 weeks, 26 weeks 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 1, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 5, 7, 8, 9 or 10 years.

In various embodiments, the decrease in severity of itch caused by administration of ASBTI to a patient is positively correlated with a decrease in sBA concentrations in the patient. In various embodiments, a greater decrease in sBA concentration in the patient correlates with a corresponding greater decrease in the severity of itch.

In various embodiments, the administration of ASBTI results in a decrease in serum LDL-C concentration relative to baseline. In some embodiments, the serum LDL-C concentration is reduced relative to baseline by about or at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% or 80%.

In some embodiments, the administration of ASBTI results in a decrease in serum total cholesterol concentration relative to baseline. In some embodiments, the administration of ASBTI results in a decrease in serum LDL-C content relative to baseline. In some embodiments, the serum total cholesterol concentration, serum LDL-C content, or both is reduced relative to baseline by about or at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80%. In various embodiments, administration of the ASBTI results in a reduction in serum total cholesterol concentration, serum LDL-C content, or both, relative to baseline of about or at least about 1mg/dL, 2mg/dL, 3mg/dL, 4mg/dL, 5mg/dL, 10mg/dL, 12.5mg/dL, 15mg/dL, 20mg/dL, 30mg/dL, 40mg/dL, or 50mg/dL.

In various embodiments, the administration of ASBTI results in a decrease in serum autotaxin concentration. In some embodiments, administration of the ASBTI results in a decrease in the concentration of the autotaxin from baseline by about or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80%.

In various embodiments, the administration of the ASBTI results in an increase in a quality of life scale score or a quality of life scale score related to fatigue. The quality of life scale score may be a health related quality of life (HRQoL) score. In some embodiments, the HRQoL score is PedsQL score. In various embodiments, the administration of the ASBTI results in an increase in PedsQL score or fatigue-related PedsQL score of about or at least about 5%, 10%, 15%, 20%, 25%, 30%, 45% or 50% from baseline.

In various embodiments, the administration of ASBTI results in a decrease in the score of a xanthoma relative to baseline. In some embodiments, the xanthoma score is reduced by about or at least about 2.5%, 5%, 10%, 15%, 20%, 35%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% relative to baseline.

In various embodiments, administration of the ASBTI results in a decrease in symptoms or a change in a disease-related laboratory metric of about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks, or 1 year.

In various embodiments, the serum bilirubin concentration is at the pre-administration level or normal level at about or to about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 2 months, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 4 months, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks, or 1 year.

In various embodiments, serum ALT concentration is at a pre-administration baseline or normal level at about or to about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 4 months, 17 weeks, 18 months, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks, or 1 year. In some embodiments, administration of the ASBTI results in a decrease in ALT content of about or at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, or 15% from baseline.

In various embodiments, the serum ALT concentration, serum AST concentration, serum bilirubin concentration, serum conjugated bilirubin concentration, or various combinations thereof is within a normal range or at a pre-administration level at about or to about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 4 months, 17 weeks, 18 months, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks, or 1 year. In various embodiments, the administration of ASBTI does not result in a statistically significant change in serum bilirubin concentration, serum AST concentration, serum ALT concentration, serum alkaline phosphatase concentration, or some combination thereof, from baseline for at least about or about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 4 months, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks, or 1 year. In various embodiments, for adult patients having a score of ITCHRO of at least 4 at baseline, the administration of the ASBTI does not result in a significant change in serum-associated bilirubin concentration from baseline for a period of at least about or about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 4 months, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks, or 1 year.

In various embodiments of the above methods of the invention, the administration of ASBTI results in a reduction, prevention, amelioration, or elimination of one or more side effects associated with the administration of ASBTI in an individual in need thereof. In various embodiments, the frequency and/or severity of side effects is reduced as compared to side effects when ASBTI is administered after ingestion of food, concurrently with food, or in combination with food. In various embodiments, the one or more side effects are diarrhea, runny stool, nausea, gastrointestinal pain, abdominal pain, cramping, anorectal discomfort, or a combination thereof.

In various embodiments of the above methods of the invention, the administration of ASBTI results in an improvement in GI tolerance of ASBTI. In some embodiments, the GI tolerance is improved compared to when ASBTI is administered at the time of a meal or immediately after food intake.

In some embodiments, the GI tolerance is improved by at least 10%, or at least 15%, or at least 20%, or at least 25%, or at least 30%, or at least 35%, or at least 40%, or at least 45%, or at least 50%, or at least 60%, or at least 70% compared to the GI tolerance when ASBTI is administered at the time of a meal or immediately after food intake.

Dose modulation

In various embodiments, the method comprises modulating the dose of ASBTI administered to the individual. The modulation includes determining a 7αc4: sBA ratio of the patient at baseline (e.g., before administration of the ASBTI or before modulating (e.g., increasing) the dose of the ASBTI), and further determining the 7αc4: sBA ratio after administration of the ASBTI at a first dose or modulating (e.g., increasing) the dose amount of the ASBTI to a second dose. If the 7αc4: sBA ratio is not increased by at least 1、1.25、1.5、1.75、2、2.5、3、4、5、6、7、8、9、10、15、20、30、40、50、75、100、150、200、300、500、750、1,000、2,000、3,000、4,000、5,000 or 10,000 times compared to baseline, then the dose of ASBTI is increased until the ratio is increased by at least about 1.25、1.5、1.75、2、2.5、3、4、5、6、7、8、9、10、15、20、30、40、50、75、100、150、200、300、500、750、1,000、2,000、3,000、4,000、5,000 or 10,000 times relative to baseline. In various embodiments, the dose of the ASBTI is increased or decreased to achieve and maintain a particular 7αc4: sBA ratio.

In various embodiments, the modulating comprises increasing the dose of ASBTI from a first dose to a second dose that is greater than the first dose, with the 7αc4: sBA ratio initially increasing from the baseline by at least 1、1.25、1.5、1.75、2、2.5、3、4、5、6、7、8、9、10、15、20、30、40、50、75、100、150、200、300、500、750、1,000、2,000、3,000、4,000、5,000 or 10,000 times and then starting to decrease or reduce to less than 1、1.25、1.5、1.75、2、2.5、3、4、5、6、7、8、9、10、15、20、30、40、50、75、100、150、200、300、500、750、1,000、2,000、3,000,4,000,5,000 or 10,000 times or more than the baseline. The dose is increased until the 7αc4: sBA ratio is increased at least 1、1.25、1.5、1.75、2、2.5、3、4、5、6、7、8、9、10、15、20、30、40、50、75、100、150、200、300、500、750、1,000、2,000、3,000、4,000、5,000 or 10,000 times compared to baseline.

In some embodiments, the modulating comprises administering a first dose of ASBTI to the patient. If the 7αc4: sBA ratio is not increased or increased by at least 1、1.25、1.5、1.75、2、2.5、3、4、5、6、7、8、9、10、15、20、30、40、50、75、100、150、200、300、500、750、1,000、2,000、3,000、4,000、5,000 or 10,000 times compared to baseline, then a second dose of ASBTI higher than the first dose is administered to the patient. The dose administered to the patient continues to be increased until the 7αc4: sBA ratio is increased by at least 1、1.25、1.5、1.75、2、2.5、3、4、5、6、7、8、9、10、15、20、30、40、50、75、100、150、200、300、500、750、1,000、2,000、3,000、4,000、5,000 or 10,000 times compared to baseline.

In various embodiments, the 7αc4: sBA ratio is measured about daily, every two weeks, weekly, every two months, monthly, every two months, every three months, every four months, every five months, every six months, or yearly, and the dose of ASBTI is modulated each time the ratio is measured, if necessary.

Pharmaceutical composition

In some embodiments, the ASBTI is administered in a pharmaceutical composition (composition or pharmaceutical composition) comprising ASBTI. Any of the compositions described herein may be formulated for ileal, rectal, and/or colonic delivery. In more particular embodiments, the composition is formulated for non-systemic or local delivery to the rectum and/or colon. It is understood that delivery to the colon, as used herein, includes delivery to the sigmoid colon (sigmoid colon), transverse colon (TRANSVERSE COLON), and/or ascending colon (ASCENDING COLON). In yet more particular embodiments, the composition is formulated for non-systemic or local delivery to the rectum and/or colon for rectal administration. In other particular embodiments, the compositions are formulated for non-systemic or local delivery to the rectum and/or colon for oral administration.

Provided herein in certain embodiments is a pharmaceutical composition comprising a therapeutically effective amount of any of the compounds described herein. In certain instances, the pharmaceutical composition comprises an ASBT inhibitor (e.g., any ASBTI described herein).

In certain embodiments, the pharmaceutical compositions are formulated in a conventional manner using one or more physiologically acceptable carriers (including, for example, excipients and auxiliaries) that facilitate processing of the active compounds into preparations which are suitable for pharmaceutical use. In certain embodiments, suitable formulations are according to the route of administration selected. An overview of the pharmaceutical compositions described herein can be found, for example, in ramington: pharmaceutical science and practice (THE SCIENCE AND PRACTICE of Pharmacy), nineteenth edition (Iston, pa.: mike publishing Co., 1995); huver, john E., lemmington's pharmaceutical science, mcAb, inc., iston, pa., 1975; liberman (Liberman, H.A.), lachman (L.), pharmaceutical dosage forms (Pharmaceutical Dosage Forms), baide company (MAREEL DECKER), new York (N.Y.), 1980; and pharmaceutical dosage forms and drug delivery systems (Pharmaceutical Dosage Forms and Drug DELIVERY SYSTEMS), seventeenth edition (LiPinscott Williams Wilkins publishing company (Lippincott Williams & Wilkins) 1999), all references to which are incorporated herein by reference in their entirety for all purposes.

As used herein, a pharmaceutical composition refers to a mixture of a compound described herein with other chemical components (e.g., carriers, stabilizers, diluents, dispersants, suspending agents, thickening agents, and/or excipients, etc.). In certain instances, the pharmaceutical composition facilitates administration of the compound to an individual or cell. In certain embodiments of practicing the methods or uses provided herein, a therapeutically effective amount of a compound described herein is administered in a pharmaceutical composition to an individual having a disease, disorder, or condition to be treated. In a particular embodiment, the individual is a human. As discussed herein, the compounds described herein are used alone or in combination with one or more additional therapeutic agents.

In certain embodiments, the pharmaceutical compositions described herein are administered to an individual in any manner, including one or more of a variety of routes of administration, such as oral (e.g., by way of non-limiting example), parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal.

In certain embodiments, the pharmaceutical compositions described herein comprise as an active ingredient one or more compounds described herein in free acid or free base form or in pharmaceutically acceptable salt form. In some embodiments, the compounds described herein are used as N-oxides or in crystalline or amorphous form (i.e., polymorphs). In some cases, the compounds described herein exist as tautomers. All tautomers are included within the scope of the compounds presented herein. In certain embodiments, the compounds described herein exist in unsolvated or solvated forms, wherein the solvated forms comprise any pharmaceutically acceptable solvents, such as, for example, water, ethanol, and the like. Solvated forms of the compounds presented herein are also considered to be described herein.

In some embodiments, a "carrier" includes pharmaceutically acceptable excipients and is selected based on compatibility with the compounds described herein (e.g., compounds of any of formulas I-VI, etc.) and release profile characteristics of the desired dosage form. Illustrative carrier materials include, for example, binders, suspending agents, disintegrants, fillers, surfactants, dissolving agents, stabilizers, lubricants, wetting agents, diluents, and the like. See, for example, ramington: pharmaceutical science and practice, nineteenth edition (Iston, pa.: mike publishing Co., 1995); pharmaceutical science of huphor, john, ramington, mike publishing company, islton, pennsylvania, 1975; liberman and Raschman, pharmaceutical dosage forms, baide Corp, new York, 1980; and pharmaceutical dosage forms and drug delivery systems, seventeenth edition (LiPinscott. Williams publication 1999), all references are incorporated herein in their entirety for all purposes.

Furthermore, in certain embodiments, the pharmaceutical compositions described herein are formulated into dosage forms. Thus, in some embodiments, provided herein is a dosage form comprising a compound described herein, suitable for administration to an individual. In certain embodiments, suitable dosage forms include, by way of non-limiting example, aqueous oral dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, solid oral dosage forms, aerosols, controlled release formulations, fast melt formulations, effervescent formulations, lyophilized formulations, lozenges, powders, pills, troches, capsules, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed real-time and controlled release formulations.

In some embodiments, provided herein is a composition comprising an enteroendocrine peptide secretion enhancing agent and optionally a pharmaceutically acceptable carrier for alleviating symptoms of cholestasis or cholestasis liver disease in an individual.

In certain embodiments, the composition comprises an enteroendocrine peptide secretion enhancing agent and an absorption inhibitor. In particular embodiments, the absorption inhibitor is an inhibitor that inhibits absorption of the particular enteroendocrine peptide secretion enhancer (or at least one thereof) to which it is combined. In some embodiments, the composition comprises an enteroendocrine peptide secretion enhancing agent, an absorption inhibitor, and a carrier (e.g., an orally suitable carrier or a rectally suitable carrier, depending on the desired mode of administration). In certain embodiments, the composition comprises an enteroendocrine peptide secretion enhancer, an absorption inhibitor, a carrier, and one or more of a cholesterol absorption inhibitor, an enteroendocrine peptide, a peptidase inhibitor, a diffusant, and a wetting agent.

In other embodiments, the compositions described herein are administered orally for non-systemic delivery of ASBTI to the rectum and/or colon, including the sigmoid colon, transverse colon, and/or ascending colon. In particular embodiments, the compositions formulated for oral administration are enteric coated (as illustrated by non-limiting examples) or formulated oral dosage forms, such as lozenges and/or capsules, and the like.

Absorption inhibitor

In certain embodiments, the compositions described herein formulated for systemic delivery of ASBTI further comprise an absorption inhibitor. As used herein, an absorption inhibitor includes an agent or group of agents that inhibit absorption of bile acids/bile salts.

Suitable bile acid absorption inhibitors (also described herein as absorption inhibitors) may include, by way of non-limiting example, anion exchange matrices, polyamines, quaternary amine-containing polymers, quaternary ammonium salts, polyallylamine polymers and copolymers, colesevelam hydrochloride, cholestaGel (chlorinated N, N-trimethyl-6- (2-propenyl-amino) -1-hexanium polymers with (chloromethyl) oxirane, 2-propen-1-amine and N-2-propen-1-decaneamine hydrochloride), cyclodextrins, chitosan derivatives, bile acid-binding carbohydrates, bile acid-binding lipids, bile acid-binding proteins and proteinaceous materials, and bile acid-binding antibodies and albumins. Suitable cyclodextrins include those that bind bile acids/bile salts, such as, by way of non-limiting example, beta-cyclodextrin and hydroxypropyl-beta-cyclodextrin. Suitable proteins include those that bind bile acids/bile salts, such as (by way of non-limiting example) bovine serum albumin, protein proteins, casein, alpha-acid glycoprotein, gelatin, soy protein, peanut protein, almond protein, and wheat plant protein, and the like.

In certain embodiments, the absorption inhibitor is pin cholic amine. In a particular embodiment, pin cholic acid is combined with cholic acid. Pin cholamine (an ion exchange resin) is a styrene polymer containing quaternary ammonium groups crosslinked with divinylbenzene. In other embodiments, the absorption inhibitor is colestipol (colestipol). In a particular embodiment, colestipol is combined with cholic acid. Colestipol, an ion exchange resin, is a copolymer of diethylenetriamine and 1-chloro-2, 3-epoxypropane.

In certain embodiments of the compositions and methods described herein, the ASBTI is linked to an absorption inhibitor, while in other embodiments, the ASBTI and absorption inhibitor are separate molecular entities.

Cholesterol absorption inhibitor

In certain embodiments, the compositions described herein optionally comprise at least one cholesterol absorption inhibitor. Suitable cholesterol absorption inhibitors include, by way of non-limiting example, ezetimibe (SCH 58235)/ezetimibe analog, ACT inhibitor, stigmastanol phosphorylcholine (STIGMASTANYL PHOSPHORYLCHOLINE), stigmastanol phosphorylcholine analog, beta-lactam cholesterol absorption inhibitor, sulfated polysaccharide, neomycin, phytostanol (sponins), phytosterols, phytostanol formulation FM-VP4, sitostanol (Sitostanol), beta-sitostanol, acyl-CoA: cholesterol-O-acyltransferase (ACAT) inhibitor, avastin (Avasiibe), indapsone (IMPLITAPIDE), steroid glycoside, and the like. Suitable ezetimibe analogs include, by way of non-limiting example, SCH 48461, SCH 58053, and the like. Suitable ACT inhibitors include, by way of non-limiting example, trimethoxy fatty acid anilines such as Cl-976, 3- [ decyl dimethylsilyl ] -N- [2- (4-methylphenyl) -1-phenylethyl ] -propionamide, toluamide (melinamide), and the like. Inhibitors of beta-lactam cholesterol absorption include, by way of non-limiting example, beta R-4S) -1, 4-bis- (4-methoxyphenyl) -3-beta-phenylpropyl) -2-azetidinone (azetidinone), and the like.

Peptidase inhibitors

In some embodiments, the compositions described herein optionally comprise at least one peptidase inhibitor. Such peptidase inhibitors include, but are not limited to, dipeptidyl peptidase-4 inhibitors (DPP-4), neutral endopeptidase inhibitors, and invertase inhibitors. Suitable dipeptidyl peptidase-4 inhibitors (DPP-4) include, by way of non-limiting example, vildagliptin (VILDAGLIPTI), 2.S) -1- {2- [ beta-hydroxy-1-adamantyl) amino ] acetyl } pyrrolidine-2-carbonitrile, sitagliptin (SITAGLIPTIN), beta R) -3-amino-1- [9- (trifluoromethyl) -1,4,7,8-tetraazabicyclo [4.3.0] non-6, 8-dien-4-yl ] -4- (2, 4, 5-trifluorophenyl) butan-1-one, sha Xilie statin (Saxagliptin) and (1S, 3S, 5S) -2- [ (2S) -2-amino-2-beta-hydroxy-1-adamantyl) acetyl ] -2-azabicyclo [3.1.0] hexane-3-carbonitrile. Such neutral endopeptidase inhibitors include, but are not limited to, canxatril (Candoxatrilat) and ecatrol (Ecadotril).

Diffusion/wetting agent

In certain embodiments, the compositions described herein optionally comprise a diffusing agent. In some embodiments, a diffusion agent is used to improve the diffusion of the composition in the colon and/or rectum. Suitable dispersing agents include, by way of non-limiting example, hydroxyethyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol, colloidal silicon dioxide, propylene glycol, cyclodextrin, microcrystalline cellulose, polyvinylpyrrolidone, polyoxyethylated glyceride, polycarbophil (polycarbophil), di-n-octyl ether, cetiol ^TM OE, fatty alcohol polyalkylene glycol ether, aethoxal ^TM B), 2-ethylhexyl palmitate, cegesoft ^TM C24), and isopropyl fatty acid esters.

In some embodiments, the compositions described herein optionally comprise a wetting agent. In some embodiments, a wetting agent is used to improve the wettability of the composition in the colon and rectum. Suitable wetting agents include, by way of non-limiting example, surfactants. In some embodiments, the surfactant is selected from polysorbate (e.g., 20 or 80), stearyl caproate, caprylic/capric fatty acid esters of saturated fatty alcohols having a chain length of C ₁₂-C₁₈, isostearyl diglycerol isostearic acid, sodium lauryl sulfate, isopropyl myristate, isopropyl palmitate, and isopropyl myristate/isopropyl stearate/isopropyl palmitate mixtures, as non-limiting examples.

Vitamins

In some embodiments, the methods provided herein further comprise administering one or more vitamins.

In some embodiments, the vitamin is vitamin A, B, B2, B3, B5, B6, B7, B9, B12, C, D, E, K, folic acid, pantothenic acid, nicotinic acid, riboflavin, thiamine, retinol, beta carotene, pyridoxine, ascorbic acid, cholecalciferol, cyanocobalamin, tocopherol, she Kun, menaquinone.

In some embodiments, the vitamin is a fat-soluble vitamin, such as vitamin A, D, E, K, retinol, beta-carotene, cholecalciferol, tocopherol, she Kun, and the like. In a preferred embodiment, the fat-soluble vitamin is Tocopheryl Polyethylene Glycol Succinate (TPGS).

Cholic acid sequestering agent/binder

In some embodiments, the labile cholic acid sequestering agent is an enzyme-dependent cholic acid sequestering agent. In certain embodiments, the enzyme is a bacterial enzyme. In some embodiments, the enzyme is a bacterial enzyme that is found in human colon or rectum at a high concentration relative to the concentration found in the small intestine. Examples of flora-activated systems include dosage forms comprising azo hydrogels of pectin, galactomannan, and/or an active agent and/or glycoside conjugates (e.g., conjugates of D-galactoside, beta-D-xylopyranoside, etc.). Examples of gastrointestinal flora enzymes include bacterial glycosidases, such as e.g. D-galactosidase, beta-D-glucosidase, alpha-L-arabinofuranosidase, beta-D-xylopyranosidase, etc.

In certain embodiments, the labile cholic acid sequestering agent is a time-dependent cholic acid sequestering agent. In some embodiments, the labile cholic acid sequestering agent releases cholic acid or is degraded after sequestering for 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 seconds. In some embodiments, the labile cholic acid sequestering agent releases cholic acid or is degraded after 15, 20, 25, 30, 35, 40, 45, 50, or 55 seconds of sequestering. In some embodiments, the labile cholic acid sequestering agent releases cholic acid or is degraded after sequestering for 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 minutes. In some embodiments, the labile cholic acid sequestering agent releases cholic acid or is degraded after sequestering for about 15, 20, 25, 30, 35, 45, 50, or 55 minutes. In some embodiments, the labile cholic acid sequestering agent releases or is degraded after sequestering for about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours. In some embodiments, the labile cholic acid sequestering agent releases cholic acid or is degraded after 1, 2, or 3 days of sequestering.

In some embodiments, the labile cholic acid sequestering agent has a low affinity for cholic acid. In certain embodiments, the labile cholic acid sequestering agent has a high affinity for primary cholic acid and a low affinity for secondary cholic acid.

In some embodiments, the labile cholic acid sequestering agent is a pH-dependent cholic acid sequestering agent. In certain embodiments, the pH-dependent bile acid sequestrant has a high affinity for bile acids at a pH of 6 or less and a low affinity for bile acids at a pH above 6. In certain embodiments, the pH-dependent bile acid sequestrant has a high affinity for bile acids at a pH of 6.5 or less and a low affinity for bile acids at a pH above 6.5. In certain embodiments, the pH-dependent bile acid sequestrant has a high affinity for bile acids at a pH of 7 or less and a low affinity for bile acids at a pH above 7. In certain embodiments, the pH-dependent bile acid sequestrant has a high affinity for bile acids at a pH of 7.1 or less and a low affinity for bile acids at a pH above 7.1. In certain embodiments, the pH-dependent bile acid sequestrant has a high affinity for bile acids at a pH of 7.2 or less and a low affinity for bile acids at a pH above 7.2. In certain embodiments, the pH-dependent bile acid sequestrant has a high affinity for bile acids at a pH of 7.3 or less and a low affinity for bile acids at a pH above 7.3. In certain embodiments, the pH-dependent bile acid sequestrant has a high affinity for bile acids at a pH of 7.4 or less and a low affinity for bile acids at a pH above 7.4. In certain embodiments, the pH-dependent bile acid sequestrant has a high affinity for bile acids at a pH of 7.5 or less and a low affinity for bile acids at a pH above 7.5. In certain embodiments, the pH-dependent bile acid sequestrant has a high affinity for bile acids at a pH of 7.6 or less and a low affinity for bile acids at a pH above 7.6. In certain embodiments, the pH-dependent bile acid sequestrant has a high affinity for bile acids at a pH of 7.7 or less and a low affinity for bile acids at a pH above 7.7. In certain embodiments, the pH-dependent bile acid sequestrant has a high affinity for bile acids at a pH of 7.8 or less and a low affinity for bile acids at a pH above 7.8. In some embodiments, the pH-dependent bile acid sequestrant degrades at a pH above 6. In some embodiments, the pH-dependent bile acid sequestrant degrades at a pH above 6.5. In some embodiments, the pH-dependent bile acid sequestrant degrades at a pH above 7. In some embodiments, the pH-dependent bile acid sequestrant degrades at a pH above 7.1. In some embodiments, the pH-dependent bile acid sequestrant degrades at a pH above 7.2. In some embodiments, the pH-dependent bile acid sequestrant degrades at a pH above 7.3. In some embodiments, the pH-dependent bile acid sequestrant degrades at a pH above 7.4. In some embodiments, the pH-dependent bile acid sequestrant degrades at a pH above 7.5. In some embodiments, the pH-dependent bile acid sequestrant degrades at a pH above 7.6. In some embodiments, the pH-dependent bile acid sequestrant degrades at a pH above 7.7. In some embodiments, the pH-dependent bile acid sequestrant degrades at a pH above 7.8. In some embodiments, the pH-dependent bile acid sequestrant degrades at a pH above 7.9.

In certain embodiments, the labile cholic acid sequestering agent is lignin or modified lignin. In some embodiments, the labile cholic acid sequestering agent is a polycationic polymer or copolymer. In certain embodiments, the labile cholic acid sequestering agent is a composition comprising one or more N-alkenyl-N-alkylamino groups; one or more N, N-trialkyl-N- (N' -alkenylamino) alkyl-ammonium nitrogen salts; one or more N, N-trialkyl-N-alkenyl-ammonium nitrogen salts groups; one or more alkenyl-amino groups; or a polymer or copolymer of a combination thereof. In some embodiments, the cholic acid binder is pin cholic acid amine, and various compositions comprising pin cholic acid amine, described, for example, in number 3,383,281; 3,308,020 th sheet; 3,769,399 th sheet; 3,846,541 th sheet; 3,974,272 th sheet; 4,172,120 th sheet; 4,252,790 th sheet; 4,340,585 th sheet; 4,814,354 th sheet; 4,874,744 th sheet; 4,895,723 th sheet; 5,695,749 th sheet; and U.S. patent 6,066,336, which are incorporated herein by reference in their entirety for all purposes. In some embodiments, the bile acid binder is choledopol (cholestipol) or kery willan (cholesevelam).

Routes of administration, dosage forms and dosage regimens

In some embodiments, the compositions described herein and the compositions administered in the methods described herein are formulated to inhibit bile acid reabsorption or to reduce serum or hepatobiliary acid content. In certain embodiments, the compositions described herein are formulated for rectal or oral administration. In some embodiments, such formulations are administered rectally or orally, respectively. In some embodiments, the compositions described herein are combined with a device for locally delivering the composition to the rectum and/or colon (S-colon, transverse colon, or ascending colon). In certain embodiments, for rectal administration, the compositions described herein are formulated as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas (retention enemas). In some embodiments, for oral administration, the compositions described herein are formulated for oral administration and intestinal delivery to the colon.

In certain embodiments, the compositions or methods described herein are non-systemic. In some embodiments, the compositions described herein deliver ASBTI to the remote ileum, colon, and/or rectum and are non-systemic (e.g., a substantial portion of the intestinal endocrine peptide secretion enhancing agent is not absorbed systemically). In some embodiments, the oral compositions described herein deliver ASBTI to the remote ileum, colon, and/or rectum and are non-systemic (e.g., a substantial portion of the intestinal endocrine peptide secretion enhancing agent is not absorbed systemically). In some embodiments, the rectal compositions described herein deliver ASBTI to the remote ileum, colon, and/or rectum and are non-systemic (e.g., a substantial portion of the enteroendocrine peptide secretion enhancing agent is not absorbed systemically). In certain embodiments, the non-systemic compositions described herein deliver less than 90% w/w of ASBTI systemically. In certain embodiments, the non-systemic compositions described herein deliver less than 80% w/w ASBTI systemically. In certain embodiments, the non-systemic compositions described herein deliver less than 70% w/w ASBTI systemically. In certain embodiments, the non-systemic compositions described herein deliver less than 60% w/w ASBT1 systemically. In certain embodiments, the non-systemic compositions described herein deliver less than 50% w/w ASBTI systemically. In certain embodiments, the non-systemic compositions described herein deliver less than 40% w/w ASBTI systemically. In certain embodiments, the non-systemic compositions described herein deliver less than 30% w/w ASBTI systemically. In certain embodiments, the non-systemic compositions described herein deliver less than 25% w/w ASBTI systemically. In certain embodiments, the non-systemic compositions described herein deliver less than 20% w/w ASBTI systemically. In certain embodiments, the non-systemic compositions described herein deliver less than 15% w/w ASBTI systemically. In certain embodiments, the non-systemic compositions described herein deliver less than 10% w/w of ASBTI systemically. In certain embodiments, the non-systemic compositions described herein deliver less than 5% w/w ASBTI systemically. In some embodiments, systemic absorption is measured in any suitable manner, including total circulation, amount cleared after administration, and the like.

In certain embodiments, the compositions and/or formulations described herein are administered at least once daily. In certain embodiments, the ASBTI-containing formulation is administered at least twice daily, while in other embodiments, the ASBTI-containing formulation is administered at least three times daily. In certain embodiments, the ASBTI-containing formulation is administered up to five times per day. It will be appreciated that in certain embodiments, the dosage regimen of the compositions containing ASBTIs described herein is determined by considering various factors such as the age, sex, and diet of the patient.

The concentration of ASBTI administered in the formulations described herein is in the range of about 1mM to about 1M. In certain embodiments, the concentration of ASBTI administered in the formulations described herein is in the range of about 1mM to about 750 mM. In certain embodiments, the concentration of ASBTI administered in the formulations described herein is in the range of about 1mM to about 500 mM. In certain embodiments, the concentration of ASBTI administered in the formulations described herein is in the range of about 5mM to about 500 mM. In certain embodiments, the concentration of ASBTI administered in the formulations described herein is in the range of about 10mM to about 500 mM. In certain embodiments, the concentration of ASBTI administered in the formulations described herein is in the range of about 25mM to about 500 mM. In certain embodiments, the concentration of ASBTI administered in the formulations described herein is in the range of about 50mM to about 500 mM. In certain embodiments, the concentration of ASBTI administered in the formulations described herein is in the range of about 100mM to about 500 mM. In certain embodiments, the concentration of ASBTI administered in the formulations described herein is in the range of about 200mM to about 500 mM.

In certain embodiments, by targeting the remote gastrointestinal tract (e.g., the remote ileum, colon, and/or rectum), the compositions and methods described herein provide efficacy (e.g., in reducing microbial growth and/or alleviating symptoms of cholestasis or cholestasis liver disease) at reduced doses of an enteroendocrine peptide secretion enhancing agent (e.g., as compared to oral doses that do not target the remote gastrointestinal tract).

Oral administration for colonic delivery

In certain aspects, the composition or formulation containing one or more compounds described herein is orally administered for topical delivery of ASBTI or a compound described herein to the colon and/or rectum. Unit dosage forms of such compositions include pills, lozenges or capsules formulated for enteral delivery to the colon. In certain embodiments, such pills, lozenges or capsules contain a composition as described herein embedded or imbedded in a microsphere. In some embodiments, the microspheres include, by way of non-limiting example, chitosan microkernel HPMC capsules and Cellulose Acetate Butyrate (CAB) microspheres. In certain embodiments, the oral dosage form is prepared using conventional methods known to those skilled in the art of pharmaceutical formulation. For example, in certain embodiments, standard lozenge processing procedures and equipment are used to manufacture the lozenge. An illustrative method for forming lozenges is by directly compressing a powdered, crystalline or granular composition containing the active agent alone or in combination with one or more carriers, additives, and the like. In alternative embodiments, a wet granulation or dry granulation process is used to prepare the lozenge. In some embodiments, the pastilles are molded (rather than compressed) starting with a moist or other easy to process (tractable) material.

In certain embodiments, lozenges prepared for oral administration contain various excipients including, by way of non-limiting example, binders, diluents, lubricants, disintegrants, fillers, stabilizers, surfactants, preservatives, colorants, flavoring agents, and the like. In some embodiments, a binder is used to impart cohesiveness (cohesive qualities) to the lozenge, ensuring that the lozenge remains intact after compression. Suitable binder materials include, by way of non-limiting example, starches (including corn starch and pregelatinized starch), gelatin, sugars (including sucrose, glucose, dextrose, and lactose), polyethylene glycols, propylene glycol, waxes, and natural and synthetic gums such as sodium alginate acacia, polyvinylpyrrolidone, cellulosic polymers (including hydroxypropyl cellulose, hydroxypropyl methylcellulose, ethylcellulose, hydroxyethylcellulose, and the like), veegum, and combinations thereof. In certain embodiments, diluents are used to increase the overall lozenge to provide a lozenge of practical size. Suitable diluents include, by way of non-limiting example, dicalcium phosphate, calcium sulfate, lactose, cellulose, kaolin, mannitol, sodium chloride, dry starches, powdered sugar (powdered sugar) and combinations thereof. In certain embodiments, lubricants are used to facilitate lozenge manufacture; examples of suitable lubricants include, by way of non-limiting example, vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and cocoa butter, glycerol, magnesium stearate, calcium stearate, stearic acid, combinations thereof, and the like. In some embodiments, disintegrants are used to facilitate the disintegration of the tablet and include, by way of non-limiting example, starches, clays, celluloses, algins, gums, cross-linked polymers, and combinations thereof. Fillers include, by way of non-limiting example, materials such as silica, titania, alumina, talc, kaolin, powdered and non-passed cellulose, and the like, as well as soluble materials such as mannitol, urea, sucrose, lactose, dextrose, sodium chloride, sorbitol, and the like. In certain embodiments, stabilizers are used to inhibit or delay drug decomposition reactions, including (by way of non-limiting example) oxidation reactions. In certain embodiments, the surfactant is an anionic, cationic, amphoteric, or nonionic surfactant.

In some embodiments, the ASBTI or other compounds described herein are administered orally in combination with a carrier suitable for delivery to the remote gastrointestinal tract (e.g., the remote ileum, colon, and/or rectum).

In certain embodiments, the compositions described herein comprise ASBTI, or other compounds described herein, in combination with a matrix that allows for controlled release of the active agent in the ileum and/or in the remote portion of the colon, such as a matrix comprising hydroxypropyl methylcellulose (hypermellose). In some embodiments, the composition comprises a polymer that is pH sensitive (e.g., MMX ^TM matrix, from kemo pharmaceutical company (Cosmo Pharmaceuticals)) and allows for controlled release of the active agent in the remote portion of the ileum. Examples of such pH-sensitive polymers suitable for controlled release include, but are not limited to, polyacrylic polymers (e.g., anionic polymers of methacrylic acid and/or methacrylate esters, such asA polymer). In some embodiments, a composition suitable for controlled release in the remote ileum comprises a microparticle active agent (e.g., a micronized active agent). In some embodiments, the non-enzymatically degraded poly (dl-lactic-co-glycolide) (PLGA) core is suitable for delivering an enteroendocrine peptide secretion enhancing agent to the remote ileum. In some embodiments, dosage forms comprising an intestinal endocrine peptide secretion enhancing agent are enteric coated polymers (e.g./>S-100, cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, anionic polymers of methacrylic acid, methacrylate esters, etc.) are coated for site-specific delivery to the remote ileum and/or colon. In some embodiments, the bacterial activation system is adapted for targeted delivery to a remote portion of the ileum. Examples of flora-activated systems include dosage forms comprising azo hydrogels of pectin, galactomannan, and/or an active agent and/or glycoside conjugates (e.g., conjugates of D-galactoside, beta-D-xylopyranoside, etc.). Examples of gastrointestinal flora enzymes include bacterial glycosidases, such as e.g. D-galactosidase, beta-D-glucosidase, alpha-L-arabinofuranosidase, beta-D-xylopyranosidase, etc.

The pharmaceutical compositions described herein optionally comprise additional therapeutic compounds described herein and one or more pharmaceutically acceptable additives, such as compatible carriers, binders, fillers, suspending agents, flavoring agents, sweeteners, disintegrants, dispersants, surfactants, lubricants, colorants, diluents, dissolving agents, humectants, plasticizers, stabilizers, penetration enhancers, wetting agents, antifoaming agents, antioxidants, preservatives, or one or more combinations thereof, and the like. In some embodiments, a film coating is provided around the formulation of the compound of formula I using standard coating procedures, such as those described in the pharmaceutical sciences of ramington, 20 th edition (2000), and the like. In one embodiment, the compounds described herein are in the form of particles and some or all of the particles of the compounds are coated. In certain embodiments, some or all of the particles of the compounds described herein are microencapsulated. In some embodiments, the particles of the compounds described herein are not microencapsulated and are not coated.

In other embodiments, a lozenge or capsule comprising an ASBTI or other compound described herein is coated with a film for delivery to a target site within the gastrointestinal tract. Examples of enteric film coatings include, but are not limited to, hydroxypropyl methylcellulose, polyvinylpyrrolidone, hydroxypropyl cellulose, polyethylene glycol 3350, 4500, 8000, methylcellulose, pseudoethylcellulose (pseudoethylcellulose), pullulan, and the like.

Child dose formulations and compositions

Provided herein in certain embodiments is a child dose formulation or composition comprising a therapeutically effective amount of any of the compounds described herein. In certain instances, the pharmaceutical composition comprises an ASBT inhibitor (e.g., any ASBTI described herein).

In certain embodiments, suitable dosage forms for a child dose formulation or composition include, by way of non-limiting example, aqueous or non-aqueous oral dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, solutions, controlled release formulations, fast melt formulations, effervescent formulations, lyophilized formulations, chewable lozenges, gummies (gummy candy), orally disintegrating lozenges, powders for reconstitution in suspension or solution, dispersed oral powders or granules, lozenges, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed real-time and controlled release formulations. In some embodiments, provided herein is a pharmaceutical composition, wherein the pediatric dosage form is selected from the group consisting of a solution, syrup, suspension, elixir, powder for reconstitution in suspension or solution, dispersible/effervescent tablet, chewable tablet, chewing gum, lollipop (lollipop), frozen soda (freezer pops), tablet, oral fine bar, orally disintegrating tablet, orally disintegrating bar, sachet, and dispersible oral powder or granule.

In another aspect, provided herein is a pharmaceutical composition, wherein at least one excipient is a flavoring or sweetening agent. In some embodiments, provided herein is a coating. In some embodiments, provided herein is a taste masking technique selected from coating drug particles with taste neutral polymers by spray drying, wet granulation, fluidized bed, and microencapsulation; coating with a molten wax of a mixture of molten wax and other pharmaceutical adjuvants; embedding the drug particles by compounding, flocculating or coagulating the aqueous polymer dispersion; adsorption of drug particles on the resin and inorganic support; and solid dispersions wherein the drug and one or more taste neutral compounds are melted and cooled or co-precipitated by solvent evaporation. In some embodiments, provided herein is a delayed or sustained release formulation comprising drug particles (particles/granules) contained in a rate controlling polymer or matrix.

Suitable sweeteners include sucrose, glucose, fructose, or intense sweeteners, i.e., agents that have a high sweetening power (e.g., at least 10 times sweeter than sucrose) when compared to sucrose. Suitable intense sweeteners include aspartame (aspartame), saccharin, sodium or potassium or calcium saccharin, potassium acesulfame, sucralose, alitame (alitame), xylitol, cyclamate (cyclamate), nivalene (neomate), neohesperidin dihydrochalcone (neohesperidine dihydrochalcone) or a mixture thereof, thaumatin (thaumatin), palatinit (palatinit), stevioside (stevioside), rebaudioside (rebaudioside),After reconstitution, the total concentration of sweetener may range from effectively zero to about 300mg/ml based on the liquid composition.

To increase the palatability of the liquid composition upon reconstitution with an aqueous medium, one or more taste masking agents may be added to the composition in order to mask the taste of the ASBT inhibitor. The taste masking agent may be a sweetener, a flavoring agent, or a combination thereof. The taste masking agent typically comprises up to about 0.1% or 5% by weight of the total pharmaceutical composition. In a preferred embodiment of the invention, the composition contains a sweetener and a flavoring agent.

Flavoring agents herein are substances that enhance the taste or aroma of the composition. Suitable natural or synthetic flavouring agents may be selected from standard reference books such as Fei Na Roly flavour ingredient handbook (Fenaroli's Handbook of Flavor Ingredients), 3 rd edition (1995). Non-limiting examples of flavoring and/or sweetening agents suitable for use in the formulations described herein include, for example, acacia syrup (acacia syrup), potassium acetylsulfamate (acesulfame K), alitame, fennel (anise), apple, aspartame, banana, bavarian cream (Bavarian stream), berry fruit, blackcurrant, butterscotch, calcium citrate, camphor, caramel, cherry cream, chocolate, cinnamon, bubble gum, citrus liqueur, citrus cream, marshmallow, cocoa, cola, cold cherry, cold citrus, sacalia, sirame (cylamate), dextrose, eucalyptus (eugenol, fructose, fruit wine, ginger, glycyrrhetate, licorice (kenaf) syrup, grape, grapefruit, honey, isomalt (isomart), lemon, lyme (lime), lemon cream, monoammonium glycyrrhizinate)Maltol, mannitol, maple sugar, marshmallow, menthol, peppermint butter, mixed raspberry fruits, neohesperidin dihydrochalcone (neohesperidine DC), and sweet (neotame), orange, pear, peach, peppermint (peppermint), peppermint cream,Powder, raspberry, sha Shigen, rum, saccharin, safrole (safrole), sorbitol, spearmint butter, strawberry butter, stevia, sucralose (sucralfate), sucrose, sodium saccharin, aspartame, potassium acesulfame, mannitol, talin (talin), xylitol, sucralose, sorbitol, swiss cream (SWISS CREAM), tagatose (tagatose), tangerine, thaumatin (thaumatin), assorted fruits (tutti frutti), vanilla, walnut, watermelon, wild cherry, wintergreen, xylitol, or any combination of such flavoring ingredients, such as fennel-menthol, cherry-fennel, cinnamon-orange, cherry-cinnamon, chocolate-mint, honey-lemon, lemon-lime, lemon-peppermint, menthol-euonymus, orange-cream, vanilla-mint, and mixtures thereof. Flavoring agents may be used singly or in combination of two or more. In some embodiments, the aqueous liquid dispersion comprises a sweetener or flavoring agent at a concentration in the range of about 0.001% to about 5.0% by volume of the aqueous dispersion. In one embodiment, the aqueous liquid dispersion comprises a sweetener or flavoring agent at a concentration in the range of about 0.001% to about 1.0% by volume of the aqueous dispersion. In another embodiment, the aqueous liquid dispersion comprises a sweetener or flavoring agent at a concentration in the range of about 0.005% to about 0.5% by volume of the aqueous dispersion. In yet another embodiment, the aqueous liquid dispersion comprises a sweetener or flavoring agent at a concentration in the range of about 0.01% to about 1.0% by volume of the aqueous dispersion. In yet another embodiment, the aqueous liquid dispersion comprises a sweetener or flavoring agent at a concentration in the range of about 0.01% to about 0.5% by volume of the aqueous dispersion.

In certain embodiments, the pediatric pharmaceutical compositions described herein comprise as an active ingredient one or more compounds described herein in free acid or free base form or in pharmaceutically acceptable salt form. In some embodiments, the compounds described herein are used as N-oxides or in crystalline or amorphous form (i.e., polymorphs). In some cases, the compounds described herein exist as tautomers. All tautomers are included within the scope of the compounds presented herein. In certain embodiments, the compounds described herein exist in unsolvated or solvated forms, wherein the solvated forms comprise any pharmaceutically acceptable solvents, such as, for example, water, ethanol, and the like. Solvated forms of the compounds presented herein are also considered as described herein.

In some embodiments, a "carrier" for a pediatric pharmaceutical composition includes a pharmaceutically acceptable excipient and is selected based on compatibility with the compounds described herein (e.g., compounds of any of formulas I-VI, etc.) and release profile characteristics of the desired dosage form. Illustrative carrier materials include, for example, binders, suspending agents, disintegrants, fillers, surfactants, dissolving agents, stabilizers, lubricants, wetting agents, diluents, and the like. See, e.g., the science and practice of the pharmacy of Lemmington, nineteenth edition (Iston, pa.: mike publishing Co., 1995); pharmaceutical science of huphor, john, ramington, mike publishing company, islton, pennsylvania, 1975; liberman and Raschman, pharmaceutical dosage forms, baide company (MARCEL DECKER), new York, 1980; and pharmaceutical dosage forms and drug delivery systems, seventh edition (LiPinscott. Williams Wills publishing company 1999), all references to which are incorporated herein by reference in their entirety for all purposes.

Furthermore, in certain embodiments, the pediatric pharmaceutical compositions described herein are formulated into dosage forms. Thus, in some embodiments, provided herein is a dosage form comprising a compound described herein, suitable for administration to an individual. In certain embodiments, suitable dosage forms include, by way of non-limiting example, aqueous oral dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, solid oral dosage forms, aerosols, controlled release formulations, fast melt formulations, effervescent formulations, lyophilized formulations, lozenges, powders, pills, troches, capsules, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed real-time and controlled release formulations.

In certain aspects, a pediatric composition or formulation containing one or more compounds described herein is orally administered for topical delivery of ASBTI or a compound described herein to the colon and/or rectum. Unit dosage forms of such compositions include pills, lozenges or capsules formulated for enteral delivery to the colon.

In certain embodiments, the child compositions described herein comprise ASBTI or other compounds described herein in combination with a matrix that allows for controlled release of an active agent in the ileum and/or remote portions of the colon (e.g., a matrix comprising hydroxypropyl methylcellulose). In some embodiments, the composition comprises a polymer that is pH sensitive (e.g., MMX ^TM matrix, from kemo pharmaceutical company) and allows for controlled release of the active agent in the remote portion of the ileum. Examples of such pH-sensitive polymers suitable for controlled release include, but are not limited to, polyacrylic polymers (e.g., anionic polymers of methacrylic acid and/or methacrylate esters, such asA polymer). In some embodiments, a composition suitable for controlled release in the remote ileum comprises a microparticle active agent (e.g., a micronized active agent). In some embodiments, the non-enzymatically degraded poly (dl-lactic-co-glycolide) (PLGA) core is suitable for delivering an enteroendocrine peptide secretion enhancing agent to the remote ileum. In some embodiments, dosage forms comprising an enteroendocrine peptide secretion enhancing agent are enteric coated polymers (e.g./>S-100, cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, anionic polymers of methacrylic acid, methacrylate esters, etc.) are coated for site-specific delivery to the remote ileum and/or colon. In some embodiments, the bacterial activation system is adapted for targeted delivery to a remote portion of the ileum. Examples of flora-activated systems include dosage forms comprising azo hydrogels of pectin, galactomannan, and/or an active agent and/or glycoside conjugates (e.g., conjugates of D-galactoside, beta-D-xylopyranoside, etc.). Examples of gastrointestinal flora enzymes include bacterial glycosidases, such as e.g. D-galactosidase, beta-D-glucosidase, alpha-L-arabinofuranosidase, beta-D-xylopyranosidase, etc.

The pediatric pharmaceutical compositions described herein optionally comprise additional therapeutic compounds described herein and one or more pharmaceutically acceptable additives, such as compatible carriers, binders, fillers, suspending agents, flavoring agents, sweeteners, disintegrants, dispersants, surfactants, lubricants, colorants, diluents, dissolving agents, humectants (moistening agent), plasticizers, stabilizers, penetration enhancers, wetting agents, defoamers, antioxidants, preservatives, or one or more combinations thereof, and the like. In some aspects, a film coating is provided around the formulation of the compound of formula I using standard coating procedures, such as those described in the pharmaceutical sciences of ramington, 20 th edition (2000), and the like. In one embodiment, the compounds described herein are in the form of particles and some or all of the particles of the compounds are coated. In certain embodiments, some or all of the particles of the compounds described herein are microencapsulated. In some embodiments, the particles of the compounds described herein are not microencapsulated and are not coated.

Liquid dosage form

The pharmaceutical liquid dosage forms of the invention may be prepared according to techniques well known in the pharmaceutical arts.

A solution refers to a liquid pharmaceutical formulation in which the active ingredient is dissolved in a liquid. Pharmaceutical solutions of the invention include syrups and elixirs. Suspensions refer to liquid pharmaceutical formulations in which the active ingredient is in the form of a precipitate contained in a liquid.

In liquid dosage forms, it is desirable to have a particular pH and/or to maintain within a particular pH range. To control the pH, a suitable buffer system may be used. Furthermore, the buffer system should have sufficient capacity to maintain the desired pH range. Examples of buffer systems suitable for use in the present invention include, but are not limited to, citrate buffers, phosphate buffers, or any other suitable buffer known in the art. Preferably, the buffer system comprises sodium citrate, potassium citrate, sodium bicarbonate, potassium bicarbonate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, and the like. The concentration of the buffer system in the final suspension will vary depending on factors such as the strength of the buffer system and the desired pH/pH range of the liquid dosage form. In one embodiment, the concentration is in the range of 0.005 to 0.5w/v% in the final liquid dosage form.

Pharmaceutical compositions comprising the liquid dosage forms of the present invention may also contain suspending/stabilizing agents to prevent sedimentation of the active material. Over time, sedimentation can cause the active agent to agglomerate to the inner walls of the product package, leading to redispersion and difficulty in accurate dispensing. Suitable stabilizers include, but are not limited to, polysaccharide stabilizers such as xanthan gum, guar gum and tragacanth gum, and the cellulose derivatives HPMC (hydroxypropyl methylcellulose), methylcellulose and Avicel RC-591 (microcrystalline cellulose/sodium carboxymethylcellulose), and the like. In another embodiment, polyvinylpyrrolidone (PVP) may also be used as a stabilizer.

In addition to the aforementioned components, the ASBTI oral suspension form may optionally contain other excipients commonly found in pharmaceutical compositions, such as alternative solvents, taste masking agents, antioxidants, fillers, acidulants, enzyme inhibitors, and other components as described in the pharmaceutical excipient handbook (Handbook of Pharmaceutical Excipients), rowe et al, 4 th edition, pharmaceutical press (Pharmaceutical Press) (2003), and the like, which are incorporated herein by reference in their entirety for all purposes.

The addition of alternative solvents may help to increase the solubility of the active ingredient in the liquid dosage form and thus increase absorption and bioavailability in the individual. Preferably, the alternative solvent comprises methanol, ethanol, propylene glycol or the like.

In another aspect, the present invention provides a process for preparing a liquid dosage form. The process includes the step of bringing ASBTI or a pharmaceutically acceptable salt thereof and components (including glycerin or syrup or mixtures thereof, preservatives, buffer systems, suspension/stabilizer, etc.) into a mixture in a liquid medium. Generally, the liquid dosage forms are prepared by uniformly and intimately mixing such various components in a liquid medium. For example, the components (e.g., glycerin or syrup or mixtures thereof, preservatives, buffer systems, and suspending/stabilizing agents, etc.) may be dissolved in water to form an aqueous solution, and the active ingredient may then be dispersed in the aqueous solution to form a suspension.

In some embodiments, the liquid dosage forms provided herein may be in a volume of between about 0.1ml to about 50 ml. In some embodiments, the liquid dosage forms provided herein may be in a volume of between about 0.2ml to about 40 ml. In some embodiments, the liquid dosage forms provided herein may be in a volume of between about 0.5ml to about 30 ml. In some embodiments, the liquid dosage forms provided herein may be in a volume of between about 1ml to about 20 ml. In some embodiments, the liquid dosage forms provided herein may be in a volume of between about 0.1ml to about 20 ml. In some embodiments, the liquid dosage forms provided herein may be in a volume of between about 0.1ml to about 20 ml. In some embodiments, the ASBTI may be in an amount ranging from about 0.001% to about 90% of the total volume. In some embodiments, the ASBTI may be in an amount ranging from about 0.01% to about 80% of the total volume. In some embodiments, the ASBTI may be in an amount ranging from about 0.1% to about 70% of the total volume. In some embodiments, the ASBTI may be in an amount ranging from about 1% to about 60% of the total volume. In some embodiments, the ASBTI may be in an amount ranging from about 1% to about 50% of the total volume. In some embodiments, the ASBTI may be in an amount ranging from about 1% to about 40% of the total volume. In some embodiments, the ASBTI may be in an amount ranging from about 1% to about 30% of the total volume. In some embodiments, the ASBTI may be in an amount ranging from about 1% to about 20% of the total volume. In some embodiments, the ASBTI may be in an amount ranging from about 1% to about 10% of the total volume. In some embodiments, the ASBTI may be in an amount ranging from about 5% to about 70% of the total volume. In some embodiments, the ASBTI may be in an amount ranging from about 5% to about 60% of the total volume. In some embodiments, the ASBTI may be in an amount ranging from about 5% to about 50% of the total volume. In some embodiments, the ASBTI may be in an amount ranging from about 5% to about 40% of the total volume. In some embodiments, the ASBTI may be in an amount ranging from about 5% to about 30% of the total volume. In some embodiments, the ASBTI may be in an amount ranging from about 5% to about 20% of the total volume. In some embodiments, the ASBTI may be in an amount ranging from about 5% to about 10% of the total volume. In some embodiments, the ASBTI may be in an amount ranging from about 10% to about 50% of the total volume. In some embodiments, the ASBTI may be in an amount ranging from about 10% to about 40% of the total volume. In some embodiments, the ASBTI may be in an amount ranging from about 10% to about 30% of the total volume. In some embodiments, the ASBTI may be in an amount ranging from about 10% to about 20% of the total volume. In one embodiment, the resulting liquid dosage form may have a liquid volume of 0.ml to 30ml, preferably 0.1ml to 20ml, and the active ingredient may be in the range of about 0.001mg/ml to about 16mg/ml, or about 0.025mg/ml to about 8mg/ml, or about 0.1mg/ml to about 4mg/ml, or about 0.25mg/ml, or about 0.5mg/ml, or about 1mg/ml, or about 2mg/ml, or about 4mg/ml, or about 5mg/ml, or about 8mg/ml, or about 9mg/ml, or about 10mg/ml, Or an amount in the range of about 12mg/ml, or about 14mg/ml, or about 16 mg/ml.

Cholic acid chelating agent

In certain embodiments, the oral formulation used in any of the methods described herein is, for example, a combination of ASBTI and an labile cholic acid sequestering agent. The labile cholic acid sequestering agent is a cholic acid sequestering agent having a labile affinity for cholic acid. In certain embodiments, the bile acid sequestrants described herein are agents that sequester (e.g., absorb or add) bile acids and/or salts thereof.

In particular embodiments, the labile cholic acid sequestering agent is an agent that sequesters (e.g., absorbs or adds) cholic acid and/or salts thereof, and releases at least a portion of the absorbed or added cholic acid and/or salts thereof in the remote gastrointestinal tract (e.g., colon, ascending colon (ASCENDING COLON), sigmoid colon (sigmoid colon), remote colon, rectum, or any combination thereof). In certain embodiments, the labile cholic acid sequestering agent is an enzyme-dependent cholic acid sequestering agent. In a particular embodiment, the enzyme is a bacterial enzyme. In some embodiments, the enzyme is a bacterial enzyme that is found in human colon or rectum at a high concentration relative to the concentration found in the small intestine. Examples of flora-activated systems include dosage forms comprising azo hydrogels of pectin, galactomannan, and/or an active agent and/or glycoside conjugates (e.g., conjugates of D-galactoside, beta-D-xylopyranoside, etc.). Examples of gastrointestinal flora enzymes include bacterial glycosidases, such as e.g. D-galactosidase, beta-D-glucosidase, alpha-L-arabinofuranosidase, beta-D-xylopyranosidase, etc. In some embodiments, the labile cholic acid sequestering agent is a time-dependent cholic acid sequestering agent (i.e., the cholic acid sequesters cholic acid and/or a salt thereof and releases at least a portion of the cholic acid and/or a salt thereof after a period of time). In some embodiments, the time-dependent bile acid sequestrant is an agent that degrades over time in an aqueous environment. In certain embodiments, the labile cholic acid sequestering agents described herein are cholic acid sequestering agents having low affinity for cholic acid and/or salts thereof, thereby allowing the cholic acid sequestering agents to continue sequestering and releasing cholic acid and/or salts thereof in environments where the cholic acid/salts and/or salts thereof are present at a high concentration and in environments where the cholic acid/salts and/or salts thereof are present with less relative difficulty. In some embodiments, the labile cholic acid sequestering agent has a high affinity for primary cholic acid and a low affinity for secondary cholic acid, allowing the cholic acid sequestering agent to sequester primary cholic acid or a salt thereof and release secondary cholic acid or a salt thereof upon subsequent conversion (e.g., metabolism) of the primary cholic acid or a salt thereof to the secondary cholic acid or a salt thereof. In some embodiments, the labile cholic acid sequestering agent is a pH-dependent cholic acid sequestering agent. In some embodiments, the pH-dependent bile acid sequestrant has a high affinity for bile acids at a pH of 6 or less and a low affinity for bile acids at a pH above 6. In certain embodiments, the pH-dependent bile acid sequestrant degrades at a pH above 6.

In some embodiments, the labile cholic acid sequestering agents described herein include any compound, such as a large structured compound, that sequesters cholic acid/salt and/or salts thereof via any suitable mechanism. For example, in certain embodiments, the bile acid sequestrant sequesters bile acids/salts and/or salts thereof through ionic interactions, polar interactions, static interactions, hydrophobic interactions, lipophilic interactions, hydrophilic interactions, steric interactions, and the like. In certain embodiments, the large structured compound sequesters cholic acid/salt and/or a sequestering agent by trapping the cholic acid/salt and/or salt thereof in the pocket of the large structured compound and optionally other interactions (e.g., those described herein above, etc.). In some embodiments, bile acid sequestrants (e.g., labile bile acid sequestrants) include (as illustrated by non-limiting examples) lignin, modified lignin, polymers, polycationic polymers and copolymers, polymers and/or copolymers comprising N-alkenyl-N-alkylamino; one or more N, N-trialkyl-N- (N' -alkenylamino) alkyl-ammonium nitrogen salt (azanium) groups; one or more N, N-trialkyl-N-alkenyl-ammonium nitrogen salts groups; one or more alkenyl-amino groups; or any one or more of a combination thereof or any combination thereof.

Covalent bonding of drugs to carriers

In some embodiments, strategies for colon targeted delivery include (illustrated by way of non-limiting example) covalently linking ASBTI or other compounds described herein to a carrier, coating the dosage form with a pH-sensitive polymer for delivery upon reaching the pH environment of the colon, using a redox-sensitive polymer, using a time-release formulation, using a coating specifically degraded by colonic bacteria, using a bioadhesive system, and using an osmotic controlled drug delivery system.

In certain embodiments of such oral administration of a composition comprising ASBTI or other compounds described herein, covalent linkage to the carrier is involved, wherein upon oral administration the linked moiety remains intact in the stomach and small intestine. After entering the colon, the covalent bonds are broken by pH changes, enzymes and/or degradation by intestinal flora. In certain embodiments, covalent linkages between ASBTI and carrier include (by way of non-limiting example) azo linkages, glycosidic linkages, glucuronide linkages, cyclodextrin linkages, polydextrose linkages, and amino acid linkages (highly hydrophilic and long chain length of carrier amino acids).

Using a polymer: pH sensitive polymer coating

In some embodiments, the oral dosage forms described herein are coated with an enteric coating to facilitate delivery of ASBTI or other compounds described herein to the colon and/or rectum. In certain embodiments, the enteric coating is one that remains intact in the low pH environment of the stomach, but readily dissolves when the most preferred dissolution pH of the particular coating is reached, depending on the chemical composition of the enteric coating. The thickness of the coating will depend on the solubility characteristics of the coating material. In certain embodiments, the coating thickness used in such formulations described herein is in the range of about 25 μm to about 200 μm.

In certain embodiments, the compositions or formulations described herein are packaged such that the ASBTI of the compositions or formulations, or other compounds described herein, are delivered to the colon and/or rectum without absorption at the upper portion of the intestine. In one particular embodiment, specific delivery to the colon and/or rectum is achieved by coating the dosage form with a polymer that only degrades in the pH environment of the colon. In an alternative embodiment, the composition is coated with an enteric coating that dissolves at the pH of the intestine and an outer matrix that erodes slowly in the intestine. In some such embodiments, the matrix slowly erodes until only the core composition comprising the enteroendocrine peptide secretion enhancing agent (and in some embodiments, the absorption inhibitor of the agent) remains and the core is delivered to the colon and/or rectum.

In certain embodiments, the pH dependent system utilizes a gradual increase in pH along the human gastrointestinal tract (GIT) from the stomach (pH 1 to 2, which increases to 4 during digestion), the small intestine (pH 6 to 7) at the site of digestion and which increases to 7 to 8 in the remote ileum. In certain embodiments, the dosage form for oral administration of the compositions described herein is coated with a pH-sensitive polymer to provide delayed release and to prevent the enteroendocrine peptide secretion enhancing agent from gastric juice. In certain embodiments, such polymers are capable of tolerating lower pH values of the stomach and proximal portions of the small intestine but disintegrate at neutral or slightly alkaline pH of the terminal ileum and/or ileocecum junction. Thus, in certain embodiments, provided herein is an oral dosage form comprising a coating comprising a pH-sensitive polymer. In some embodiments, the polymer for colon and/or rectal targeting includes (by way of non-limiting example) methacrylic acid copolymer, methacrylic acid and methyl methacrylate copolymer, eudragit L100, eudragit S100, eudragit L-30D, eudragit FS-30D, eudragit L100-55, polyethylene acetate phthalate, hydroxypropyl ethyl cellulose phthalate, hydroxypropyl methyl cellulose phthalate 50, hydroxypropyl methyl cellulose phthalate 55, cellulose acetate trimellitate, cellulose acetate phthalate, and combinations thereof.

In certain embodiments, oral dosage forms suitable for delivery to the colon and/or rectum include coatings with biodegradable and/or bacterially degradable polymers that are degraded by flora (bacteria) in the colon. In such biodegradable systems, suitable polymers include, by way of non-limiting example, azo polymers, azo-containing linear segmented polyurethanes, polygalactomannans, pectins, glutaraldehyde-crosslinked polyglucans, polysaccharides, amylose, guar gum, pectins, chitosan, inulin, cyclodextrins, chondroitin sulfate, polydextrose, locust bean gum, chondroitin sulfate, chitosan, poly (-caprolactone), polylactic acid, and poly (lactic-co-glycolic acid).

In certain embodiments of such oral administration of a composition containing one or more ASBTIs or other compounds described herein, the composition is delivered to the colon without absorption at the upper part of the intestine by coating the dosage form with a redox-sensitive polymer that degrades through the flora (bacteria) in the colon. In such biodegradable systems, such polymers include, by way of non-limiting example, redox-sensitive polymers containing azo and/or disulfide linkages in the backbone.

In some embodiments, compositions formulated for delivery to the colon and/or rectum are formulated for extended release. In some embodiments, the extended release formulation resists the acidic environment of the stomach, thereby delaying release of the enteroendocrine peptide secretion enhancing agent until the dosage form enters the colon and/or rectum.

In certain embodiments, the time-release formulations described herein comprise capsules (comprising an enteroendocrine peptide secretion enhancing agent and optionally an absorption inhibitor) with a hydrogel plug. In certain embodiments, the capsule and hydrogel plug are covered by a water-soluble cap and the entire unit is coated with enteric polymer. When the capsule enters the small intestine, the enteric coating dissolves and after a period of time the hydrogel plug swells and moves out of the capsule and the composition is released from the capsule. The amount of hydrogel is used to adjust the time period to release the contents.

In some embodiments, provided herein is an oral dosage form comprising a multi-layer coating, wherein the coating comprises different layers of polymers having different pH sensitivities. As the coated dosage form moves along the GIT, the different layers dissolve depending on the pH encountered. The polymers used in such formulations include, by way of non-limiting example, polymethyl methacrylate (PMMA) having suitable pH dissolution characteristics,RL/>RS (inner layer)/>FS (outer layer). In other embodiments, the dosage form is an enteric coated lozenge having a shell of hydroxypropyl cellulose or hydroxypropyl methyl cellulose acetate succinate (HPMCAS).

In some embodiments, provided herein is an oral dosage form comprising a coating having cellulose butyrate phthalate, hydrogen phthalate, cellulose propionate phthalate, polyvinyl acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate, dioxypropyl methylcellulose succinate, carboxymethyl ethylcellulose, hydroxypropyl methylcellulose acetate succinate, polymers and copolymers formed from acrylic acid, methacrylic acid, and combinations thereof.

Combination therapy

In some embodiments, the methods provided herein comprise administering a compound (e.g., ASBTI) or composition described herein in combination with one or more additional agents. In some embodiments, the invention also provides a composition comprising a compound (e.g., ASBTI) and one or more additional agents.

Fat-soluble vitamins

In some embodiments, the methods provided herein further comprise administering one or more vitamins. In some embodiments, the vitamin is vitamin A, B, B2, B3, B5, B6, B7, B9, B12, C, D, E, K, folic acid, pantothenic acid, nicotinic acid, riboflavin, thiamine, retinol, beta carotene, pyridoxine, ascorbic acid, cholecalciferol, cyanocobalamin, tocopherol, she Kun, menaquinone.

ASBTI and PPAR agonists

In various embodiments, the invention provides methods of using ASBTI in combination with PPAR (peroxisome proliferator-activated receptor) agonists. In various embodiments, the PPAR agonist is a fibrate. In some embodiments, the fibrate drug is clofibrate (clofibrate), gemfibrozil (gemfibrozil), ciprofibrate (ciprofibrate), bezafibrate (benzafibrate), fenofibrate (fenofibrate), or various combinations thereof. In various embodiments, the PPAR agonist is aloglizab (aleglitazar), moglizab (muraglitazar), tegglizab (tesaglitazar), saglizab (saroglitazar), GW501516, GW-9662, thiazolidinedione (TZD), an NSAID (e.g., IBUPROFEN), indole, or various combinations thereof.

ASBTI and FXR drugs

In various embodiments, the invention provides methods of using ASBTI in combination with farnesoid (farnesoid) X receptor (FXR) targeted drugs. In various embodiments, the FXR targeted drug is avermectin (avermectin) B1a, benpurol (bepridil), fluticasone propionate (fluticasone propionate), GW4064, gliquidone (gliquidone), nicardipine (nicardipine), triclosan (triclosan), CDCA, ivermectin, chloroestrel (chlorotrianisene), tribenzoside (tribenoside), mometasone furoate (mometasone furoate), miconazole (miconazole), amiodarone (amiodarone), butoconazole (butoconazolee), bromocriptine mesylate (bromocryptine mesylate), benzothiadiane malate (pizotifen malate), or various combinations thereof.

Partial bile external shunt (PEBD)

In some embodiments, the methods provided herein further comprise using partial extrabiliary bypass as a treatment for patients who have not yet developed cirrhosis. Such treatment helps reduce the circulation of bile acids/salts in the liver in order to reduce complications and prevent the need for early transplantation in many patients.

This surgical technique involves separating a length of 10cm of intestine from the rest of the intestine for use as a biliary tract catheter (biliary pathway). One end of the catheter is attached to the gallbladder and the other end is brought out to the skin to form a stoma (stoma) (the opening is surgically constructed to allow waste to pass through). Partial extrabiliary bypass may be used in patients (especially elderly, large patients) who are not effective for all medical therapies. This procedure may not be helpful for young patients (e.g., infants, etc.). Partial extrabiliary bypass can reduce the intensity of itching and abnormally low levels of cholesterol in the blood.

ASBTI and Xiong Erchun

In some embodiments, ASBTI is administered in combination with bear diol or ursodeoxycholic acid, chenodeoxycholic acid, cholic acid, taurocholic acid, ursodeoxycholic acid (ursocholic acid), glycocholic acid, glycodeoxycholic acid (glycodeoxycholic acid), taurodeoxycholic acid (taurodeoxycholic acid), taurocholate ester, glycochenodeoxycholic acid (glycochenodeoxycholic acid), tauroursodeoxycholic acid. In some cases, an increase in the concentration of bile acid/salt in the remote intestine induces intestinal regeneration, reduces intestinal damage, reduces bacterial translocation, inhibits release of free radical oxygen, inhibits production of pro-inflammatory cytokines, or any combination thereof.

In certain embodiments, the patient is administered Xiong Erchun at a daily dose of about or at least about 5mg、10mg、15mg、20mg、25mg、30mg、35mg、36mg、40mg、45mg、50mg、55mg、60mg、65mg、70mg、75mg、80mg、85mg、90mg、95mg、100mg、150mg、200mg、250mg、300mg、350mg、400mg、450mg、500mg、550mg、600mg、650mg、700mg、750mg、800mg、850mg、900mg、950mg、1,000mg、1,250mg、1,500mg、1,750mg、2,000mg、2,250mg、2,500mg、2,750mg or 3,000 mg. In certain embodiments, the patient is administered Xiong Erchun at a daily dose of about or no greater than about 10mg、15mg、20mg、25mg、30mg、35mg、36mg、40mg、45mg、50mg、55mg、60mg、65mg、70mg、75mg、80mg、85mg、90mg、95mg、100mg、150mg、200mg、250mg、300mg、350mg、400mg、450mg、500mg、550mg、600mg、650mg、700mg、750mg、800mg、850mg、900mg、950mg、1,000mg、1,250mg、1,500mg、1,750mg、2,000mg、2,250mg、2,500mg、2,750mg、3,000mg or 3,500 mg. In various embodiments, the patient is administered Xiong Erchun at or at least a daily dose of about 3mg to about 300mg, about 30mg to about 250mg, about 36mg to about 200mg, about 10mg to about 3000mg, about 1000mg to about 2000mg, or about 1500 to about 1900 mg.

In various embodiments, the Xiong Erchun is administered in a lozenge. In various embodiments, the Xiong Erchun is administered as a suspension. In various embodiments, the concentration of bear glycol in the suspension is from about 10mg/mL to about 200mg/mL, from about 50mg/mL to about 150mg/mL, from about 10mg/mL to about 500mg/mL, or from about 40mg/mL to about 60mg/mL. In various embodiments, the concentration of bear glycol in the suspension is about or at least about 20mg/mL, 25mg/mL, 30mg/mL, 35mg/mL, 40mg/mL, 45mg/mL, 50mg/mL, 55mg/mL, 60mg/mL, 65mg/mL, 70mg/mL, 75mg/mL, or 80mg/mL. In various embodiments, the concentration of bear glycol in the suspension is no greater than about 25mg/mL, 30mg/mL, 35mg/mL, 40mg/mL, 45mg/mL, 50mg/mL, 55mg/mL, 60mg/mL, 65mg/mL, 70mg/mL, 75mg/mL, 80mg/mL, or 85mg/mL.

The use of ASBTI and a second active ingredient allows the combination to be present in a therapeutically effective amount. The therapeutically effective amount results from the use of a combination of ASBTI and other active ingredients (e.g., xiong Erchun), each of which is used in a therapeutically effective amount or in accordance with additives or synergistic effects due to the use of the combination, each of which may also be used in a sub-clinically therapeutically effective amount (i.e., an amount that provides reduced effectiveness for the therapeutic purposes described herein if used alone), provided that the use of the combination is therapeutically effective. In some embodiments, the use of a combination of ASBTI and any other active ingredient as described herein encompasses a combination in which the ASBTI or other active ingredient is present in a therapeutically effective amount, and the other is present in a subclinical therapeutically effective amount, provided that the use of the combination is therapeutically effective due to its additive or synergistic effect. As used herein, the term "additive effect" describes the combined effect of two (or more) pharmaceutically active agents, which is equal to the sum of the effects of each agent administered alone. A synergistic effect is one in which the combined effect of two (or more) pharmaceutically active agents is greater than the sum of the effects of each agent administered alone. Any suitable combination of ASBTI with one or more of the foregoing other active ingredients, and optionally with one or more other pharmaceutically active substances, is contemplated as being within the scope of the methods described herein.

In some embodiments, the particular choice of compound is based on the diagnosis of the attending physician and his judgment of the individual condition and the appropriate treatment regimen. The compounds are optionally administered concurrently (e.g., simultaneously, substantially simultaneously or within the same treatment regimen) or sequentially, depending on the nature of the disease, disorder or condition, the condition of the individual, and the actual choice of compound employed. In some cases, the order of administration and the number of repetitions of administration of each therapeutic agent during a treatment regimen is determined based on an assessment of the disease being treated and the individual condition.

In some embodiments, the therapeutically effective dose is altered when the drugs are used in therapeutic combination. Methods for experimentally determining therapeutically effective dosages of drugs and other agents for use in combination treatment regimens are described in the literature.

In some embodiments of the combination therapies described herein, the dosage of the co-administered compounds varies depending on the type of co-drug employed, the particular drug employed, the disease or disorder being treated, and the like. Furthermore, when co-administered with one or more bioactive agents, the compounds provided herein are optionally administered simultaneously or sequentially with the bioactive agents. In some cases, if administered sequentially, the attending physician will determine the appropriate order of combination of the therapeutic compounds described herein with additional therapeutic agents.

The plurality of therapeutic agents, at least one of which is a therapeutic compound described herein, are optionally administered in any order or even simultaneously. If simultaneously, the multiple therapeutic agents are optionally provided in a single, unified form or in multiple forms (for example only, as a single pill or as two separate pills). In certain instances, one of the therapeutic agents is optionally administered in multiple doses. In other cases, both are optionally administered in multiple doses. If not simultaneous, the time between doses is any suitable time; for example, more than zero weeks to less than four weeks. Furthermore, the combination methods, compositions, and formulations are not limited to the use of only two agents; it is also contemplated to use a variety of therapeutic combinations (including two or more compounds described herein).

In certain embodiments, the dosage regimen for treating, preventing, or ameliorating a disorder for which relief is sought is modified according to various factors. Such factors include the disorder the individual is suffering from, as well as the age, weight, sex, diet, and medical condition of the individual. Thus, in various embodiments, the dosage regimen actually employed varies and deviates from the dosage regimen described herein.

In some embodiments, the pharmaceutical agents comprising the combination therapies described herein are provided in a combined dosage form or in separate dosage forms intended for substantially simultaneous administration. In certain embodiments, the pharmaceutical agents comprising the combination therapy are administered sequentially, wherein any therapeutic compound is administered by a regimen that requires two-step administration. In some embodiments, a two-step dosing regimen entails sequential dosing of the active agents or separate dosing of the individual active agents. In certain embodiments, the period of time between the multiple administration steps (illustrated by way of non-limiting example) varies from a few minutes to a few hours, depending on the nature of each agent, such as potency, solubility, bioavailability, plasma half-life, and kinetic profile of the agent, etc.

In certain embodiments, provided herein are combination therapies. In certain embodiments, the compositions described herein comprise an additional therapeutic agent. In some embodiments, the methods described herein comprise administering a second dosage form comprising an additional therapeutic agent. In certain embodiments, the combination therapies (compositions described herein) are administered as part of a regimen. Thus, additional therapeutic agents and/or additional pharmaceutical dosage forms may be administered to a patient directly or indirectly and concomitantly or sequentially with the compositions and formulations described herein.

Set of parts

In another aspect, provided herein are kits containing a device for oral administration and a pharmaceutical composition as described herein. In certain embodiments, the kit comprises a pre-filled pouch or bottle for oral administration. In certain embodiments, the kit comprises a prefilled syringe for administration of an oral enema.

Release in the remote ileum and/or colon

In certain embodiments, the dosage form comprises a matrix (e.g., a matrix comprising hydroxypropyl methylcellulose) that allows controlled release of the active agent in the remote jejunum, proximal ileum, remote ileum, and/or colon. In some embodiments, the dosage form comprises a polymer that is pH sensitive (e.g., MMX ^TM matrix, from kemo pharmaceutical company) and allows for controlled release of the active agent in the ileum and/or colon. Examples of such pH-sensitive polymers suitable for controlled release include, but are not limited to, polyacrylic polymers (e.g., anionic polymers of methacrylic acid and/or methacrylate esters, such asA polymer). In some embodiments, a dosage form suitable for controlled release in the remote ileum comprises a microparticle active agent (e.g., a micronized active agent). In some embodiments, the non-enzymatically degraded poly (dl-lactic-co-glycolide) (PLGA) core is suitable for delivering ASBTI to the remote ileum. In some embodiments, the dosage form comprising ASBTI is an enteric polymer (e.g./>S-100, cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, anionic polymers of methacrylic acid, methacrylate esters, etc.) are coated for site-specific delivery to the ileum and/or colon. In some embodiments, the bacterial activation system is suitable for targeted delivery to the ileum. Examples of flora-activated systems include dosage forms comprising azo hydrogels of pectin, galactomannan, and/or an active agent and/or glycoside conjugates (e.g., conjugates of D-galactoside, beta-D-xylopyranoside, etc.). Examples of gastrointestinal flora enzymes include bacterial glycosidases, such as e.g. D-galactosidase, beta-D-glucosidase, alpha-L-arabinofuranosidase, beta-D-xylopyranosidase, etc.

The pharmaceutical solid dosage forms described herein optionally comprise additional therapeutic compounds described herein and one or more pharmaceutically acceptable additives, such as compatible carriers, binders, fillers, suspending agents, flavoring agents, sweeteners, disintegrants, dispersing agents, surfactants, lubricants, colorants, diluents, dissolving agents, humectants, plasticizers, stabilizers, penetration enhancers, wetting agents, antifoaming agents, antioxidants, preservatives, or one or more combinations thereof, and the like. In some aspects, a film coating is provided around the ASBTI formulation using standard coating procedures, such as those described in the pharmaceutical sciences of ramington, 20 th edition (2000), and the like. In one embodiment, the compounds described herein are in the form of particles and some or all of the particles of the compounds are coated. In certain embodiments, some or all of the particles of the compounds described herein are microencapsulated. In some embodiments, the particles of the compounds described herein are not microencapsulated and are not coated.

The ASBT inhibitors may be used in the manufacture of a medicament for the prophylactic and/or therapeutic treatment of cholestatic or cholestatic liver disease. Methods for treating any of the diseases or conditions described herein in a subject in need of such treatment may involve administering to the subject a pharmaceutical composition comprising at least one ASBT inhibitor or pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof described herein in a therapeutically effective amount.

Examples

The following examples are provided to further describe some of the embodiments disclosed herein. The examples are intended to illustrate, but not limit, the disclosed embodiments.

Example 1 administration of apical sodium-dependent bile acid transporter inhibitors (ASBTI) in a fasted state minimizes adverse gastrointestinal effects while maintaining pharmacodynamic effects

Apical sodium-dependent bile acid transporter inhibitors (ASBTIs), also known as Ileal Bile Acid Transporter Inhibitors (IBATi), reduce the intestinal hepatic circulation of Bile Acids (BAs) by reducing their resorption and increasing fecal BA (fBA) excretion. ASBTI, including Ma Lali sibat (MRX; recently approved for the treatment of cholestatic pruritus in >1 year old patients with algo-gekom [ ALGS ], and Fu Lixi bat (VLX), reduces toxic accumulation of BA in the liver and reduces cholestasis. GI adverse effects (AE; diarrhea, abdominal pain) are potential side effects of ASBTI, but MRX and VLX can be taken 30 minutes before meal in fasted state, which can minimize GI AE. The objective of the analysis is to understand the effect of time of ASBTI administration on Pharmacodynamic (PD) effects and GI AE relative to meal time.

AE data from 3 independent phase 1 clinical studies based on MRX and VLX among healthy participants were compiled to assess the effect of ASBTI dosing and meal time on GI AE (table 1, fig. 1). In each clinical study, ASBTI was administered in fed and fasted states, and the ratio of GI AEs was compared. AE data from Placebo (PBO) control experiments in patients with ALGS alone, where MRX was administered 30 minutes before the meal, allowed comparison of the GI AE ratio of MRX to PBO.

In phase 1 clinical study, the rate of GI Adverse Events (AEs) was lower when ASBTI was administered in the fasted state (GI AEs reported at 0%, 0% and 50% in study 1, 2 and 3, respectively) than in the fed state or at meal time (75%, 33% and 100% in study 1, 2 and 3, respectively), fig. 2. In the PBO control trial in patients with ALGS, where MRX was administered 30 minutes before the meal in a fasted state, diarrhea was reported at similar frequency in drug and PBO based patients (43.6% of MRX versus 44.4% of PBO).

The PD effect of ASBTI dosing time to meal time was studied in healthy dogs (fig. 3). In healthy dogs, MRX significantly increased fBA excretion (p <0.01 compared to pretreatment baseline, by paired t-test) regardless of dosing time relative to daily meals. The maximum increase in fBA excretion was seen when administered 30 minutes before meal (231% increase) to 4 hours after meal (229% increase), indicating that the ASBTI administration was elastic over the time of meal time to maintain maximum PD effect (fig. 4). P <0.01, compared to pre-treatment, was tested by single tail paired t-test. Data are presented as ± SEM (n=7 to 8). Change in% = compared to pre-treatment value. The groups were dosed at the indicated times. Fecal samples were taken 48 hours before the start of treatment and the last 72 hours of the 7 day treatment period and analyzed for cholic acid content.

Animal PD data demonstrated herein show that: has elasticity in ASBTI administration relative to meals to increase fBA excretion. Most preferably GI tolerance given by ASBTI in healthy individuals is achieved by administration in the fasting state. The ratio of GI AEs in patients with ALGS dosed MRX in the fasted state was similar to PBO. Future studies may allow for more detailed description of the relationship between food, ASBTI administration, GI AE, and efficacy.

These data demonstrate an improvement in GI tolerance when ASBTI is administered in a fasted state compared to administration at the time of a meal or immediately after food intake. Animal data shows that PD effects are maintained regardless of time of administration relative to meal time, indicating that efficacy can be maintained while GI effects are minimized.

Table 1: comparison of the incidence of GI TEAE following ASBTI administration in fed versus fasted state

***

All references cited anywhere in this specification are incorporated herein by reference in their entirety for all purposes.

While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only.

Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value and each separate end point falling within the range, unless otherwise indicated herein, and each separate value and end point is incorporated into the specification as if it were individually recited herein.

Many modifications, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

1. A method of reducing, minimizing, preventing, ameliorating or eliminating one or more side effects associated with administration of a sodium-apical dependent bile acid transporter inhibitor (ASBTI) in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of the ASBTI prior to ingestion of food.

2. The method of claim 1, wherein the one or more side effects associated with administration of the ASBTI are reduced, minimized, prevented, ameliorated, or eliminated compared to side effects when the ASBTI is administered after ingestion of food, concurrently with food, or in combination with food.

3. A method of improving Gastrointestinal (GI) tolerance of an ASBTI in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the ASBTI prior to ingestion of food.

4. The method of claim 3, wherein the improvement in GI tolerance comprises reduction, minimization, prevention, amelioration, or elimination of one or more GI adverse events.

5. The method of claim 3 or 4, wherein the improvement in GI tolerance comprises one or more of reduction, minimization, prevention, amelioration, or elimination of diarrhea, runny stool, nausea, abdominal pain, and anorectal discomfort.

6. The method of any one of claims 3-5, wherein the GI tolerance is improved compared to GI tolerance when the ASBTI is administered at a meal time or immediately after food intake.

7. The method of any one of claims 3-6, wherein the GI tolerance is improved by at least 10% as compared to GI tolerance when the ASBTI is administered at a meal time or immediately after food intake.

8. The method of any one of claims 3-7, wherein the GI tolerance is improved by at least 20% as compared to the GI tolerance when the ASBTI is administered at a meal time or immediately after food intake.

9. The method of any one of claims 3-8, wherein the GI tolerance is improved by at least 50% as compared to the GI tolerance when the ASBTI is administered at a meal time or immediately after food intake.

10. A method of treating cholestatic liver disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an ASBTI prior to ingestion of food, wherein the subject experiences a reduction in frequency and/or severity of one or more side effects associated with administration of the ASBTI.

11. The method of claim 10, wherein the frequency and/or severity of side effects is reduced compared to side effects when the ASBTI is administered after ingestion of food, concurrently with food, or in admixture with food.

12. The method of claim 10 or 11, wherein the cholestatic liver disease is pediatric cholestatic liver disease.

13. The method of claim 10 or 11, wherein the cholestatic liver disease is an adult cholestatic liver disease.

14. The method of any one of claims 10-13, wherein the cholestatic liver disease is non-obstructive cholestasis, extrahepatic cholestasis, intrahepatic cholestasis, primary intrahepatic cholestasis, secondary intrahepatic cholestasis, progressive Familial Intrahepatic Cholestasis (PFIC), PFIC type 1, PFIC type 2, PFIC type 3, benign Recurrent Intrahepatic Cholestasis (BRIC), BRIC type 1, BRIC type 2, BRIC type 3, total venous nutrient-related cholestasis, paraneoplastic cholestasis, stokes-Fur syndrome, intrahepatic cholestasis of pregnancy, contraceptive-related cholestasis, drug-related cholestasis, infection-related cholestasis, durbin-Jiang Sener syndrome, primary Biliary Cirrhosis (PBC), primary Sclerosing Cholangitis (PSC), cholelithiasis, alagel syndrome, biliary blocking, post Ge Xishu biliary blocking, post-liver-transplant cholestasis, post-liver-transplant-related biliary stasis, liver failure, liver cirrhosis-related liver disease, or liver disease-mediated liver disease, liver cirrhosis, or post-transplant liver disease-related liver disease, liver failure, or primary biliary cirrhosis.

15. The method of any one of claims 10-14, wherein the cholestatic liver disease is arg Ji Ouzeng syndrome, PFIC, BRIC, PSC, PBC, or biliary atresia.

16. The method of any one of claims 1, 2, and 10-15, wherein the one or more side effects is diarrhea, runny stool, nausea, gastrointestinal pain, abdominal pain, cramps, anorectal discomfort, or a combination thereof.

17. The method of any one of claims 1-16, wherein the ASBTI is administered to the individual in a fasted state.

18. The method of any one of claims 1-16, wherein the ASBTI is administered less than about 60 minutes prior to ingestion of food.

19. The method of any one of claims 1-18, wherein the ASBTI is administered less than about 30 minutes prior to ingestion of food.

20. The method of any one of claims 1-19, wherein the ASBTI is administered immediately prior to ingestion of food.

21. The method of any one of claims 1-20, wherein the ASBTI is administered at least 4 hours after the last meal.

22. The method of any one of claims 1-21, wherein the ASBTI is administered once daily.

23. The method of any one of claims 1-23, wherein the ASBTI is administered twice daily.

24. The method of any one of claims 1-23, wherein the ASBTI is administered in an amount of about 0.1mg to about 100mg per dose.

25. The method of claim 24, wherein the ASBTI is administered in an amount of about 10mg to about 100mg per dose.

26. The method of claim 24 or 25, wherein the ASBTI is administered in an amount of about 20mg to about 80mg per dose.

27. The method of any one of claims 1-26, wherein the ASBTI is administered in an amount of about 100 ug/kg/day to 1400 ug/kg/day.

28. The method of claim 27, wherein the ASBTI is administered in an amount of about 400 ug/kg/day to about 800 ug/kg/day.

29. The method of any one of claims 1-28, wherein the ASBTI is selected from the group consisting of(Ma Lali Xibatt) and/>(Fu Lixi bat) or a pharmaceutically acceptable salt thereof.

30. The method of claim 29, wherein the ASBTI is(Chloro Ma Lali cilazabat).

31. The method of claim 29, wherein the ASBTI is Fu Lixi bat or a pharmaceutically acceptable salt thereof.

32. The method of any one of claims 1-31, wherein the individual does not ingest food about 0.5 to about 16 hours before administering the ASBTI.

33. The method of any one of claims 1-32, wherein the individual is a pediatric individual.

34. The method of claim 33, wherein the pediatric individual is 0 to 18 years old.

35. The method of any one of claims 1-26, wherein the ASBTI is administered orally.

36. The method of any one of claims 1-35, wherein less than 10% of the ASBTI is systemically absorbed.

37. The method of any one of claims 1-35, wherein less than 30% of the ASBTI is systemically absorbed.