Dosing regimens for apical sodium-dependent bile acid transporter inhibitors (ASBTIs)

Abstract

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

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 63 / 271,916, filed October 26, 2021, U.S. Provisional Application No. 63 / 280,470, filed November 17, 2021, and U.S. Provisional Application No. 63 / 354,424, filed June 22, 2022, the disclosures of which are incorporated by reference in their entireties herein. [Technical field]

[0002] The present invention generally relates to methods for 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 a subject in need thereof by administering a therapeutically effective amount of ASBTI to the subject prior to ingestion of food. The present invention also relates to a method of treating cholestatic liver disease in a subject, comprising administering a therapeutically effective amount of ASBTI to the subject prior to ingestion of food and / or in a fasted state. [Background technology]

[0003] Hypercholestasis and cholestatic liver disease are liver diseases associated with impaired bile secretion (i.e., cholestasis) related to and often secondary to intracellular accumulation of bile acids / salts in hepatocytes. Hypercholestasis is characterized by increased serum concentrations of bile acids or bile salts. Cholestasis can be classified clinically and pathologically into two major categories: obstructive, often extrahepatic, cholestasis, and nonobstructive or intrahepatic cholestasis. Nonobstructive intrahepatic cholestasis can be further classified into two major subgroups: primary intrahepatic cholestasis, resulting from constitutively defective bile secretion, and secondary intrahepatic cholestasis, resulting from hepatocellular injury. Primary intrahepatic cholestasis includes diseases such as benign recurrent intrahepatic cholestasis, which is the adult form with mainly similar clinical symptoms, and progressive familial intrahepatic cholestasis (PFIC) types 1, 2, and 3, which are diseases that affect children.

[0004] Pediatric cholestatic liver disease affects a small percentage of children, but treatment incurs significant healthcare costs each year. Currently, many pediatric cases of cholestatic liver disease require invasive and costly procedures such as liver transplantation or surgery. There are no available effective, minimally invasive treatments with medications that have minimal gastrointestinal adverse effects suitable for the pediatric population.

[0005] In recent years, apical sodium-dependent bile acid transporter inhibitors (ASBTIs) have emerged as an important new class of therapeutic agents that can reduce serum and / or hepatic bile acids and thus alleviate cholestasis. There is a further urgent need to reduce the adverse effects of ASBTIs and / or to develop methods of treating cholestasis and cholestatic liver disease with reduced adverse effects. Summary of the Invention [Means for solving the problem]

[0006] Various non-limiting aspects and embodiments of the present invention are described below.

[0007] In one aspect, the present invention provides a method for 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 a subject in need thereof, comprising administering a therapeutically effective amount of ASBTI to the subject prior to ingestion of food.

[0008] In certain embodiments, one or more side effects associated with administration of ASBTI are reduced, minimized, prevented, ameliorated, or eliminated compared to side effects when ASBTI is administered after ingestion of food, simultaneously with food, or mixed with food.

[0009] In another aspect, the present invention provides a method for improving gastrointestinal (GI) tolerability of an ASBTI in a subject in need thereof, comprising administering a therapeutically effective amount of an ASBTI to the subject prior to ingestion of food.

[0010] In some embodiments, improving GI tolerability includes reducing, minimizing, preventing, ameliorating, or eliminating one or more adverse GI events.

[0011] In some embodiments, improving GI tolerability includes reducing, minimizing, preventing, ameliorating, or eliminating one or more of diarrhea, loose stools, nausea (retching), abdominal pain, and anorectal discomfort.

[0012] In some embodiments, the GI tolerability is improved compared to the GI tolerability when the ASBTI is administered with a meal or immediately following ingestion of food.

[0013] In some embodiments, the GI tolerability is improved by at least 10% compared to the GI tolerability when the ASBTI is administered with a meal or immediately following ingestion of food.

[0014] In some embodiments, the GI tolerability is improved by at least 20% compared to the GI tolerability when the ASBTI is administered with a meal or immediately following ingestion of food.

[0015] In some embodiments, the GI tolerability is improved by at least 50% compared to the GI tolerability when the ASBTI is administered with a meal or immediately following ingestion of food.

[0016] In one aspect, the present invention provides a method of treating cholestatic liver disease in a subject in need thereof, comprising administering a therapeutically effective amount of ASBTI to the subject prior to ingestion of food, wherein the subject experiences a reduction in the frequency and / or severity of one or more side effects associated with administration of ASBTI.

[0017] In certain embodiments, the frequency and / or severity of side effects are reduced as compared to side effects when the ASBTI is administered after ingestion of food, simultaneously with food, or mixed with food.

[0018] In certain embodiments, the cholestatic liver disease is pediatric cholestatic liver disease. In certain embodiments, the cholestatic liver disease is adult cholestatic liver disease. In certain embodiments, the cholestatic liver disease is nonobstructive 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 parenteral nutrition associated cholestasis, paraneoplastic cholestasis, and the like. cholestasis, Stauffer syndrome, intrahepatic cholestasis of pregnancy, contraceptive-associated cholestasis, drug-associated cholestasis, infection-associated cholestasis, Dubin-Johnson syndrome, primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), cholelithiasis, Alagille syndrome, biliary atresia, post-Kasai biliary atresia, post-liver transplant cholestasis, post-liver transplant associated liver disease, intestinal failure associated liver disease, bile acid-mediated liver injury, MRP2 deficiency syndrome, or neonatal sclerosing cholangitis. In certain embodiments, the cholestatic liver disease is Alagille syndrome, PFIC, BRIC, PSC, PBC, or biliary atresia.

[0019] In certain embodiments, ASBTI is administered to subject in fasting state.In certain embodiments, ASBTI is administered less than about 60 minutes before eating food.In certain embodiments, ASBTI is administered less than about 30 minutes before eating food.In certain embodiments, ASBTI is administered immediately before eating food.In certain embodiments, ASBTI is administered at least 4 hours after last meal.

[0020] In certain embodiments, ASBTI is administered once daily. In certain embodiments, ASBTI is administered twice daily.

[0021] In certain embodiments, ASBTI is administered in an amount of about 0.1 mg to about 100 mg per dose. In certain embodiments, ASBTI is administered in an amount of about 10 mg to about 100 mg per dose. In certain embodiments, ASBTI is administered in an amount of about 20 mg to about 80 mg per dose. In certain embodiments, ASBTI is administered in an amount of about 100 μg / kg / day to about 1400 μg / kg / day. In certain embodiments, ASBTI is administered in an amount of about 400 μg / kg / day to about 800 μg / kg / day.

[0022] In certain embodiments, the ASBTI is [ka] or a pharma- ceutically acceptable salt thereof. In certain embodiments, ASBTI is selected from: [ka] In certain embodiments, the ASBTI is vorixibat or a pharma- ceutically acceptable salt thereof. In certain embodiments, the ASBTI is vorixibat potassium.

[0023] In certain embodiments, the subject has not consumed food for about 0.5 to about 16 hours prior to administration of the ASBTI.

[0024] In certain embodiments, the subject is a pediatric subject. In certain embodiments, the pediatric subject is 0-18 years old.

[0025] In certain embodiments, the ASBTI is administered orally.

[0026] In certain embodiments, less than 10% of the ASBTI is systemically absorbed. In certain embodiments, less than 30% of the ASBTI is systemically absorbed. [Brief description of the drawings]

[0027] [Figure 1] Shown is the study design, drugs (MRX=maralixibat, VLX=vorixibat), doses and fed / fasted timeline for certain embodiments according to the present disclosure. *Fasting began 10-12+ hours prior to MRX administration. **Patients were randomized 1:1 into two cohorts to receive fasted followed by fed or fed followed by fasted administrations sequentially. [Diagram 2] Pie charts showing the percentage of healthy participants who experienced a gastrointestinal (GI) treatment-emergent adverse event (AE) after administration of ASBTI with or without food in the fed or fasted state for each of the three studies. [Diagram 3] FIG. 1 shows the effect of maralixibat (MRX) on fecal bile acid (fBA) excretion in dogs: study drug and dosing / mealtime schedule. [Figure 4] 1 is a bar graph of the effect of maralixibat (MRX) on fecal bile acids (fBA) in dogs: change in fBA excretion from pre-treatment to day 7. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0028] Detailed embodiments of the present invention are disclosed herein; however, it should be understood that the disclosed embodiments are merely exemplary of the present invention, which may be embodied in various forms. Moreover, each of the examples given in connection with the various embodiments of the present invention is intended to be illustrative, not limiting. Therefore, the specific structural and functional details disclosed herein should not be construed as limiting, but merely as a representative basis for teaching those skilled in the art to use the present invention in various ways.

[0029] Bile acids / salts play an important role in activating digestive enzymes and solubilizing fats and fat-soluble vitamins, and are involved in liver, biliary and intestinal diseases. Bile acids are synthesized in the liver by a multistep, multiorganelle pathway. Hydroxyl groups are added to specific sites on the steroid structure, the double bond in the B ring of cholesterol is reduced, the hydrocarbon chain is shortened by three carbon atoms, and a carboxyl group is provided at the end of the chain. The most common bile acids are cholic acid and chenodeoxycholic acid (the "primary bile acids"). Before leaving the hepatocyte to form bile, bile acids are conjugated to glycine (to produce glycocholic acid or glycochenodeoxycholic acid) or taurine (to produce taurocholic acid or taurochenodeoxycholic acid). The conjugated bile acids are called bile salts, and their amphiphilic nature makes them more efficient surfactants than bile acids. Bile salts, but not bile acids, are found in bile.

[0030] Bile salts are secreted by hepatocytes into the bile canaliculi to form bile. The canaliculi empty into the left and right hepatic ducts, and the bile flows to the gallbladder. Bile is released from the gallbladder and travels to the duodenum, where it contributes to fat metabolism and breakdown. Bile salts are reabsorbed in the terminal ileum and transported back to the liver via the portal vein. Bile salts often undergo multiple enterohepatic circulations before being excreted via the feces. A small proportion of bile salts can be absorbed in the proximal intestine by either passive or carrier-mediated transport processes. Most bile salts are recycled in the distal ileum by a sodium-dependent, apically located bile acid transporter called the apical sodium-dependent bile acid transporter (ASBT). At the basolateral surface of enterocytes, a truncated version of ASBT is involved in the vectorial transport of bile acids / salts to the portal circulation. Completion of the enterohepatic circulation occurs at the basolateral surface of hepatocytes by a transport process mediated primarily by sodium-dependent bile acid transporters. Intestinal bile acid transport plays a key role in the enterohepatic circulation of bile salts. Molecular analysis of this process has recently led to important advances in our understanding of the biology, physiology, and pathophysiology of intestinal bile acid transport.

[0031] In the intestinal lumen, bile acid concentration fluctuates according to the large amount of reuptake that occurs in the distal intestine.Described herein is a specific composition and method that controls the concentration of bile acid in the intestinal lumen, thereby controlling the hepatocellular damage caused by bile acid accumulation in the liver, and also administers in fasting state to minimize gastrointestinal adverse effects.

[0032] The subject matter of the present disclosure is based, at least in part, on the discovery that administering ASBTI to a subject in need thereof prior to ingestion of food unexpectedly results in the reduction, minimization, prevention, amelioration, and / or elimination of one or more side effects associated with administration of ASBTI.

[0033] Classes of Cholestasis and Cholestatic Liver Disease As used herein, "cholestasis" refers to a disease or condition involving impaired bile formation and / or bile flow. As used herein, "cholestatic liver disease" refers to a liver disease associated with cholestasis. Cholestatic liver disease is often accompanied by jaundice, fatigue, and pruritus (itching). Biomarkers of cholestatic liver disease include elevated serum bile acid concentrations, elevated serum alkaline phosphatase (AP), elevated gamma-glutamyl transpeptidase, elevated conjugated hyperbilirubinemia, and elevated serum cholesterol.

[0034] Cholestatic liver diseases can be divided clinicopathologically into two main categories: obstructive, often extrahepatic, and nonobstructive or intrahepatic cholestasis, in which cholestasis occurs when bile flow is mechanically blocked, for example by gallstones or tumors, or in extrahepatic biliary atresia.

[0035] The latter group with nonobstructive intrahepatic cholestasis is further divided into two main subgroups. In the first subgroup, cholestasis occurs when the processes of bile secretion and modification or synthesis of bile components are secondarily involved in hepatocellular injury so severe that nonspecific impairment of many functions, including those subserving bile formation, can be expected. In the second subgroup, no presumed cause of hepatocellular injury can be identified. Cholestasis in such patients appears to occur when one of the steps in bile secretion or modification or synthesis of bile components is constitutively impaired. Such cholestasis is considered primary.

[0036] Thus, provided herein are methods and compositions for stimulating epithelial proliferation and / or regeneration of the intestinal lining and / or enhancing adaptive processes in individuals with hypercholesterolemia and / or cholestatic liver disease. In some such embodiments, the methods include increasing bile acid and / or GLP-2 concentrations in the intestinal lumen.

[0037] Elevated bile acid levels and elevated levels of AP (alkaline phosphatase), LAP (leukocyte alkaline phosphatase), γGT (γ-glutamyl transpeptidase) and 5'-nucleotidase are biochemical characteristics of cholestasis and cholestatic liver disease.Therefore, methods and compositions are provided herein for stimulating epithelial proliferation and / or intestinal lining regeneration and / or enhancement of adaptive process in the intestine in individuals with hypercholesterolemia and elevated levels of AP (alkaline phosphatase), LAP (leukocyte alkaline phosphatase), γGT (γ-glutamyl transpeptidase or GGT) and / or 5'-nucleotidase.In some of such embodiments, the method comprises increasing the bile acid concentration in the intestinal lumen. Provided herein are methods and compositions for alleviating hypercholesterolemia and elevated levels of AP (alkaline phosphatase), LAP (leukocyte alkaline phosphatase), γGT (γ-glutamyl transpeptidase or GGT), and / or 5'-nucleotidase, including reducing the overall serum bile acid load by excreting bile acids in the feces.

[0038] Pruritus is often associated with hypercholesterolemia and cholestatic liver disease. It has been suggested that pruritus is due to bile salts acting on peripheral pain afferents. The severity of pruritus varies from individual to individual (i.e., some individuals are more sensitive to elevated levels of bile acids / salts).

[0039] Administration of an agent that reduces serum bile acid concentration has been shown to alleviate pruritus in certain individuals.Therefore, provided herein are methods and compositions for stimulating intestinal epithelial proliferation and / or intestinal lining regeneration and / or enhanced adaptive processes in individuals with pruritus.In some of such embodiments, the method comprises increasing the bile acid concentration in the intestinal lumen.Further provided herein are methods and compositions for treating pruritus, comprising reducing overall serum bile acid load by excreting bile acid in feces.

[0040] Another symptom of hypercholesterolemia and cholestatic liver disease is an increase in the serum concentration of conjugated bilirubin. Elevated serum concentration of conjugated bilirubin results in jaundice and dark urine. The magnitude of the increase is not diagnostically significant, since no relationship has been established between serum levels of conjugated bilirubin and the severity of hypercholesterolemia and cholestatic liver disease. Conjugated bilirubin concentrations rarely exceed 30 mg / dL. Thus, provided herein are methods and compositions for stimulating epithelial proliferation in the intestine and / or regeneration of the intestinal lining and / or enhancing adaptive processes in individuals with elevated serum concentrations of conjugated bilirubin. In some such embodiments, the methods include increasing bile acid concentrations in the intestinal lumen. Further provided herein are methods and compositions for treating elevated serum concentrations of conjugated bilirubin, including reducing the overall serum bile acid load by excreting bile acids in the feces.

[0041] Increased serum concentration of unconjugated bilirubin is also considered to be a sign of hypercholesterolemia and cholestatic liver disease. A portion of serum bilirubin is covalently bound to albumin (delta (δ) bilirubin or biliprotein). This fraction may account for a large proportion of total bilirubin in patients with cholestatic jaundice. The presence of large amounts of δ-bilirubin indicates long-term cholestasis. δ-bilirubin in umbilical cord blood or newborn blood is an indicator of cholestasis / cholestatic liver disease occurring before birth. Thus, provided herein are methods and compositions for stimulating epithelial proliferation and / or intestinal lining regeneration and / or enhanced adaptive processes in the intestine in individuals with elevated serum concentration of unconjugated bilirubin or δ-bilirubin. In some such embodiments, the method comprises increasing bile acid concentration in the intestinal lumen. Further provided herein are methods and compositions for treating elevated serum concentrations of unconjugated bilirubin and delta-bilirubin, including reducing overall serum bile acid load by excreting bile acids in the feces.

[0042] Cholestasis and cholestatic liver disease cause hypercholesterolemia. During metabolic cholestasis, hepatocytes retain bile salts. Bile salts reflux from hepatocytes into serum, resulting in an increased concentration of bile salts in the peripheral circulation. In addition, the uptake of bile salts entering the liver in portal blood is inefficient, resulting in bile salts spilling into the peripheral circulation. Thus, provided herein are methods and compositions for stimulating epithelial proliferation in the intestine and / or enhanced regeneration and / or adaptive processes of the intestinal lining in individuals with hypercholesterolemia. In some such embodiments, the methods include increasing bile acid concentrations in the intestinal lumen. Further provided herein are methods and compositions for treating hypercholesterolemia, including reducing overall serum bile acid load by excreting bile acids in feces.

[0043] Hyperlipidemia is a feature of some, but not all, cholestatic diseases. Serum cholesterol is elevated in cholestasis due to a decrease in circulating bile salts, which contribute to cholesterol metabolism and degradation. Cholesterol retention is associated with increased membrane cholesterol content and decreased membrane fluidity and membrane function. Furthermore, because bile salts are metabolic products of cholesterol, decreased cholesterol metabolism leads to decreased bile acid / salt synthesis. Serum cholesterol observed in children with cholestasis ranges between about 1,000 mg / dL and about 4,000 mg / dL. Thus, provided herein are methods and compositions for stimulating epithelial proliferation in the intestine and / or enhanced regeneration and / or adaptive processes of the intestinal lining in individuals with hyperlipidemia. In some such embodiments, the methods include increasing bile acid concentrations in the intestinal lumen. Further provided herein are methods and compositions for treating hyperlipidemia, including reducing the overall serum bile acid load by excreting bile acids in the feces.

[0044] In individuals with hypercholesterolemia and cholestatic liver disease, xanthomas develop from the deposition of excess circulating cholesterol in the dermis. The development of xanthomas is more characteristic of obstructive cholestasis than hepatocellular cholestasis. Planar xanthomas develop first around the eyes, then in the creases of the palms and soles, and then on the neck. Nodular xanthomas are associated with chronic and long-term cholestasis. Thus, provided herein are methods and compositions for stimulating epithelial proliferation in the intestine and / or enhanced regeneration and / or adaptive processes of the intestinal lining in individuals with xanthomas. In some such embodiments, the methods include increasing bile acid concentrations in the intestinal lumen. Further provided herein are methods and compositions for treating xanthomas, including reducing the overall serum bile acid load by excreting bile acids in the feces.

[0045] In children with chronic cholestasis, one of the major consequences of hypercholesterolemia and cholestatic liver disease is failure to thrive. Failure to thrive is the result of reduced delivery of bile salts to the intestine, which contributes to inefficient digestion and absorption of fats, and reduced intake of vitamins (vitamins E, D, K, and A are all malabsorbed in cholestasis). In addition, delivery of fats to the colon can cause colonic secretions and diarrhea. Treatment of failure to thrive includes dietary substitution and supplementation with long-chain triglycerides, medium-chain triglycerides, and vitamins. Ursodeoxycholic acid is used to treat some cholestatic conditions, but does not form mixed micelles and has no effect on fat absorption. Thus, provided herein are methods and compositions for stimulating epithelial proliferation in the intestine and / or regeneration of the intestinal lining and / or enhancement of adaptive processes in individuals (e.g., children) with failure to thrive. In some such embodiments, the method comprises increasing the concentration of bile acids in the intestinal lumen.Further provided herein are methods and compositions for treating growth disorders comprising reducing overall serum bile acid load by excreting bile acids in the feces.

[0046] Primary Biliary Cirrhosis (PBC) Primary biliary cirrhosis is an autoimmune disease of the liver characterized by the destruction of the bile ducts. Damage to the bile ducts results in the accumulation of bile in the liver (i.e., cholestasis). Retention of bile in the liver can damage liver tissue, leading to scarring, fibrosis, and cirrhosis. PBC usually develops in adulthood (e.g., over age 40). Individuals with PBC often present with fatigue, pruritus, and / or jaundice. PBC is diagnosed when an individual has elevated AP concentrations, elevated γGT levels, antimitochondrial antibodies (AMA) in serum (>1:40), and florid bile duct lesions for at least 6 months. Serum ALT and serum AST and conjugated bilirubin may also be elevated, but these are not considered diagnostic. Cholestasis associated with PBC has been treated or ameliorated by administration of ursodeoxycholic acid (UDCA or ursodiol). Corticosteroids (e.g., prednisone and budesonide) and immunosuppressants (e.g., azathioprine, cyclosporine A, methotrexate, chlorambucil, and mycophenolate) have been used to treat cholestasis associated with PBC. Sulindac, bezafibrate, tamoxifen, and lamivudine have also been shown to treat or ameliorate cholestasis associated with PBC.

[0047] Progressive familial intrahepatic cholestasis (PFIC) PFIC is a rare genetic disorder that causes progressive liver disease that typically results in liver failure. In people with PFIC, liver cells have a reduced ability to secrete bile. The resulting accumulation of bile causes liver disease in affected individuals. Signs and symptoms of PFIC typically begin during infancy. Patients experience severe itching, jaundice, failure to grow at the expected rate (failure to thrive), and increased liver dysfunction (liver failure). The disease is estimated to affect 1 in 50,000 to 100,000 people in the United States and Europe. Six types of PFIC have been genetically identified, all of which are similarly characterized by impaired bile flow and progressive liver disease.

[0048] PFIC1 PFIC1 (also known as Byler's disease or FIC1 deficiency) is associated with mutations in the ATP8B1 gene (also called FIC1). This gene, which encodes a P-type ATPase, is located on human chromosome 18 and is also mutated in the milder phenotypes, benign recurrent intrahepatic cholestasis type 1 (BRIO) and Greenland familial cholestasis. The FIC1 protein is located in the canalicular membrane of hepatocytes, but in the liver it is expressed mainly in cholangiocytes. The P-type ATPase appears to be an aminophospholipid transporter responsible for maintaining an abundance of phosphatidylserine and phosphatidylethanolamine in the inner leaflet of the 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 canalicular lumen. Abnormal protein function may indirectly interfere with biliary secretion of bile acids. Abnormal secretion of bile acids / salts leads to hepatocyte bile acid overload.

[0049] PFIC1 typically presents in infants (e.g., 6-18 months of age). Infants may show signs of pruritus, jaundice, abdominal distension, diarrhea, malnutrition, and short stature. Biochemically, individuals with PFIC1 have elevated serum transaminases, elevated bilirubin, elevated serum bile acid levels, and low γGT levels. Individuals may also have liver fibrosis. Individuals with PFIC1 typically do not have bile duct proliferation. Most individuals with PFIC1 develop end-stage liver disease by age 10. No medical treatment has proven beneficial for the long-term treatment of PFIC1. Children are often given medium-chain triglycerides and fat-soluble vitamins to reduce extrahepatic symptoms (e.g., malnutrition and failure to thrive). Ursodiol has not been demonstrated to be effective in individuals with PFIC1.

[0050] PFIC2 PFIC2 (also known as Byler syndrome, BSEP deficiency) is associated with mutations in the ABCB11 gene (also called BSEP). The ABCB11 gene encodes the ATP-dependent canalicular bile salt export pump (BSEP) in human liver and is located on human chromosome 2. The BSEP protein, expressed in the hepatocyte canalicular membrane, is the major exporter of primary bile acids / salts against extreme concentration gradients. Mutations in this protein are responsible for the reduced bile salt secretion described in affected patients, leading to reduced bile flow with ongoing severe hepatocellular damage and accumulation of bile salts inside hepatocytes.

[0051] PFIC2 typically presents in infants (e.g., 6-18 months of age). Infants may show signs of pruritus. Biochemically, individuals with PFIC2 have elevated serum transaminases, elevated bilirubin, elevated serum bile acid levels, and low γGT levels. Individuals may also have portal inflammation and giant cell hepatitis. Additionally, individuals often develop hepatocellular carcinoma. No medical therapies have proven beneficial for the long-term treatment of PFIC2. Children are often given medium-chain triglycerides and fat-soluble vitamins to reduce extrahepatic symptoms (e.g., malnutrition and failure to thrive). The PFIC2 patient population represents approximately 60% of the PFIC population.

[0052] PFIC3 PFIC3 (also known as MDR3 deficiency) is caused by a genetic deficiency in the ABCB4 gene (also called MDR3) located on chromosome 7. Class III multidrug resistance (MDR3) P-glycoprotein (P-gp) is a phospholipid translocator involved in the export of bile phospholipids (phosphatidylcholine) at the canalicular membrane of hepatocytes. PFIC3 results from bile toxicity, where detergent bile salts are not inactivated by phospholipids, causing damage to the canaliculi and bile duct epithelium.

[0053] PFIC3 also develops in early childhood. In contrast to PFIC1 and PFIC2, individuals have elevated γGT levels. Individuals also have portal inflammation, fibrosis, cirrhosis, and massive bile duct proliferation. Individuals may also develop intrahepatic cholelithiasis. Ursodiol is effective in treating or ameliorating PFIC3.

[0054] Benign recurrent intrahepatic cholestasis (BRIC) BRIC1 BRIC1 results from a genetic deficiency of the FIC1 protein in the canalicular membrane of hepatocytes. BRIC1 is typically associated with normal serum cholesterol and gamma-glutamyl transpeptidase levels, but elevated serum bile salts. Residual FIC1 expression and function are associated with BRIC1. Despite repeated attacks of cholestasis or cholestatic liver disease, there is no progression to chronic liver disease in the majority of patients. During attacks, patients develop severe jaundice and have pruritus, steatorrhea, and weight loss. Some patients also have kidney stones, pancreatitis, and diabetes.

[0055] BRIC2 BRIC2 is caused by mutations in ABCB11, leading to defective BSEP expression and / or function in the bile canalicular membrane of hepatocytes.

[0056] BRIC3 BRIC3 is associated with defective MDR3 expression and / or function in the canalicular membrane of hepatocytes. Patients with MDR3 deficiency typically show elevated serum gamma-glutamyl transpeptidase levels in the presence of normal or slightly elevated bile acid levels.

[0057] Dubin-Johnson Syndrome (DJS) DJS is characterized by conjugated hyperbilirubinemia due to inherited dysfunction of MRP2. Liver function is preserved in affected patients. Several different mutations have been associated with the condition, resulting in either a complete absence of immunohistochemically detectable MRP2 in affected patients or impaired maturation and sorting of the protein.

[0058] Acquired cholestatic disorders Primary Biliary Cirrhosis (PBC) PBC is a chronic inflammatory liver disorder that slowly progresses to end-stage liver failure in most affected patients. In PBC, the inflammatory process primarily affects the bile ducts.

[0059] Primary sclerosing cholangitis (PSC) PSC is a chronic inflammatory liver disorder that slowly progresses to end-stage liver failure in most affected patients. Fibrosis and obstruction of large and medium-sized intrahepatic and extrahepatic bile ducts predominates in PSC inflammation.

[0060] PSC is characterized by progressive cholestasis, which can often lead to severe pruritus that significantly impairs quality of life.

[0061] Intrahepatic cholestasis of pregnancy (ICP) ICP is characterized by the development of transient cholestasis or cholestatic liver disease in pregnant women, typically occurring in the third trimester of pregnancy, when circulating levels of estrogen are high. ICP is associated with pruritus and biochemical cholestasis or cholestatic liver disease of variable severity, and constitutes a risk factor for prematurity and intrauterine fetal death. A genetic predisposition has been suspected based on strong regional clustering, high prevalence in women of ICP patients' families, and susceptibility of ICP patients to developing intrahepatic cholestasis or cholestatic liver disease under other hormonal challenges, such as oral contraceptives. The heterogeneous state of MDR3 gene deficiency may represent a genetic predisposition.

[0062] cholelithiasis Cholelithiasis is one of the most common and costly of all gastrointestinal diseases, with a prevalence of up to 17% in white women. Cholesterol-containing gallstones are the predominant form of gallstones, and therefore supersaturation of bile with cholesterol is a prerequisite for gallstone formation. ABCB4 mutations may be involved in the pathogenesis of cholesterol cholelithiasis.

[0063] Drug-induced cholestasis Inhibition of BSEP function by drugs is an important mechanism of drug-induced cholestasis, leading to hepatic accumulation of bile salts and subsequent hepatocellular injury. Several drugs are involved in BSEP inhibition. Most of these agents, such as rifampicin, cyclosporine, glibenclamide, or troglitazone, directly cis-inhibit ATP-dependent taurocholate transport in a competitive manner, whereas estrogen and progesterone metabolites indirectly trans-inhibit BSEP after secretion into the bile canaliculi by Mrp2. Alternatively, drug-mediated stimulation of MRP2 can promote cholestasis or cholestatic liver disease by altering bile composition.

[0064] Total Parenteral Nutrition-Associated Cholestasis TPNAC represents one of the most serious clinical scenarios in which cholestatic or cholestatic liver disease develops rapidly and is highly associated with early mortality. Infants, usually premature and who have undergone intestinal resection, who depend on TPN for growth, frequently develop cholestatic or cholestatic liver disease that progresses rapidly to fibrosis, cirrhosis, and portal hypertension, usually before 6 months of age. The extent of cholestatic or cholestatic liver disease and chances of survival in these infants are related to the number of septic episodes, probably initiated by repeated bacterial translocation across the intestinal mucosa. Although there is also a cholestatic effect from intravenous preparations, septic mediators are most likely to contribute to the alterations in liver function in these infants.

[0065] Total Parenteral Nutrition-Associated Cholestasis TPNAC represents one of the most serious clinical scenarios in which cholestatic or cholestatic liver disease develops rapidly and is highly associated with early mortality. Infants, usually premature and who have undergone intestinal resection, who depend on TPN for growth, frequently develop cholestatic or cholestatic liver disease that progresses rapidly to fibrosis, cirrhosis, and portal hypertension, usually before 6 months of age. The extent of cholestatic or cholestatic liver disease and chances of survival in these infants are related to the number of septic episodes, probably initiated by repeated bacterial translocation across the intestinal mucosa. Although there is also a cholestatic effect from intravenous preparations, septic mediators are most likely to contribute to altered liver function in these infants.

[0066] Alagille Syndrome (ALGS) Alagille syndrome is a genetic disease that affects the liver and other organs. ALGS is also known as syndromic intrahepatic cholangiopancreas or arteriohepatic dysplasia. ALGS is a rare genetic disorder in which bile ducts are abnormally narrow, malformed, and reduced in number, leading to bile accumulation in the liver and ultimately progressive liver disease. ALGS is autosomal dominant, caused by mutations in JAG1 (>90% of cases) or NOTCH2. The estimated incidence of ALGS is 1 in 30,000 or 50,000 in the United States and Europe. In patients with ALGS, multiple organ systems can be affected by the mutations, including the liver, heart, kidneys, and central nervous system. The accumulation of bile acids prevents the liver from functioning properly to clear waste products from the bloodstream, resulting in progressive liver disease that ultimately requires a liver transplant in 15% to 47% of patients. Signs and symptoms resulting from liver damage in ALGS can include jaundice, pruritus, and xanthomas, as well as reduced growth. The pruritus experienced by people with ALGS is one of the most severe manifestations of chronic liver disease and is present in most affected children by the third year of life.

[0067] ALGS often presents during infancy (e.g., 6-18 months) to early childhood (e.g., 3-5 years) and may stabilize after age 10. Symptoms may include chronic progressive cholestasis, cholangiocele, jaundice, pruritus, xanthomas, congenital heart defects, paucity of intrahepatic bile ducts, poor linear growth, hormone resistance, posterior embryotoxon, Axenfeld anomaly, retinitis pigmentosa, pupillary abnormalities, heart murmurs, atrial septal defect, ventricular septal defect, patent ductus arteriosus, and tetralogy of Fallot. Individuals diagnosed with Alagille syndrome have been treated with ursodiol, hydroxyzine, cholestyramine, rifampicin, and phenobarbital. Due to a decreased ability to absorb fat-soluble vitamins, individuals with Alagille syndrome are additionally given high doses of multivitamins.

[0068] biliary atresia Biliary atresia is a life-threatening condition in infants who do not have normal openings in the bile ducts inside or outside the liver. In biliary atresia, bile becomes trapped, builds up, and damages the liver. The damage leads to scarring, loss of liver tissue, and cirrhosis. Without treatment, the liver will eventually fail and the infant will require a liver transplant to stay alive. The two types of biliary atresia are fetal and perinatal. Fetal biliary atresia is present while the baby is in the womb. Perinatal biliary atresia is more common and does not become evident until 2-4 weeks after birth.

[0069] Biliary atresia after Kasai operation Biliary atresia is treated with a surgical procedure called the Kasai procedure or with a liver transplant. The Kasai procedure is usually the first method of treatment for biliary atresia. During the Kasai procedure, a pediatric surgeon removes the infant's damaged bile ducts and replaces them with uplifted loops of intestine. Although the Kasai procedure can restore biliary flow and correct many problems caused by biliary atresia, the surgery does not cure biliary atresia. If the Kasai procedure is unsuccessful, the infant will usually require a liver transplant within one to two years. Even after successful surgery, most infants with biliary atresia will slowly develop cirrhosis over the years and require a liver transplant by adulthood. Possible complications after the Kasai procedure include ascites, bacterial cholangitis, portal hypertension, and pruritus.

[0070] Biliary atresia after liver transplantation Once complete, liver transplantation is the only option. Although liver transplantation is generally successful in treating biliary atresia, liver transplantation can lead to complications, such as organ rejection, and there are also cases where a donor liver is no longer available. Additionally, in some patients, liver transplantation may not be successful in curing biliary atresia.

[0071] xanthomas Xanthomas are skin conditions associated with cholestatic liver disease in which certain fats accumulate under the skin's surface. Cholestasis causes several disturbances in lipid metabolism, leading to the formation of abnormal lipid particles in the blood called lipoprotein X. Lipoprotein X is formed by the reflux of bile lipids from the liver into the blood and does not bind to the LDL receptor to deliver cholesterol to cells throughout the body like normal LDL does. Lipoprotein X increases hepatic cholesterol production five-fold and blocks the liver's normal removal of lipoprotein particles from the blood.

[0072] General definition Unless otherwise defined, 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.

[0073] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural references 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 that will become apparent to those skilled in the art upon reading this disclosure.

[0074] The term "baseline" or "pre-administration baseline" as used herein refers to information collected at the beginning of a study or a known initial value used for comparison with later data. A baseline is an initial measurement of a measurable condition taken at an early time point and used to compare over time to look for changes in the measurable condition. For example, a patient's serum bile acid concentration before drug administration (baseline) and after drug administration. A baseline is an observation or value that represents a normal or starting level of a measurable quality that is used for comparison with a value that represents a response to an intervention or environmental stimulus. A baseline is time "zero" before a study participant receives an experimental drug or intervention, or a negative control. For example, "baseline" can refer in some instances to 1) the state of a measurable quantity immediately prior to the start of a clinical trial, or 2) the state of a measurable quantity immediately prior to changing the dosage level or composition administered to a patient from a first dosage level or composition to a second dosage level or composition.

[0075] As used herein, the terms "level" and "concentration" are used interchangeably. For example, "high serum bilirubin level" can be replaced with "high serum bilirubin concentration."

[0076] As used herein, the term "normalized" or "normal range" refers to an age-specific value that is within a range applicable to healthy individuals (i.e., a normal or normalized value). For example, the phrase "serum bilirubin concentration was normalized within 3 weeks" means that the serum bilirubin concentration was within a range known in the art to be within a healthy individual's concentration (i.e., within a normal range, e.g., not an elevated range) within 3 weeks. In various embodiments, the normalized serum bilirubin concentration is from about 0.1 mg / dL to about 1.2 mg / dL. In various embodiments, the normalized serum bile acid concentration is from about 0 μmol / L to about 25 μmol / L.

[0077] As used herein, the terms "ITCHRO(OBS)" and "ITCHRO" (or "ItchRO(Pt)") are used interchangeably, with the proviso that the ITCHRO(OBS) scale is used to measure the severity of pruritus in children under 18 years of age, and the ITCHRO scale is used to measure the severity of pruritus in adults 18 years of age or older. Thus, when the ITCHRO(OBS) scale is referred to in relation to an adult patient, the ITCHRO scale is the scale that is prescribed. Similarly, when the ITCHRO scale is referred to in relation to a pediatric patient, the ITCHRO(OBS) scale is usually the scale that is prescribed (though some older children are permitted to report their scores as ITCHRO scores). The ITCHRO(OBS) scale ranges from 0 to 4, and the ITCHRO scale ranges from 0 to 10.

[0078] The term "bile acid(s)" as used herein includes steroid acids (and / or their carboxylate anions) found in the bile of animals (e.g., humans), and their salts, including, by way of non-limiting example, cholic acid, cholate, deoxycholic acid, deoxycholate, hyodeoxycholic acid, hyodeoxycholate, glycocholic acid, glycocholate, taurocholic acid, taurocholate, chenodeoxycholic acid, ursodeoxycholic acid, ursodiol, tauroursodeoxycholic acid, glycoursodeoxycholic acid, 7-B-methylcholic acid, methyllithocholic acid, chenodeoxycholate, lithocholic acid, lithocholate, and the like. Taurocholic acid and / or taurocholate are referred to herein as TCA. Any reference to a bile acid as used herein includes reference to a bile acid, one and only one bile acid, one or more bile acids, or at least one bile acid. Thus, the terms "bile acid", "bile salt", "bile acid / salt", "bile acids", "bile salts", and "bile acid / salt" are used interchangeably herein unless otherwise indicated. Any reference to a bile acid as used herein includes a reference to a bile acid or its salt. Additionally, pharma- ceutically acceptable bile acid esters are optionally utilized as "bile acids" as described herein, e.g., bile acids / salts conjugated to an amino acid (e.g., glycine or taurine). Other bile acid esters include, e.g., 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 "bile acid" includes cholic acid conjugated to either glycine or taurine: glycocholic acid and taurocholic acid (and their salts), respectively. Any reference to a bile acid as used herein includes a reference to the same compound, whether naturally or synthetically prepared. Furthermore, any singular reference to a component (bile acid or otherwise) as used herein should be understood to include a reference to one and only one, one or more, or at least one of such components.Similarly, a plurality of references to elements as used herein includes a reference to one and only one, one or more, or at least one of such elements unless specifically stated otherwise.

[0079] The terms "subject," "patient," "participant," or "individual" are used interchangeably herein and refer to mammals and non-mammals, e.g., suffering from a disorder described herein. Examples of mammals include, but are not limited to, any member of the class Mammalia: humans, non-human primates such as chimpanzees, and other ape and monkey species; domestic animals such as cows, horses, sheep, goats, and pigs; domestic animals such as rabbits, dogs, and cats; and 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.

[0080] As used herein, the term "about" includes any value within 10% of the stated value.

[0081] The term "composition" as used herein includes disclosure of both compositions and compositions administered in the manner described herein. Furthermore, in some embodiments, the compositions of the invention are or include a "formulation," an oral dosage form, or a rectal dosage form, as described herein.

[0082] The terms "treat", "treating" or "treatment" and other grammatical equivalents used herein include alleviating, suppressing or relieving symptoms, reducing or suppressing the severity of a disease or condition, reducing the occurrence of a disease or condition, reducing or suppressing the recurrence of a disease or condition, delaying the onset of a disease or condition, delaying the recurrence of a disease or condition, ameliorating or ameliorating a disease or condition, ameliorating the underlying cause of symptoms, inhibiting a disease or condition, e.g., arresting the progression of a disease or condition, relieving a disease or condition, causing regression of a disease or condition, alleviating a condition caused by a disease or condition, or halting the symptoms of a disease or condition. These terms further include achieving a therapeutic benefit. A therapeutic benefit refers to the eradication or amelioration of the underlying disease being treated and / or the eradication or amelioration of one or more physiological symptoms associated with the underlying disease such that an improvement is observed in the patient.

[0083] The term "effective amount" or "therapeutically effective amount" as used herein refers to a sufficient amount of at least one agent (e.g., a therapeutically active agent) being administered to achieve a desired result in a subject or individual, such as, for example, alleviating to some extent one or more symptoms of the disease or condition being treated. In certain instances, the result is a reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired change in a biological system. In certain instances, an "effective amount" for therapeutic use is the amount of a composition comprising an agent as described herein that is required to provide a clinically significant alleviation of a disease. The appropriate "effective" amount in any individual case is determined using any suitable technique, such as a dose escalation study. In some embodiments, a "therapeutically effective amount" or "effective amount" of ASBTI refers to an amount of ASBTI sufficient to treat cholestasis or cholestatic liver disease in a subject or individual.

[0084] The terms "administer", "administering", "administration" and the like used herein refer to the methods that can be used to allow delivery of an agent or composition to the site where biological action is desired. These methods include, but are not limited to, oral route, intraduodenal route, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion), topical administration and rectal administration. Administration techniques that are optionally used with the agents and methods described herein can be found, for example, in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., 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.

[0085] The term "ASBT inhibitor" refers to a compound that inhibits apical sodium-dependent bile acid transport or any restorable bile salt transport. The term apical sodium-dependent bile acid transporter (ASBT) is used interchangeably with the term ileal bile acid transporter (IBAT).

[0086] The phrase "pharmacologically acceptable" when used in connection with the compositions of the present invention refers to molecular entities and other components of such compositions that are physiologically tolerated and do not normally produce adverse reactions when administered to a mammal (e.g., a human). Preferably, as used herein, the term "pharmacologically acceptable" means approved by a federal or state government regulatory agency or listed in the United States Pharmacopeia or other generally recognized pharmacopoeias for use in mammals, more specifically, in humans.

[0087] In various embodiments, pharma- ceutically acceptable salts described herein include, by way of non-limiting example, nitrate, chloride, bromide, phosphate, sulfate, acetate, hexafluorophosphate, citrate, gluconate, benzoate, propionate, butyrate, salicylate, maleate, laurate, malate, fumarate, succinate, tartrate, amsonate, pamoate, p-toluenesulfonate, mesylate, etc. Additionally, pharma-ceutically acceptable salts include, by way of non-limiting example, alkaline earth metal salts (e.g., calcium or magnesium), alkali metal salts (e.g., sodium or potassium), ammonium salts, etc.

[0088] As used herein, the term "fasted state" is defined as a state in which a subject has completely assimilated and digested their last meal, and the subject's insulin level is at a low or baseline level. In some embodiments, fasted state is defined as a state in which no food has been consumed for at least 4 hours for subjects aged 18 years or older. In some embodiments, fasted state is defined as a state in which no food has been consumed for at least 2 hours for pediatric subjects. In some embodiments, fasted state is defined as a state about 30 minutes before a meal.

[0089] As used herein, a fasting patient is defined as a patient who has not eaten any food, i.e., fasting for at least 4 hours (for subjects aged 18 years or older) or at least 2 hours (for pediatric subjects) prior to administration of ASBTI and at least 30 minutes following administration of ASBTI. ASBTI is optionally administered with water during the fasting period, which may be consumed ad libitum.

[0090] As used herein, tolerability refers to the degree to which the adverse effects of a drug can be tolerated by a patient.In certain embodiments, gastrointestinal (GI) tolerability refers to the degree to which a patient tolerates GI adverse effects.In some embodiments, improving GI tolerability includes reducing, minimizing, preventing, improving, or eliminating one or more GI adverse effects.

[0091] bile acids Bile contains water, electrolytes, and numerous organic molecules (such as bile acids, cholesterol, phospholipids, and bilirubin). Bile is secreted from the liver and stored in the gallbladder, and upon contraction of the gallbladder due to ingestion of a fatty meal, bile passes through the bile duct into the intestine. Bile acids / salts are important for the digestion and absorption of fats and fat-soluble vitamins in the small intestine. Adults produce 400-800 mL of bile per day. Bile secretion can be thought of as occurring in two steps. First, hepatocytes secrete bile into the bile canaliculi, from which it flows into the bile ducts; this hepatic bile contains large amounts of bile acids, cholesterol, and other organic molecules. Second, as the bile flows through the bile ducts, it is modified by the addition of watery bicarbonate-rich secretions from the bile duct epithelial cells. Bile is typically concentrated five-fold during its storage in the gallbladder.

[0092] Bile flow is lowest during fasting, with most of it being directed to the gallbladder for concentration. When the chyme of an ingested meal enters the small intestine, acid and partially digested fats and proteins stimulate the secretion of cholecystokinin and secretin, both of which are important for bile secretion and flow. Cholecystokinin (cholecyst = gallbladder and kinin = motor) is a hormone that stimulates contraction of the gallbladder and common bile duct, resulting in the delivery of bile to the intestine. The most powerful stimulus for the release of cholecystokinin is the presence of fat in the duodenum. Secretin is a hormone secreted in response to acid in the duodenum that stimulates cholangiocytes to secrete bicarbonate and water, thereby increasing the amount of bile and increasing its outflow to the intestine.

[0093] Bile acids / salts are derivatives of cholesterol. Cholesterol, either ingested as part of the diet or derived from synthesis in the liver, is converted to bile acids / salts in hepatocytes. Examples of such bile acids / salts include cholic acid and chenodeoxycholic acid, which are then conjugated to amino acids (such as glycine or taurine) to produce conjugated forms that are actively secreted into the bile canaliculi. The most abundant bile salts in humans are cholate and deoxycholate, which are usually conjugated with either glycine or taurine to produce glycocholate or taurocholate, respectively.

[0094] Free cholesterol is practically insoluble in aqueous solutions, but is soluble in bile due to the presence of bile acids / salts and lipids. Hepatic synthesis of bile acids / salts accounts for the majority of cholesterol breakdown in the body. In humans, approximately 500 mg of cholesterol is converted to bile acids / salts and excreted in bile each day. Thus, secretion into bile is the major route for cholesterol elimination. Although large amounts of bile acids / salts are secreted into the intestine each day, relatively small amounts are lost from the body. This is because approximately 95% of the bile acids / salts delivered to the duodenum are absorbed back into the blood in the ileum by a process known as the "enterohepatic circulation".

[0095] Venous blood from the ileum goes straight into the portal vein and thus passes through the hepatic sinusoids. Hepatocytes extract bile acids / salts from the sinusoidal blood very efficiently, with very little escaping from a healthy liver into the systemic circulation. The bile acids / salts are then transported across the hepatocytes and re-secreted into the bile canaliculi. The net effect of this enterohepatic circulation is that each bile salt molecule is reused approximately 20 times, often 2-3 times during one digestive stage. Bile biosynthesis represents the major metabolic fate of cholesterol, accounting for just over half of the approximately 800 mg / day of cholesterol consumed by the average adult in metabolic processes. In comparison, the biosynthesis of steroid hormones consumes only about 50 mg of cholesterol per day. Much more than 400 mg of bile salts per day are required 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 the dietary lipids they emulsify at the lower end of the small intestine. They are separated from dietary lipids and returned to the liver for reuse, thus allowing 20-30 g of bile salts to be secreted into the small intestine each day.

[0096] Bile acids / salts are amphiphilic, the cholesterol-derived moieties contain both hydrophobic (fat-soluble) and polar (hydrophilic) moieties, whereas amino acid conjugates are generally polar and hydrophilic. This amphiphilicity allows bile acids / salts to fulfill two important functions: emulsification of lipid aggregates and solubilization and transport of lipids to aqueous environments. Bile acids / salts have a detergent action on particles of dietary fat, breaking down or emulsifying fat globules. Emulsification is important because it greatly increases the surface area of ​​fat available for digestion by lipases that cannot access the interior of the lipid droplets. In addition, bile acids / salts are lipid carriers and can solubilize many lipids by forming micelles, which are important for the transport and absorption of fat-soluble vitamins.

[0097] The term "non-systemic" or "minimally absorbed" as used herein refers to low systemic bioavailability and / or absorption of an administered compound. In some embodiments, a non-systemic compound is a compound that is not substantially systemically absorbed. In some embodiments, the ASBTI compositions described herein deliver ASBTI to the distal ileum, colon, and / or rectum and not to the system (e.g., a significant portion of ASBTI is not systemically absorbed). In some embodiments, the systemic absorption of the 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% (wt% or mol%) of the dosage. In some embodiments, the systemic absorption of the non-systemic compound is less than ten percent (<10%) of the dosage. In some embodiments, the systemic absorption of the non-systemic compound is less than fifteen percent (<15%) of the dosage. In some embodiments, the systemic absorption of the non-systemic compound is less than 25% (<25%) of the dosage. In another approach, the non-systemic ASBTI is a compound that has a lower systemic bioavailability compared to the systemic bioavailability of the systemic ASBTI (e.g., compounds 100A, 100C). In some embodiments, the bioavailability of the non-systemic ASBTI described herein is <30%, <40%, <50%, <60%, or <70% of the bioavailability of the systemic ASBTI (e.g., compounds 100A, 100C).

[0098] In another alternative approach, the compositions described herein are formulated to deliver less than 10% of the administered dose of ASBTI to the system. In some embodiments, the compositions described herein are formulated to deliver less than 20% of the administered dose of ASBTI to the system. In some embodiments, the compositions described herein are formulated to deliver less than 30% of the administered dose of ASBTI to the system. In some embodiments, the compositions described herein are formulated to deliver less than 40% of the administered dose of ASBTI to the system. In some embodiments, the compositions described herein are formulated to deliver less than 50% of the administered dose of ASBTI to the system. In some embodiments, the compositions described herein are formulated to deliver less than 60% of the administered dose of ASBTI to the system. In some embodiments, the compositions described herein are formulated to deliver less than 70% of the administered dose of ASBTI to the system. In some embodiments, systemic absorption is determined in any suitable manner, including total circulating amount, amount cleared after administration, etc.

[0099] ASBT inhibitors In various embodiments of the method of the present invention, an ASBT inhibitor is administered to the subject. The ASBT inhibitor (ASBTI) reduces or inhibits the recycling of bile acids in the distal gastrointestinal tract (GI), including the distal ileum, colon and / or rectum. Inhibition of apical sodium-dependent bile acid transport disrupts the enterohepatic circulation of bile acids, resulting in more bile acids being excreted in feces, leading to reduced systemic bile acid levels, thereby reducing bile acid-mediated liver damage and associated effects and complications. In certain embodiments, the ASBTI is systemically absorbed. In certain embodiments, the ASBTI is not systemically absorbed. In some embodiments, the ASBTI described herein is modified or substituted to be non-systemic.

[0100] 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 exist in optically active or racemic forms. It is understood that the compounds of the present invention encompass racemic, optically active, regioisomeric and stereoisomeric forms, or combinations thereof, that have the therapeutically useful properties described herein. Preparation of optically active forms is accomplished in any suitable manner, including, by way of non-limiting examples, by resolution of racemates by recrystallization techniques, by synthesis from optically active starting materials, by chiral synthesis, or by chromatographic separation using chiral stationary phases. In some embodiments, a mixture of one or more isomers is utilized as a therapeutic compound described herein. In certain embodiments, the compounds described herein include one or more chiral centers. These compounds are prepared by any means, including enantioselective synthesis and / or separation of mixtures of enantiomers and / or diastereomers. Resolution of the compounds and their isomers is accomplished by any means, including, by way of non-limiting examples, chemical processes, enzymatic processes, fractional crystallization, distillation, chromatography, and the like.

[0101] In some embodiments, the ASBTI is [ka] It is.

[0102] In some embodiments, the ASBTI is [ka] (maralixibat chloride, LUM-001, SHP625, ropixibat chloride) or an alternative pharma- ceutically acceptable salt thereof.

[0103] In some embodiments, the ASBTI is [ka] (volixibat, (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-5-yl)-phenyl]-ureido}-3,5-dihydroxy-tetrahydro-pyran-2-ylmethyl) hydrogen sulfate), or a pharma- ceutically acceptable salt thereof.

[0104] In some embodiments, the ASBTI is [ka] (LUM-002; SHP626; SAR548304; vorixibat potassium), or an alternative pharma- ceutically acceptable salt thereof.

[0105] In various embodiments, the ASBTI is [ka] (odevixibat; AZD8294; WH010706; 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-benzothiadiazepine), or a pharma- ceutically acceptable salt thereof.

[0106] In some embodiments, the ASBTI is [ka] (elobixibat; 2-[[(2R)-2-[[2-[(3,3-dibutyl-7-methylsulfanyl-1,1-dioxo-5-phenyl-2,4-dihydro-1λ6,5-benzothiazepin-8-yl)oxy]acetyl]amino]-2-phenylacetyl]amino]acetic acid), or a pharma- ceutically acceptable salt thereof.

[0107] In some embodiments, the ASBTI is [ka] (GSK2330672; linerixibat; 3-((((3R,5R)-3-butyl-3-ethyl-7-(methyloxy)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl)methyl)amino)pentanedioic acid), or a pharma- ceutically acceptable salt thereof.

[0108] In some embodiments, the ASBTI used in the methods or compositions of the invention is maralixibat (e.g., as maralixibat chloride), vorixibat (e.g., as vorixibat potassium), or odevixibat (A4250), or a pharmaceutically acceptable salt thereof.

[0109] In some embodiments, the ASBTI used in the methods or compositions of the invention is maralixibat, or a pharma- ceutically acceptable salt thereof.

[0110] In some embodiments, the ASBTI used in the methods or compositions of the invention is vorixibat, or a pharma- ceutically acceptable salt thereof.

[0111] In some embodiments, the ASBTI used in the methods or compositions of the invention is odevixibat, or a pharma- ceutically acceptable salt thereof.

[0112] In some embodiments, the ASBTI used in the methods or compositions of the invention is elobixibat, or a pharma- ceutically acceptable salt thereof.

[0113] In some embodiments, the ASBTI used in the methods or compositions of the invention is GSK2330672, or a pharma- ceutically acceptable salt thereof.

[0114] In some embodiments, the ASBTI can include a mixture of different ASBTIs; for example, the ASBTI can be a composition that includes maralixibat, vorixibat, odebixibat, GSK2330672, elobixibat, or various combinations thereof.

[0115] Methods for Treating Cholestasis and Minimizing Adverse Gastrointestinal Effects - Patent application Provided herein is a method for treating cholestasis in a subject with liver disease. The method includes administering an apical sodium-dependent bile acid transporter inhibitor (ASBTI) to a subject in need of treatment. The ASBTI is maralixibat or vorixibat, or a pharma- ceutically acceptable salt thereof. The ASBTI is administered in an amount of about 100 μg / kg / day to about 1400 μg / kg / day.

[0116] Provided herein is a method for treating cholestatic liver disease in a subject in need thereof, comprising administering a therapeutically effective amount of ASBTI to the subject prior to ingestion of food, wherein the subject experiences a reduction in the frequency and / or severity of one or more side effects associated with administration of ASBTI. The method comprises administering ASBTI to the subject in need of treatment prior to ingestion of food. In certain embodiments, the ASBTI is maralixibat or vorixibat, or a pharma- ceutically acceptable salt thereof. The ASBTI is administered in an amount of about 100 μg / kg / day to about 1400 μg / kg / day.

[0117] Provided herein is a method for reducing, minimizing, preventing, improving, or eliminating one or more side effects associated with the administration of ASBTI in a subject in need thereof, comprising administering a therapeutically effective amount of ASBTI to the subject before ingestion of food.In certain embodiments, one or more side effects associated with the administration of ASBTI are reduced, minimized, prevented, improved, or eliminated, compared to the side effects when ASBTI is administered after ingestion of food, simultaneously with food, or mixed with food.

[0118] In certain embodiments, the one or more side effects are diarrhea, loose stools, nausea (retching), gastrointestinal pain, abdominal pain, cramps, anorectal discomfort, or a combination thereof.

[0119] In certain embodiments, ASBTI is administered to subject in fasting state.In certain embodiments, 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 before eating food.In certain embodiments, ASBTI is administered immediately before eating food.

[0120] In various embodiments, the liver disease is cholestatic liver disease.In some embodiments, the liver disease is PFIC, ALGS, PSC, biliary atresia, intrahepatic cholestasis of pregnancy, PBC, any of the above-mentioned cholestatic liver diseases, or various combinations thereof.

[0121] In certain embodiments, the cholestatic liver disease is selected from the group consisting of progressive familial intrahepatic cholestasis (PFIC), PFIC type 1, PFIC type 2, PFIC type 3, Alagille syndrome, Dubin-Johnson syndrome, biliary atresia, post-Kasai biliary atresia, post-liver transplant biliary atresia, post-liver transplant cholestasis, post-liver transplant associated liver disease, intestinal failure associated liver disease, and the like. The biliary liver disease is a pediatric type of liver disease, bile acid-mediated liver injury, primary sclerosing cholangitis in children, MRP2 deficiency syndrome, neonatal sclerosing cholangitis, obstructive cholestasis in children, nonobstructive cholestasis in children, extrahepatic cholestasis in children, intrahepatic cholestasis in children, primary intrahepatic cholestasis in children, secondary intrahepatic cholestasis in children, benign recurrent intrahepatic cholestasis (BRIC), BRIP type 1, BRIC type 2, BRIC type 3, total parenteral nutrition-associated cholestasis, paraneoplastic cholestasis, Stauffer syndrome, drug-associated cholestasis, infection-associated cholestasis, or cholelithiasis. In some embodiments, the biliary liver disease is a pediatric type of liver disease. In some embodiments, the subject has intrahepatic cholestasis of pregnancy (ICP).

[0122] In certain embodiments, the cholestatic liver disease is characterized by one or more symptoms selected from jaundice, pruritus, cirrhosis, hypercholesterolemia, neonatal respiratory distress syndrome, pneumonia, increased serum concentrations of bile acids, increased hepatic concentrations of bile acids, increased serum concentrations of bilirubin, hepatocellular injury, hepatic scarring, liver failure, hepatomegaly, xanthomas, malabsorption, splenomegaly, diarrhea, pancreatitis, hepatocellular necrosis, giant cell formation, hepatocellular carcinoma, gastrointestinal bleeding, portal hypertension, hearing loss, fatigue, loss of appetite, anorexia, characteristic odor, dark urine, light stools, steatorrhea, failure to thrive, and / or renal failure.

[0123] In various embodiments, the liver disease is PFIC2, and the subject has a non-truncating mutation in the ABCB11 gene. In various embodiments, the non-truncating mutation in the ABCB11 gene is a missense mutation. In various embodiments, the missense mutation can be selected from one of the mutations listed in Byrne, et al., "Missense Mutations and Single Nucleotide Polymorphisms in ABCB11 Impair Bile Salt Export Pump Processing and Function or Disrupt Pre-Messanger RNA Splicing," Hepatology, 49:553-567 (2009), which is incorporated herein by reference in its entirety for all purposes.

[0124] In various embodiments, the subject has a condition related to, caused by, or partially caused by BSEP deficiency.In certain embodiments, the condition related to, caused by, or partially caused by BSEP deficiency is neonatal hepatitis, primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), PFIC2, benign recurrent intrahepatic cholestasis (BRIC), intrahepatic cholestasis of pregnancy (ICP), drug-induced cholestasis, oral contraceptive-induced cholestasis, biliary atresia, or combinations thereof.

[0125] In various embodiments, the patient is a pediatric patient under the age of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18. In certain embodiments, the pediatric subject is a newborn, a premature infant, an infant, a toddler, a preschooler, a school-age child, a prepubescent child, a postpubescent child, an adolescent, or a teenager under the age of 18. In some embodiments, the pediatric subject is a newborn, a premature infant, an infant, a toddler, a preschooler, or a school-age child. In some embodiments, the pediatric subject is a newborn, a premature infant, an infant, a toddler, or a preschooler. In some embodiments, the pediatric subject is a newborn, a premature infant, an infant, or a toddler. In some embodiments, the pediatric subject is a newborn, a premature infant, or an infant. In some embodiments, the pediatric subject is a newborn. In some embodiments, the pediatric subject is an infant. In some embodiments, the pediatric subject is a toddler. In various embodiments, the pediatric patient has PFIC2, PFIC1, or ALGS. In some embodiments, the patient is an adult over 18, 20, 30, 40, 50, 60, or 70 years of age. In some patients, the adult patient has PSC. In some embodiments, the pediatric patient has a pediatric cholestatic condition that results in less than normal growth, height, or weight.

[0126] In certain embodiments, the method of the present invention comprises non-systemic administration of a therapeutically effective amount of ASBTI. In certain embodiments, the method comprises contacting the gastrointestinal tract, including the distal ileum and / or colon and / or rectum, of an individual in need thereof with ASBTI. In various embodiments, the method of the present invention results in a reduction in bile acids in intraenterocytes, or a reduction in damage to liver cells or intestinal structures caused by cholestasis or cholestatic liver disease.

[0127] 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.

[0128] In various embodiments, the methods of the invention include reducing damage to liver cells or intestinal structures or cells due to cholestasis or cholestatic liver disease, comprising administering a therapeutically effective amount of ASBTI. In certain embodiments, the methods of the invention include reducing bile acids / salts in intestinal cells by administering a therapeutically effective amount of ASBTI to an individual in need thereof.

[0129] In some embodiments, the method of the present invention provides inhibition of bile salt recycling by administering any of the compounds described herein to an individual. In some embodiments, the ASBTI described herein is systemically absorbed upon administration. In some embodiments, the ASBTI described herein is not systemically absorbed. In some embodiments, the ASBTI described herein is orally administered to an individual. In some embodiments, the ASBTI described herein is delivered to and / or released in the distal ileum of an individual.

[0130] In various embodiments, contacting an individual's distal ileum with an ASBTI (e.g., any ASBTI described herein) inhibits bile acid reuptake and increases the concentration of bile acids / salts in the vicinity of L-cells in the distal ileum and / or colon and / or rectum, thereby reducing bile acids in enterocytes, lowering serum and / or liver bile acid levels, reducing overall serum bile acid load, and / or reducing damage to ileal structure caused by cholestasis or cholestatic liver disease. Without being limited to any particular theory, reducing serum and / or liver bile acid levels ameliorates hypercholesterolemia and / or cholestatic disease.

[0131] Administration of the compounds described herein can be accomplished in any suitable manner, including, by way of non-limiting examples, oral, enteric, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal routes of administration. Any compound or composition described herein can be administered in a suitable manner or formulation for treating a neonate or infant. Any compound or composition described herein can be administered in an oral formulation (e.g., solid or liquid) for treating a neonate or infant. Any compound or composition described herein can be administered before, with, or after the ingestion of food.

[0132] In certain embodiments, the compound or composition comprising the compound described herein is administered for preventive and / or therapeutic treatment.In therapeutic application, the composition is administered to an individual who is already suffering from a disease or condition in an amount sufficient to cure or at least partially prevent the symptoms of the disease or condition.In various cases, the amount effective for this use depends on the severity and course of the disease or condition, previous treatment, individual's health condition, weight, and response to drugs, and the judgment of the treating physician.

[0133] In preventive applications, the compounds described herein or compositions containing the compounds may be administered to individuals susceptible to or otherwise at risk of a particular disease, disorder or condition.In certain embodiments of this use, the exact amount of compound administered will depend on the individual's health status, weight, etc.Furthermore, in some cases, when the compounds or compositions described herein are administered to an individual, the effective amount for this use will depend on the severity and course of the disease, disorder or condition, previous treatments, the individual's health status and response to the drug, and the judgment of the treating physician.

[0134] In certain embodiments of the methods of the present invention, if an individual's condition does not improve following administration of a selected dose of a compound or composition described herein, at the physician's discretion, a compound or composition described herein is optionally administered chronically, i.e., administered for an extended period of time, including over the course of an individual's life, to ameliorate or otherwise control or limit the symptoms of the individual's disorder, disease, or condition.

[0135] In certain embodiments of the method of the present invention, the effective amount of a given agent varies depending on one or more of several factors, such as the specific compound, the disease or condition and its severity, the identity (e.g., weight) of the subject or host requiring treatment, and is determined according to the specific circumstances surrounding the case, such as the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated. In some embodiments, the dose administered comprises a dose up to the maximum tolerated dose. In some embodiments, the dose administered comprises a dose up to the maximum tolerated dose by a newborn or infant.

[0136] In various embodiments of the method of the present invention, the desired dose is conveniently provided in a single dose or in divided doses administered simultaneously (or over a short period of time) or at appropriate intervals, for example, as two, three, four or more subdoses 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 once a week. In some embodiments, the total single dose of ASBTI is within the ranges described below.

[0137] In various embodiments of the methods of the invention, if the patient's condition improves, at the discretion of the physician, ASBTI is optionally given continuously; alternatively, the dose of the administered drug is temporarily reduced or temporarily suspended for a specified period of time (i.e., a "drug holiday"). The length of the drug holiday optionally varies between 2 days and 1 year, and includes, 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 reductions during drug holidays include 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 set forth below.

[0138] Once improvement of the patient's condition occurs, a maintenance dose is administered as necessary.Then, the dosage or frequency of administration, or both, is reduced as a function of symptoms to a level at which the improved disease, disorder or condition is maintained.In some embodiments, the patient requires long-term intermittent treatment upon recurrence of any symptoms.

[0139] In certain instances, there are many variables with respect to individual treatment regimens, and significant deviations from these recommendations are contemplated within the ranges described herein. The dosages described herein are optionally varied depending on many variables, including, but not limited to, the activity of the compound used, the disease or condition being treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.

[0140] The toxicity and therapeutic efficacy of such treatment regimens are discussed in detail below. 50 (lethal dose for 50% of the population) and ED 50The LD50 is optionally determined by pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, determining the 50% therapeutically effective dose in the population. The dose ratio between toxic and therapeutic effects is the therapeutic index, and the LD 50 and ED 50 The therapeutic index can be expressed as a ratio of ED to ED. Compounds that exhibit high therapeutic indices are preferred. In certain embodiments, data obtained from cell culture assays and animal studies are used in formulating a range of dosages for use in humans. In certain embodiments, dosages of the compounds described herein are administered at ED 100 mg / kg with minimal toxicity. 50 The dosage optionally varies within this range depending upon the dosage form employed and the route of administration utilized.

[0141] In certain embodiments, the composition used or administered includes an absorption inhibitor, a carrier, and one or more of a cholesterol absorption inhibitor, an enteroendocrine peptide, a peptidase inhibitor, a spreading agent, and a wetting agent.

[0142] In some embodiments of the method of the present invention, the composition used to prepare an oral dosage form or orally administered comprises an absorption inhibitor, an orally suitable carrier, an optional cholesterol absorption inhibitor, an optional enteroendocrine peptide, an optional peptidase inhibitor, an optional spreading agent, and an optional wetting agent. In certain embodiments, the orally administered composition induces an anorectal response. In certain embodiments, the anorectal response is an increase in the secretion of one or more enteroendocrine secretions by cells in the colon and / or rectum (e.g., L cells in the epithelial layer of the colon, ileum, rectum, or combinations thereof). In some embodiments, the anorectal response lasts 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 lasts for between 24 hours and 48 hours, while in other embodiments, the anorectal reaction lasts for a period of more than 48 hours.

[0143] Dosage In various embodiments, the ASBTI is maralixibat or vorixibat, or a pharma- ceutically acceptable salt thereof.

[0144] In various embodiments, the ASBTI is administered to the subject prior to ingestion of food.

[0145] In various embodiments, the efficacy and safety of administering ASBTI to patients is monitored by measuring the serum level of 7α-hydroxy-4-cholesten-3-one (7αC4), sBA concentration, the ratio of 7αC4 to sBA (7αC4:sBA), serum conjugated bilirubin concentration, serum autotaxin concentration, serum bilirubin concentration, serum total cholesterol concentration, serum LDL-C concentration, serum ALT concentration, serum AST concentration, or combinations thereof.In various embodiments, the efficacy of administering ASBTI is measured by monitoring observer-reported itch-reported outcomes (ITCHRO (OBS)) score, HRQoL (e.g., PedsQL) score, CSS score, xanthomas score, height Z score, weight Z score, or various combinations thereof. In various embodiments, the method includes monitoring the serum level of 7α-hydroxy-4-cholesten-3-one (7αC4), sBA concentration, the ratio of 7αC4 to sBA (7αC4:sBA), serum conjugated bilirubin concentration, serum total cholesterol concentration, serum LDL-C concentration, serum autotaxin concentration, serum bilirubin concentration, serum ALT concentration, serum AST concentration, or combinations thereof.In various embodiments, the method includes monitoring observer-reported itch-reported outcomes (ITCHRO(OBS)) score, weight Z score, HRQoL (e.g., PedsQL) score, xanthomas score, CSS score, height Z score, or various combinations thereof.

[0146] In some embodiments, the ASBTI is about or at least about 0.5 μg / kg, 1 μg / kg, 2 μg / kg, 3 μg / kg, 4 μg / kg, 5 μg / kg, 6 μg / kg, 7 μg / kg, 8 μg / kg, 9 μg / kg, 10 μg / kg, 15 μg / kg, 20 μg / kg, 25 μg / kg, 30 μg / kg, 35 μg / kg, 40 μg / kg, 45 μg / kg, 50 μg / kg, 55 μg / kg, 60 μg / kg, 65 μg / kg, 70 μg / kg, 75 μg / kg, 80 μg / kg, 85 μg / kg, 90 μg / kg, 100 μg / kg, 140 μg / kg, 150 μg / kg, 2 00μg / kg, 240μg / kg, 250μg / kg, 280μg / kg, 300μg / kg, 360μg / kg, 380μg / kg, 400μ g / 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, Administered at doses of 1,600μg / kg, 1,700μg / kg, 1,800μg / kg, 1,900μg / kg, or 2,000μg / kg.In various embodiments, the ASBTI is about 1 μg / kg, 2 μg / kg, 3 μg / kg, 4 μg / kg, 5 μg / kg, 6 μg / kg, 7 μg / kg, 8 μg / kg, 9 μg / kg, 10 μg / kg, 15 μg / kg, 20 μg / kg, 25 μg / kg, 30 μg / kg, 35 μg / kg, 40μg / kg, 45μg / kg, 50μg / kg, 55μg / kg, 60μg / kg, 65μg / kg, 70μg / kg, 75μg / kg, 8 0μg / kg, 85μg / kg, 90μg / kg, 100μg / kg, 140μg / kg, 150μg / kg, 200μg / kg, 240μg / k g, 250 μg / kg, 280 μg / kg, 300 μg / kg, 360 μg / kg, 380 μg / kg, 400 μg / kg, 500 μg / kg, 560 μg / kg, 600 μg / kg, 700 μg / kg, 800 μg / kg, 880 μg / kg, 900 μg / kg, 1,000 μg / kg, 1,100 μg / kg, 1,200 μg / kg, 1,300 μg / kg, 1,400 μg / kg, 1,500 μg / kg, 1,600 μg / kg, 1,700 μg / kg, 1,800 μg / kg, 1,900 μg / kg, 2,000, or 2,100 μg / kg. In various embodiments, ASBTI is administered at 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 , 19mg / day, 20mg / day, 30mg / day, 40mg / day, 50mg / day, 60mg / day, 70mg / day, 80mg / day, 90mg / day, 100mg / day, 150mg / day, 200mg / day, 300mg / day, 500mg / day, 600mg / day, 700mg / day, 800mg / day, 900mg / day, 1000mg / day.In various embodiments, ASBTI is administered at 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, It is administered in doses of 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, or 1,100 mg / day.

[0147] In some embodiments, ASBTI is administered at a dose of about 140 μg / kg / day to about 1400 μg / kg / day. In various embodiments, ASBTI is administered at a dose 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, 300 μg / kg / day, 350 μg / kg / day, 400 μg / kg / day, 450 μg / kg / day, 500 μg / kg / day, 1000 μg / kg / day, 1400 μg / kg / day, 1500 μg / kg / day, 2000 μg / kg / day, 3 ... The drug is administered at doses of 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, ASBTI is administered at 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, Administered at a dose not exceeding 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, ASBTI is administered at a dose 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 ~1400μg / kg / day, approximately 250~550μg / kg / day, approximately 560μg / kg / day~1400μg / kg / day, from700μg / kg / day~1400μg / kg / day, approximately 560μg / kg / day~approx. 1200μg / kg / day, about 700μg / kg / day to about 1200μg / kg / day, about 560μg / kg / day to about 1000μg / kg / day, about 700μg / kg / day to about 1000μg / kg / day, about 800μg / kg / day ~1000μg / kg / day, approximately 200μg / kg / day ~600μg / kg / day, approximately 300μg / kg / day ~600μg / kg / day, approximately 400μg / kg / day ~ 500μg / kg / day, approximately 400μg / kg / day ~about 600μg / kg / day, about 400μg / kg / day to about 700μg / kg / day, about 400μg / kg / day to about 800μg / kg / day, about 500μg / kg / day to about 800μg / kg / day, about 500μg / kg / day to about The compound is administered at a dose of 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 about 400 μg / kg / day to about 2000 μg / kg / day.

[0148] In some embodiments, ASBTI is administered at a dose of about 30 μg / kg to about 1400 μg / kg per administration. In some embodiments, ASBTI is administered at a dose of about 0.5 μg / kg to about 2000 μg / kg per administration, about 0.5 μg / kg to about 1500 μg / kg per administration, about 100 μg / kg to about 700 μg / kg per administration, about 5 μg / kg to about 100 μg / kg per administration, about 10 μg / kg to about 500 μg / kg per administration, about 50 μg / kg to about 1400 μg / kg per administration, about 300 μg / kg to about 2000 μg / kg per administration, about 60 μg / kg to about 1200 μg / kg per administration, about 70 μg / kg to about 1000 μg / kg per administration, about 70 It is administered at a dose of 100μg / kg to about 600μg / kg, 150μg / kg to about 700μg / kg, 150μg / kg to about 500μg / kg, 200μg / kg to about 400μg / kg, 200μg / kg to about 300μg / kg, or 300μg / kg to about 400μg / kg.

[0149] In some embodiments, ASBTI is administered at a dose of about 0.5 mg / day to about 550 mg / day. In various embodiments, ASBTI is administered at a dose 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 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, or 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 10 mg / day to about 40 mg / day, about 10 mg / day to about 20 mg / day, about 20 mg / day to about 100 mg / day, about 20 mg / day to about 80 mg / day, about 20 mg / day to about 50 mg / day, or about 20 mg / day to about 40 mg / day, or about 20 mg / day to about 30 mg / day.

[0150] In some embodiments, ASBTI is administered twice daily (BID) in an amount of about 200 μg / kg to about 400 μg / kg per dose. In some embodiments, ASBTI is administered in an amount of about 280 μg / kg / day to about 1400 μg / kg / day. In some embodiments, ASBTI is administered in an amount of about 400 μg / kg / day to about 800 μg / kg / day. In some embodiments, ASBTI is administered in an amount of about 20 mg / day to about 50 mg / day. In some embodiments, ASBTI is administered in an amount of about 5 mg / day to about 15 mg / day. In some embodiments, ASBTI is administered in an amount of about 560 μg / kg / day to about 1,400 μg / kg / day. In some embodiments, ASBTI is administered in an amount of about 700 μg / kg / day to about 1,400 μg / kg / day. In some embodiments, ASBTI is administered in an amount of about 400 μg / kg / day to about 800 μg / kg / day. In some embodiments, ASBTI is administered in an amount of about 700 μg / kg / day to about 900 μg / kg / day. In some embodiments, ASBTI is administered in an amount of about 560 μg / kg / day to about 1400 μg / kg / day. In some embodiments, ASBTI is administered in an amount of 700 μg / kg / day to about 1400 μg / kg / day. In some embodiments, ASBTI is administered in an amount of about 200 μg / kg / day to about 600 μg / kg / day. In some embodiments, ASBTI is administered in an amount of about 400 μg / kg / day to about 600 μg / kg / day.

[0151] In various embodiments, the dose of ASBTI is at a first dose level. In various embodiments, the dose of ASBTI is at a second dose level. In some embodiments, the second dose level is higher than the first dose level. In some embodiments, the second dose level is about or at least about 1.5 times, 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, 10 times, 15 times, 20 times, 30 times, 40 times, 50 times, 60 times, 70 times, 80 times, 90 times or 100 times higher than the first dose level. In some embodiments, the second dose level is not more than about 1.5x, 2x, 3x, 4x, 5x, 6x, 7x, 8x, 9x, 10x, 15x, 20x, 30x, 40x, 50x, 60x, 70x, 80x, 90x, 100x, or 150x the first dose level.

[0152] In various embodiments, ASBTI is administered once a day (QD) at one of the doses or within one of the dose ranges above. In various embodiments, ASBTI is administered twice a day (BID) at one of the doses or within one of the dose ranges above. In various embodiments, doses of ASBTI are administered daily, every other day, twice a week, or once a week.

[0153] In various embodiments, the ASBTI is administered periodically for 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 a period not exceeding 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 not more than about 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 15 years.

[0154] Relief of symptoms of cholestatic liver disease or changes in disease-related laboratory values In various embodiments of the above methods of the invention, administration of ASBTI results in a reduction in symptoms of cholestatic liver disease or a change in a disease-relevant laboratory measure (i.e., an improvement in the patient's condition) that occurs within 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, 53 weeks, 54 weeks, 55 weeks, 56 weeks, 57 weeks, 58 weeks, 59 weeks, 60 weeks, 61 weeks, 62 weeks, 63 weeks, 64 weeks, 65 weeks, 66 weeks, 67 weeks, 68 weeks, 69 weeks, 70 weeks, 71 weeks, 72 weeks, 73 weeks, 74 weeks, 75 weeks, 76 weeks, 77 weeks, 78 weeks, 79 weeks, 80 weeks, 81 weeks, 82 weeks, 83 weeks, 84 weeks, 85 weeks, 86 weeks maintained for 5 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, 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 various embodiments, the symptom reduction or disease-related laboratory change includes a reduction in sBA concentration, an increase in serum 7αC4 concentration, an increase in 7αC4:sBA ratio, an increase in fBA excretion, a reduction in pruritus, a reduction in serum total cholesterol concentration, a reduction in serum LDL-C cholesterol concentration, a reduction in ALT levels, an increase in quality of life inventory score, an increase in quality of life inventory score for fatigue, a reduction in xanthomas score, a reduction in serum autotaxin concentration, an increase in growth, or a combination thereof. In various embodiments, the symptom reduction or disease-related laboratory change is determined relative to baseline levels. That is, the symptom reduction or disease-related laboratory change is determined relative to the symptom measurement or disease-related laboratory change 1) before a change in the dose level of ASBTI administered to the patient, 2) before a change in the dosing regimen followed by the patient, 3) before the start of administration of ASBTI, or 4) before various other changes made to reduce symptoms or change disease-related laboratory changes in the patient. In various embodiments, the symptom reduction or disease-related laboratory change is a statistically significant reduction.

[0155] In various embodiments, the reduction in symptoms of cholestatic liver disease or change in disease-related laboratory values ​​is achieved within 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, 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, as measured as a progressive reduction in symptoms or change in disease-related laboratory values.

[0156] In some embodiments, the patient is a pediatric patient and the reduction in symptoms or change in disease-related laboratory value comprises an increase or improvement in growth. In some embodiments, the increase in growth is measured compared to baseline. 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 increase in height Z-score, weight Z-score, or both is 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, 0.40, 0.41, 0.42, 0.43, 0.44, 0.45, 0.46, 0.47, 0.48, 0.49, 0.50, 0.51, 0.52, 0.53, 0.54, 0.55, 0.56, 0.57, 0.58, 0.59, 0.60, 0.61, 0.62, 0.63, 0.64, 0.65, 0.66, 0.67, 0.68, 0.69, 0.70, 0.71, 0.72, 0.73, 0.74, 0 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. In some embodiments, the height Z-score, weight Z-score, or both, increase incrementally during administration of the ASBTI for a period 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.

[0157] In various embodiments, administration of ASBTI results in an increase in serum 7αC4 concentration.In various embodiments, serum 7αC4 concentration increases 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 compared to baseline.In various embodiments, serum 7αC4 concentration increases 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% compared to baseline.

[0158] In various embodiments, administration of ASBTI increases the 7αC4:sBA ratio by about 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-fold or fold over baseline.

[0159] In various embodiments, administration of ASBTI results in an increase in fBA excretion. In some embodiments, administration of 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% relative to baseline. In various embodiments, fBA excretion is increased 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 times relative to baseline. In some embodiments, fBA excretion is increased 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 over baseline. In various embodiments, administration of ASBTI results in a dose-dependent increase in fBA excretion, with administration of higher doses of ASBTI resulting in corresponding higher levels of fBA excretion. In various embodiments, ASBTI is administered at a dose sufficient to result in an increase in bile acid secretion of 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 over baseline.

[0160] In various embodiments, administration of ASBTI results in a decrease in sBA concentrations 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% relative to baseline.

[0161] In some embodiments, administration of ASBTI results in a reduction in the severity of pruritus. In various embodiments, the severity of pruritus is measured using ITCHRO (OBS) score, ITCHRO score, CSS score, or a combination thereof. In various embodiments, administration of ASBTI results in a reduction in ITCHRO (OBS) score on a scale of 1 to 4 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, relative to baseline. In various embodiments, administration of ASBTI results in a decrease in the ITCHRO score on a scale of 1 to 10 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. In various embodiments, administration of ASBTI results in a decrease in the ITCHRO(OBS) score, the ITCHRO score, or both, to zero. In various embodiments, administration of ASBTI results in a decrease in the ITCHRO(OBS) score or the ITCHRO score to 1.0 or less. In various embodiments, administration of ASBTI results in a reduction in the CSS score relative to baseline of about or at least about 0.1, 0.2, 0.3, 0.4, 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, administration of ASBTI results in a reduction in the CSS score to zero. In various embodiments, administration of ASBTI results in a reduction in the CSS score, ITCHRO(OBS) score, ITCHRO score, or a combination thereof of about or at least about a 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 decrease in CSS score, ITCHRO(OBS) score, ITCHRO score, or a combination thereof compared 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 days.

[0162] In some embodiments, patients with a higher baseline ITCHRO (OBS) score show a greater reduction in symptoms or a greater change in disease-related laboratory values ​​than patients with a lower baseline ITCHRO (OBS) score. In some embodiments, patients with a baseline ITCHRO (OBS) score of at least 2, 3, or 4 or an ITCHRO score of at least 4, 5, 6, 7, 8, 9, or 10 have a greater reduction in symptoms or a greater change in disease-related laboratory values ​​compared to baseline than a lower reduction in patients with a lower baseline severity of pruritus scores. In various embodiments, patients with PSC and a baseline ITCHRO score of at least 4 show a greater reduction in symptoms or a greater change in disease-related laboratory values ​​than patients with a baseline ITCHRO score of less than 4. In various embodiments, the method includes predicting that a patient will have a greater reduction in symptoms or a greater change in disease-related laboratory values ​​if the patient's baseline ITCHRO score is at least 4 compared to patients with 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% or less of the higher reduction. In various embodiments, the difference in symptom relief or disease-related laboratory change (i.e., the difference between the greater and lesser reduction) between patients with an ITCHRO score of at least 4 at baseline and patients with an ITCHRO score of less than 4 at baseline is 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 after the first administration of ASBTI at the first dose or the second dose.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 later.

[0163] In various embodiments, the reduction in the severity of pruritus resulting from administration of ASBTI to a patient is positively correlated with a reduction in the concentration of sBA in the patient. In various embodiments, a greater reduction in the concentration of sBA in a patient is correlated with a corresponding greater reduction in the severity of pruritus.

[0164] In various embodiments, administration of ASBTI results in a decrease in serum LDL-C concentration compared to baseline. In some embodiments, serum LDL-C concentration is decreased by about or at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% relative to baseline.

[0165] In some embodiments, administration of ASBTI results in a decrease in serum total cholesterol concentration compared to baseline. In some embodiments, administration of ASBTI results in a decrease in serum LDL-C levels compared to baseline. In some embodiments, serum total cholesterol concentration, serum LDL-C levels, or both are reduced by about or at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% relative to baseline. In various embodiments, administration of an ASBTI results in a reduction in serum total cholesterol concentration, serum LDL-C levels, or both, of about or at least about 1 mg / dL, 2 mg / dL, 3 mg / dL, 4 mg / dL, 5 mg / dL, 10 mg / dL, 12.5 mg / dL, 15 mg / dL, 20 mg / dL, 30 mg / dL, 40 mg / dL or 50 mg / dL relative to baseline.

[0166] In various embodiments, administration of ASBTI causes serum autotaxin concentration to decrease.In some embodiments, administration of ASBTI causes about or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% or 80% decrease in autotaxin concentration compared to baseline.

[0167] In various embodiments, administration of ASBTI results in an increase in a quality of life scale score, or an increase in a quality of life scale score for fatigue. The quality of life scale score can be a health-related quality of life (HRQoL) score. In some embodiments, the HRQoL score is a PedsQL score. In various embodiments, administration of ASBTI results in an increase in a PedsQL score or a PedsQL score for fatigue of about or at least about 5%, 10%, 15%, 20%, 25%, 30%, 45%, or 50% relative to baseline.

[0168] In various embodiments, administration of ASBTI results in a decrease in xanthomas score compared to baseline. In some embodiments, the xanthomas score is decreased 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.

[0169] In various embodiments, administration of ASBTI is for 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, by 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, resulting in a reduction in symptoms or a change in disease-related laboratory values.

[0170] In various embodiments, the serum bilirubin concentration is 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 , pre-dose baseline levels or normal levels at or by Week 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, or 1 year.

[0171] In various embodiments, the serum ALT concentration is at or near 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, pre-administration baseline or normal levels at or by 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 ASBTI results in a decrease in ALT levels of about or at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, or 15% relative to baseline.

[0172] In various embodiments, the serum ALT concentration, serum AST concentration, serum bilirubin concentration, serum conjugated bilirubin concentration, or various combinations thereof, is measured at 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, , within normal range or pre-dose baseline levels at or by 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, administration of ASBTI is 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, 53 weeks, 54 weeks, 55 weeks, 56 weeks, 57 weeks, 58 weeks, 59 weeks, 60 weeks, 61 weeks, 62 weeks, 63 weeks, 64 weeks, 65 weeks, 66 weeks, 67 weeks, 68 weeks, 69 weeks, 70 weeks, 71 weeks, 72 weeks, 73 weeks, 74 weeks, 75 weeks, 76 weeks, 77 weeks, 78 weeks, 79 weeks, 80 weeks, 81 weeks, 82 weeks, 83 weeks, 84 weeks, 85 weeks, 86 weeks, 87 weeks, 88 weeks, 89 weeks, 90 weeks, 91 weeks, 92 weeks, 93 weeks, 94 weeks, 95 weeks, does not result in a statistically significant change from baseline in serum bilirubin concentration, serum AST concentration, serum ALT concentration, serum alkaline phosphatase concentration, or some combination thereof at 3 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 with an ITCHRO score of at least 4 at baseline, administration of ASBTI is for 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, 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, or 31 weeks.does not result in a significant change from baseline in serum conjugated bilirubin concentrations for 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.

[0173] In various embodiments of the above-mentioned method of the present invention, the administration of ASBTI results in the reduction, prevention, amelioration or elimination of one or more side effects associated with the administration of ASBTI in a subject in need thereof.In various embodiments, the frequency and / or severity of side effects is reduced compared to the side effects when ASBTI is administered after food intake, simultaneously with food, or mixed with food.In various embodiments, the one or more side effects are diarrhea, loose stool, nausea, gastrointestinal pain, abdominal pain, cramps, anorectal discomfort, or a combination thereof.

[0174] In various embodiments of the above methods of the invention, administration of the ASBTI results in an improvement in the GI tolerability of the ASBTI. In some embodiments, the improvement is compared to the GI tolerability when the ASBTI is administered with a meal or immediately after ingestion of food.

[0175] In some embodiments, the GI tolerability 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 tolerability when the ASBTI is administered with a meal or immediately after ingestion of food.

[0176] Dose adjustment In various embodiments, the method includes adjusting the dosage of ASBTI administered to the patient. Adjusting includes determining the patient's 7αC4:sBA ratio at baseline (e.g., before administration of ASBTI or before adjusting (e.g., increasing) the dosage of ASBTI) and further determining the 7αC4:sBA ratio after administering ASBTI at a first dose or adjusting (e.g., increasing) the dosage of ASBTI to a second dose. If the 7αC4:sBA ratio does not increase 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-fold from baseline, The dose of ASBTI is increased until there is at least about a 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 increase relative to baseline. In various embodiments, the dose of ASBTI is increased or decreased to achieve and maintain a particular 7αC4:sBA ratio.

[0177] In various embodiments, modulating refers to an initial increase in the 7αC4:sBA ratio of 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 fold from baseline and then begins to decrease or return to a normal level relative to baseline. In some embodiments, the method further comprises increasing the dose of the ASBTI from the first dose level to a second dose level higher than the first dose level if the ASBTI has decreased 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 higher than the first dose level. Dose levels are escalated until the 7αC4:sBA ratio increases from 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-fold.

[0178] In some embodiments, the adjustment comprises administering a first dose of ASBTI to the patient, and if the 7αC4:sBA ratio does not increase or does not increase from 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 fold, the patient is then administered a second dose of ASBTI that is greater than the first dose. The dose administered to the patient continues to be escalated until the 7αC4:sBA ratio increases from 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-fold.

[0179] In various embodiments, the 7αC4:sBA ratio is measured about daily, every other week, weekly, bimonthly, monthly, every two months, every three months, every four months, every five months, every six months, or yearly, and the dose of ASBTI is adjusted as needed each time the ratio is measured.

[0180] Pharmaceutical Compositions In some embodiments, the ASBTI is administered as a pharmaceutical composition (composition or pharmaceutical composition) comprising the ASBTI. Any of the compositions described herein may be formulated for ileal, rectal and / or colonic delivery. In more specific embodiments, the composition is formulated for non-systemic or localized delivery to the rectum and / or colon. As used herein, delivery to the colon is understood to include delivery to the sigmoid colon, transverse colon and / or ascending colon. In even more specific embodiments, the composition is formulated for non-systemic or localized delivery to the rectum and / or colon and administered rectally. In other specific embodiments, the composition is formulated for non-systemic or localized delivery to the rectum and / or colon and administered orally.

[0181] In certain embodiments, provided herein is a pharmaceutical composition comprising a therapeutically effective amount of any of the compounds described herein. In certain examples, the pharmaceutical composition comprises an ASBT inhibitor (e.g., any of the ASBTIs described herein).

[0182] In certain embodiments, pharmaceutical compositions are formulated in a conventional manner using one or more physiologically acceptable carriers, including, for example, excipients and auxiliaries that facilitate the processing of active compounds into preparations suitable for pharmaceutical use.In certain embodiments, suitable formulations depend on the route of administration selected.Summaries of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L., Eds., Pharmaceutical Dosage Forms, Mareel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), all of which are incorporated herein in their entirety for all purposes.

[0183] As used herein, a pharmaceutical composition refers to a mixture of a compound described herein with other chemical components, such as carriers, stabilizers, diluents, dispersants, suspending agents, thickeners, and / or excipients. In certain instances, the pharmaceutical composition facilitates administration of the compound to an individual or cell. In certain embodiments of carrying out the methods of treatment or use 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 certain embodiments, the individual is a human. As discussed herein, the compounds described herein are utilized alone or in combination with one or more additional therapeutic agents.

[0184] In certain embodiments, the pharmaceutical formulations described herein are administered to an individual by any manner, including one or more of a variety of routes of administration, such as, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal routes of administration.

[0185] In certain embodiments, the pharmaceutical compositions described herein contain one or more compounds described herein as active ingredients in the form of free acid or free base, or in the form of a pharma- ceutically acceptable salt. In some embodiments, the compounds described herein are utilized as N-oxides, or in crystalline or amorphous form (i.e., polymorphs). In some situations, 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, and the solvated forms include any pharma- ceutically acceptable solvent, such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be described herein.

[0186] "Carriers" in some embodiments comprise pharma- ceutically acceptable excipients, selected based on compatibility with the compounds described herein, such as any of the compounds of Formulae I-VI, and the release profile characteristics of the desired dosage form. Exemplary carrier materials include, for example, binders, suspending agents, disintegrants, fillers, surfactants, solubilizers, stabilizers, lubricants, wetting agents, diluents, and the like. See, e.g., Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L., Eds., Pharmaceutical Dosage Forms, Mareel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999); all of which are incorporated herein in their entireties for all purposes.

[0187] Furthermore, in certain embodiments, the pharmaceutical compositions described herein are formulated as dosage forms.Thus, in some embodiments, dosage forms comprising the compounds described herein are provided herein that are suitable for administration to individuals.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-dissolving formulations, effervescent formulations, lyophilized formulations, tablets, powders, pills, dragees, capsules, delayed release formulations, sustained release formulations, pulsed release formulations, multiparticulate formulations, and mixed immediate release and controlled release formulations.

[0188] In some embodiments, provided herein is a composition for alleviating a symptom of cholestasis or cholestatic liver disease in an individual comprising an enteroendocrine peptide secretion enhancing agent, and optionally a pharma- ceutically acceptable carrier.

[0189] In certain embodiments, the composition comprises an enteroendocrine peptide secretagogue and an absorption inhibitor. In certain embodiments, the absorption inhibitor is an inhibitor that inhibits the absorption of the particular enteroendocrine peptide secretagogue (or at least one of) with which it is combined. In some embodiments, the composition comprises an enteroendocrine peptide secretagogue, an absorption inhibitor, and a carrier (e.g., a carrier suitable for oral administration or a carrier suitable for rectal administration, depending on the intended method of administration). In certain embodiments, the composition comprises an enteroendocrine peptide secretagogue, an absorption inhibitor, a carrier, and one or more of a cholesterol absorption inhibitor, an enteroendocrine peptide, a peptidase inhibitor, a spreading agent, and a wetting agent.

[0190] 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, transverse, and / or ascending colon. In certain embodiments, the compositions formulated for oral administration are enteric coated or enteric formulated oral dosage forms, such as, by way of non-limiting example, tablets and / or capsules.

[0191] Absorption inhibitors In certain embodiments, the compositions described herein as formulated for non-systemic delivery of ASBTI further comprise an absorption inhibitor. As used herein, absorption inhibitors include an agent or agents that inhibit the absorption of bile acids / salts.

[0192] Suitable bile acid absorption inhibitors (also referred to 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, colesevelam hydrochloride, CholestaGel (polymer of N,N,N-trimethyl-6-(2-propenylamino)-1-hexanaminium chloride with (chloromethyl)oxirane, 2-propen-1-amine, and N-2-propenyl-1-decaneamine hydrochloride), cyclodextrins, chitosan, chitosan derivatives, carbohydrates that bind bile acids, lipids that bind bile acids, proteins and proteinaceous substances that bind bile acids, and antibodies and albumins that bind bile acids. Suitable cyclodextrins include, by way of non-limiting example, those that bind bile acids / salts, such as β-cyclodextrin and hydroxypropyl-β-cyclodextrin. Suitable proteins include, by way of non-limiting example, those that bind bile acids / salts, such as bovine serum albumin, egg albumin, casein, alpha-acid glycoprotein, gelatin, soy protein, peanut protein, almond protein, and wheat plant protein.

[0193] In certain embodiments, the absorption inhibitor is cholestyramine. In certain embodiments, cholestyramine binds bile acids. The ion exchange resin cholestyramine is a styrene polymer containing quaternary ammonium groups crosslinked by divinylbenzene. In other embodiments, the absorption inhibitor is colestipol. In certain embodiments, colestipol binds bile acids. The ion exchange resin colestipol is a copolymer of diethylenetriamine and 1-chloro-2,3-epoxypropane.

[0194] In certain embodiments of the compositions and methods described herein, the ASBTI is linked to a resorption inhibitor, while in other embodiments, the ASBTI and the resorption inhibitor are separate molecular entities.

[0195] Cholesterol absorption inhibitors In certain embodiments, the compositions described herein optionally include at least one cholesterol absorption inhibitor.Suitable cholesterol absorption inhibitors include, but are not limited to, ezetimibe (SCH58235), ezetimibe analogs, ACT inhibitors, stigmastanyl phosphorylcholine, stigmastanyl phosphorylcholine analogs, β-lactam cholesterol absorption inhibitors, sulfated polysaccharides, neomycin, phytosponin, phytosterol, phytostanol preparation FM-VP4, sitostanol, β-sitosterol, acyl-CoA:cholesterol-O-acyltransferase (ACAT) inhibitors, avasimibe, implitapide, steroid glycosides, etc.Suitable ezetimibe analogs include, but are not limited to, SCH48461, SCH58053, etc. Suitable ACT inhibitors include, but are not limited to, trimethoxy fatty acid anilides such as Cl-976, 3-[decyldimethylsilyl]-N-[2-(4-methylphenyl)-1-phenylethyl]-propanamide, melinamide, etc. Beta-lactam cholesterol absorption inhibitors include, but are not limited to, (3R,4S)-1,4-bis-(4-methoxyphenyl)-3-beta-phenylpropyl)-2-azetidinone, etc.

[0196] Peptidase inhibitors In some embodiments, the compositions described herein optionally comprise at least one peptidase inhibitor, including, but not limited to, dipeptidyl peptidase-4 inhibitors (DPP-4), neutral endopeptidase inhibitors, and convertase inhibitors. Suitable dipeptidyl peptidase-4 inhibitors (DPP-4) include, by way of non-limiting example, Vildagliptin, (2S)-1-{2-β-hydroxy-1-adamantyl)amino]acetyl}pyrrolidine-2-carbonitrile, Sitagliptin, (3R)-3-amino-1-[9-(trifluoromethyl)-1,4,7,8-tetraazabicyclo[4.3.0]nona-6,8-dien-4-yl]-4-(2,4,5-trifluorophenyl)butan-1-one, Saxagliptin, and (1S,3S,5S)-2-[(2S)-2-amino-2-β-hydroxy-1-adamantyl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile. Such neutral endopeptidase inhibitors include, but are not limited to, Candoxatrilat and Ecadotril.

[0197] Spreading agent / wetting agent In certain embodiments, the compositions described herein optionally include a spreading agent. In some embodiments, the spreading agent is utilized to improve the spreadability of the composition in the colon and / or rectum. Suitable spreading agents include, by way of non-limiting example, hydroxyethyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol, colloidal silicon dioxide, propylene glycol, cyclodextrin, microcrystalline cellulose, polyvinylpyrrolidone, polyoxyethylated glycerides, polycarbophil, di-n-octyl ether, Cetiol™ OE, fatty alcohol polyalkylene glycol ether, Aethoxal™ B, 2-ethylhexyl palmitate, Cegesoft™ C24, and isopropyl fatty acid esters.

[0198] In some embodiments, the compositions described herein optionally include a wetting agent. In some embodiments, the wetting agent is utilized 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 surfactants include, by way of non-limiting example, polysorbates (e.g., 20 or 80), stearyl heptanoate, chain length C 12 ~C 18 caprylic / capric fatty acid esters of saturated fatty alcohols, isostearyl diglycerol isostearic acid, sodium dodecyl sulfate, isopropyl myristate, isopropyl palmitate, and a mixture of isopropyl myristate / isopropyl stearate / isopropyl palmitate.

[0199] vitamin In some embodiments, the methods provided herein further comprise administering one or more vitamins.

[0200] In some embodiments, the vitamin is vitamin A, B1, B2, B3, B5, B6, B7, B9, B12, C, D, E, K, folic acid, pantothenic acid, niacin, riboflavin, thiamine, retinol, beta carotene, pyridoxine, ascorbic acid, cholecalciferol, cyanocobalamin, tocopherol, phylloquinone, menaquinone.

[0201] In some embodiments, the vitamin is a fat-soluble vitamin such as vitamin A, D, E, K, retinol, beta-carotene, cholecalciferol, tocopherol, phylloquinone, etc. In a preferred embodiment, the fat-soluble vitamin is tocopherol polyethylene glycol succinate (TPGS).

[0202] Bile Acid Sequesterants / Binding Agents In some embodiments, the labile bile acid sequestrant is an enzyme-dependent bile acid sequestrant. In certain embodiments, the enzyme is a bacterial enzyme. In some embodiments, the enzyme is a bacterial enzyme found in high concentrations in the human colon or rectum compared to concentrations found in the small intestine. Examples of microflora activation systems include dosage forms that include pectin, galactomannan, and / or Azo hydrogels and / or glycoside conjugates of active agents (e.g., conjugates of D-galactosides, β-D-xylopyranosides, etc.). Examples of gastrointestinal microflora enzymes include bacterial glycosidases, such as, for example, D-galactosidase, β-D-glucosidase, α-L-arabinofuranosidase, β-D-xylopyranosidase, etc.

[0203] In certain embodiments, the labile bile acid sequestrant is a time-dependent bile acid sequestrant. In some embodiments, the labile bile acid sequestrant releases or degrades bile acid after 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 seconds of sequestration. In some embodiments, the labile bile acid sequestrant releases or degrades bile acid after 15, 20, 25, 30, 35, 40, 45, 50, or 55 seconds of sequestration. In some embodiments, the labile bile acid sequestrant releases or degrades bile acid after 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 minutes of sequestration. In some embodiments, the labile bile acid sequestrant releases or degrades bile acid after about 15, 20, 25, 30, 35, 45, 50, or 55 minutes of sequestration. In some embodiments, the labile bile acid sequestrant releases the bile acid or is degraded after 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 of sequestration, in some embodiments, the labile bile acid sequestrant releases the bile acid or is degraded after 1, 2, or 3 days of sequestration.

[0204] In some embodiments, the labile bile acid sequestrant has a low affinity for bile acids, hi certain embodiments, the labile bile acid sequestrant has a high affinity for primary bile acids and a low affinity for secondary bile acids.

[0205] In some embodiments, the labile bile acid sequestrant is a pH-dependent bile acid sequestrant. 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 of greater than 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 of greater than 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 of greater than 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 of greater than 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 of greater than 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 greater than 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 greater than 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 greater than 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 greater than 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 greater than 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 greater than 7.8. In some embodiments, the pH dependent bile acid sequestrant degrades at a pH greater than 6. In some embodiments, the pH dependent bile acid sequestrant degrades at a pH greater than 6.5. In some embodiments, the pH dependent bile acid sequestrant degrades at a pH greater than 7.In some embodiments, the pH dependent bile acid sequestrant degrades at a pH greater than 7.1. In some embodiments, the pH dependent bile acid sequestrant degrades at a pH greater than 7.2. In some embodiments, the pH dependent bile acid sequestrant degrades at a pH greater than 7.3. In some embodiments, the pH dependent bile acid sequestrant degrades at a pH greater than 7.4. In some embodiments, the pH dependent bile acid sequestrant degrades at a pH greater than 7.5. In some embodiments, the pH dependent bile acid sequestrant degrades at a pH greater than 7.6. In some embodiments, the pH dependent bile acid sequestrant degrades at a pH greater than 7.7. In some embodiments, the pH dependent bile acid sequestrant degrades at a pH greater than 7.8. In some embodiments, the pH dependent bile acid sequestrant degrades at a pH greater than 7.9.

[0206] In certain embodiments, the labile bile acid sequestrant is lignin or modified lignin.In some embodiments, the labile bile acid sequestrant is a polycationic polymer or copolymer.In certain embodiments, the labile bile acid sequestrant is a polymer or copolymer that comprises one or more N-alkenyl-N-alkylamine residues; one or more N,N,N-trialkyl-N-(N'-alkenylamino)alkyl-azanium residues; one or more N,N,N-trialkyl-N-alkenyl-azanium residues; one or more alkenylamine residues; or combinations thereof. In some embodiments, the bile acid binder is cholestyramine and various compositions containing cholestyramine, which are described, for example, in U.S. Pat. Nos. 3,383,281; 3,308,020; 3,769,399; 3,846,541; 3,974,272; 4,172,120; 4,252,790; 4,340,585; 4,814,354; 4,874,744; 4,895,723; 5,695,749; and 6,066,336, all of which are incorporated by reference herein in their entireties for all purposes. In some embodiments, the bile acid binding agent is colestipol or colesevelam.

[0207] Route of Administration, Dosage Forms, and Dosing Regimen In some embodiments, the compositions described herein and the compositions administered in the methods described herein are formulated to inhibit bile acid reuptake or reduce serum or hepatic bile acid levels. 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 localized delivery of the composition to the rectum and / or colon (sigmoid, transverse, or ascending colon). In certain embodiments, for rectal administration, the compositions described herein are formulated as enemas, rectal gels, enema foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas. In some embodiments, for oral administration, the compositions described herein are formulated for oral administration and enteral delivery to the colon.

[0208] In certain embodiments, the compositions or methods described herein are non-systemic. In some embodiments, the compositions described herein deliver ASBTI to the distal ileum, colon, and / or rectum, but not to the systemic (e.g., a substantial portion of the enteroendocrine peptide secretagogue is not systemically absorbed). In some embodiments, the oral compositions described herein deliver ASBTI to the distal ileum, colon, and / or rectum, but not to the systemic (e.g., a substantial portion of the enteroendocrine peptide secretagogue is not systemically absorbed). In some embodiments, the rectal compositions described herein deliver ASBTI to the distal ileum, colon, and / or rectum, but not to the systemic (e.g., a substantial portion of the enteroendocrine peptide secretagogue is not systemically absorbed). In certain embodiments, the non-systemic compositions described herein deliver less than 90% w / w of ASBTI to the systemic. In certain embodiments, the non-systemic compositions described herein deliver less than 80% w / w of ASBTI to the systemic. In certain embodiments, the non-systemic compositions described herein deliver less than 70% w / w of the ASBTI to the system. In certain embodiments, the non-systemic compositions described herein deliver less than 60% w / w of the ASBTI to the system. In certain embodiments, the non-systemic compositions described herein deliver less than 50% w / w of the ASBTI to the system. In certain embodiments, the non-systemic compositions described herein deliver less than 40% w / w of the ASBTI to the system. In certain embodiments, the non-systemic compositions described herein deliver less than 30% w / w of the ASBTI to the system. In certain embodiments, the non-systemic compositions described herein deliver less than 25% w / w of the ASBTI to the system. In certain embodiments, the non-systemic compositions described herein deliver less than 20% w / w of the ASBTI to the system. In certain embodiments, the non-systemic compositions described herein deliver less than 15% w / w of the ASBTI to the system. In certain embodiments, the non-systemic compositions described herein deliver less than 10% w / w of the ASBTI systemically. In certain embodiments, the non-systemic compositions described herein deliver less than 5% w / w of the ASBTI systemically.In some embodiments, systemic absorption is determined in any suitable manner, including total circulating amount, amount cleared following administration, etc.

[0209] In certain embodiments, the compositions and / or formulations described herein are administered at least once a day. In certain embodiments, the formulations comprising ASBTI are administered at least twice a day, and in other embodiments, the formulations comprising ASBTI are administered at least three times a day. In certain embodiments, the formulations comprising ASBTI are administered up to five times a day. It should be understood that in certain embodiments, the administration regimen of the compositions comprising ASBTI described herein is determined by considering various factors such as the age, sex, and diet of the patient.

[0210] The concentration of ASBTI administered in the formulations described herein ranges from about 1 mM to about 1M. In certain embodiments, the concentration of ASBTI administered in the formulations described herein ranges from about 1 mM to about 750 mM. In certain embodiments, the concentration of ASBTI administered in the formulations described herein ranges from about 1 mM to about 500 mM. In certain embodiments, the concentration of ASBTI administered in the formulations described herein ranges from about 5 mM to about 500 mM. In certain embodiments, the concentration of ASBTI administered in the formulations described herein ranges from about 10 mM to about 500 mM. In certain embodiments, the concentration of ASBTI administered in the formulations described herein ranges from about 25 mM to about 500 mM. In certain embodiments, the concentration of ASBTI administered in the formulations described herein ranges from about 50 mM to about 500 mM. In certain embodiments, the concentration of ASBTI administered in the formulations described herein ranges from about 100 mM to about 500 mM. In certain embodiments, the concentration of ASBTI administered in the formulations described herein ranges from about 200 mM to about 500 mM.

[0211] In certain embodiments, by targeting the distal digestive tract (e.g., the distal ileum, colon, and / or rectum), the compositions and methods described herein provide efficacy (e.g., efficacy in reducing microbial growth and / or alleviating symptoms of cholestasis or cholestatic liver disease) at reduced doses of enteroendocrine peptide secretagogues (e.g., compared to oral doses that do not target the distal digestive tract).

[0212] Oral Administration for Colonic Delivery In certain aspects, compositions or formulations comprising one or more compounds described herein are orally administered for ASBTI or local delivery of the compounds described herein to the colon and / or rectum. Unit dosage forms of such compositions include pills, tablets or capsules formulated for enteral delivery to the colon. In certain embodiments, such pills, tablets or capsules comprise the compositions described herein encapsulated or embedded in microspheres. In some embodiments, the microspheres include, by way of non-limiting examples, chitosan micro-core HPMC capsules and cellulose acetate butyrate (CAB) microspheres. In certain embodiments, oral dosage forms are prepared using conventional methods known in the field of pharmaceutical formulation. For example, in certain embodiments, tablets are manufactured using standard tablet processing procedures and equipment. An exemplary method for forming tablets is by direct compression of a powdered, crystalline, or granular composition comprising the above-mentioned active agents, alone or in combination with one or more carriers, additives, and the like. In alternative embodiments, tablets are prepared using wet granulation or dry granulation processes. In some embodiments, tablets are molded rather than compressed, starting with a moist or otherwise tractable material.

[0213] In certain embodiments, tablets 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, binders are used to impart cohesion to the tablet and ensure that it 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 glycol, propylene glycol, waxes, and natural and synthetic gums, such as acacia, sodium alginate, polyvinylpyrrolidone, cellulosic polymers (including hydroxypropyl cellulose, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, and the like), Veegum, and combinations thereof. In certain embodiments, diluents are utilized to increase the bulk of the tablet to provide a tablet of practical size. Suitable diluents include, but are not limited to, dicalcium phosphate, calcium sulfate, lactose, cellulose, kaolin, mannitol, sodium chloride, dry starch, powdered sugar, and combinations thereof. In certain embodiments, lubricants are used to facilitate tablet manufacture; suitable lubricants include, but are not limited to, vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and theobroma oil, glycerin, magnesium stearate, calcium stearate, stearic acid, and combinations thereof. In some embodiments, disintegrants are used to facilitate tablet disintegration, but are not limited to, starch, clay, cellulose, algin, gum, cross-linked polymer, and combinations thereof. Fillers include, but are not limited to, materials such as silicon dioxide, titanium dioxide, alumina, talc, kaolin, powdered cellulose, and microcrystalline cellulose, as well as soluble materials such as mannitol, urea, sucrose, lactose, dextrose, sodium chloride, and sorbitol.In certain embodiments, stabilizers are used to inhibit or retard drug decomposition reactions, including, by way of example, oxidation reactions, hi certain embodiments, the surfactant is an anionic, cationic, amphoteric or nonionic surfactant.

[0214] In some embodiments, ASBTI, or other compounds described herein, are administered orally with a carrier suitable for delivery to the distal gastrointestinal tract (eg, the distal ileum, colon, and / or rectum).

[0215] In certain embodiments, the compositions described herein include ASBTI or other compounds described herein in association with a matrix (e.g., a matrix including hypermellose) that allows for controlled release of the active agent in the distal portion of the ileum and / or the colon. In some embodiments, the compositions include a polymer that is pH sensitive (e.g., MMX™ matrix from Cosmo Pharmaceuticals) that allows for controlled release of the active agent in the distal portion of the ileum. Examples of such pH sensitive polymers suitable for controlled release include, but are not limited to, polyacrylic acid polymers (e.g., anionic polymers of methacrylic acid and / or methacrylic acid esters, e.g., Carbopol® polymers) that include acidic groups (e.g., -COOH, -SO3H) and swell at the basic pH of the intestine (e.g., a pH of about 7 to about 8). In some embodiments, the compositions suitable for controlled release in the distal ileum include a particulate active agent (e.g., a micronized active agent). In some embodiments, a non-enzymatically degrading poly(dl-lactide-co-glycolide) (PLGA) core is suitable for delivery of enteroendocrine peptide secretagogues to the distal ileum. In some embodiments, dosage forms containing enteroendocrine peptide secretagogues are coated with enteric polymers (e.g., Eudragit® S-100, cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, anionic polymers of methacrylic acid, methacrylic acid esters, etc.) for site-specific delivery to the distal ileum and / or colon. In some embodiments, a bacteria-activating system is suitable for targeted delivery to the distal portion of the ileum. Examples of microflora-activating systems include dosage forms containing pectin, galactomannan, and / or Azo hydrogels and / or glycoside conjugates of active agents (e.g., conjugates of D-galactosides, β-D-xylopyranosides, etc.). Examples of gut microflora enzymes include bacterial glycosidases, such as D-galactosidase, β-D-glucosidase, α-L-arabinofuranosidase, β-D-xylopyranosidase.

[0216] The pharmaceutical compositions described herein optionally include an additional therapeutic compound as described herein, as well as one or more pharma- ceutically acceptable additives, such as a compatible carrier, binder, filler, suspending agent, flavoring agent, sweetener, disintegrant, dispersant, surfactant, lubricant, colorant, diluent, solubilizer, humectant, plasticizer, stabilizer, permeation enhancer, wetting agent, antifoaming agent, antioxidant, preservative, or one or more combinations thereof. 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 Remington's Pharmaceutical Sciences, 20th Edition (2000). In one embodiment, the compound described herein is in the form of particles, and some or all of the particles of the compound are coated. In certain embodiments, some or all of the particles of the compound described herein are microencapsulated. In some embodiments, the particles of the compound described herein are not microencapsulated and are not coated.

[0217] In further embodiments, the tablet or capsule containing ASBTI or other compounds described herein is film-coated for delivery to target sites in the gastrointestinal tract.Examples of enteric film coating include, but are not limited to, hydroxypropylmethylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose, polyethylene glycol 3350, 4500, 8000, methylcellulose, pseudoethylcellulose, amylopectin, etc.

[0218] Pediatric Formulations and Compositions In certain embodiments, provided herein is a pediatric formulation or composition comprising a therapeutically effective amount of any of the compounds described herein. In certain examples, the pharmaceutical composition comprises an ASBT inhibitor (e.g., any of the ASBTIs described herein).

[0219] In certain embodiments, dosage forms suitable for pediatric formulations or compositions include, by way of non-limiting example, aqueous or non-aqueous oral dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, solutions, controlled release formulations, fast dissolving formulations, effervescent formulations, lyophilized formulations, chewable tablets, gummy candies, orally disintegrating tablets, powders for reconstitution as suspensions or solutions, sprinkle oral powders or granules, sugar-coated tablets, delayed release formulations, sustained release formulations, pulsed release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations. In some embodiments, provided herein are pharmaceutical compositions in which the pediatric dosage form is selected from solutions, syrups, suspensions, elixirs, powders for reconstitution as suspensions or solutions, dispersible / effervescent tablets, chewable tablets, gummy candies, lollipops, freezer pops, lozenges, oral flakes, orally disintegrating tablets, orally disintegrating strips, sachets, and sprinkle oral powders or granules.

[0220] In another aspect, provided herein is a pharmaceutical composition in which 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 technology selected from: coating drug particles with taste-neutral polymers by spray drying, wet granulation, fluid bed, and microencapsulation; coating a mixture of molten wax and other pharmaceutical auxiliary with molten wax; entrapment of drug particles by complexation, aggregation, or solidification of aqueous polymer dispersions; adsorption of drug particles to resins and inorganic supports; and solid dispersions in which drug and one or more neutral taste 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 or granules in a rate-controlling polymer or matrix.

[0221] Suitable sweeteners include sucrose, glucose, fructose, or high-intensity sweeteners, i.e., agents with a high sweetening power compared to sucrose (e.g., at least 10 times sweeter than sucrose). Suitable high-intensity sweeteners include aspartame, saccharin, sodium or potassium or calcium saccharin, acesulfame potassium, sucralose, alitame, xylitol, cyclamate, neomate, neohesperidin dihydrochalcone or mixtures thereof, thaumatin, palatinit, stevioside, rebaudioside, Magnasweet®. The total concentration of sweeteners can range from substantially zero to about 300 mg / ml, based on the liquid composition upon reconstitution.

[0222] In order to enhance the palatability of the liquid composition when reconstituted with an aqueous medium, one or more taste-masking agents can be added to the composition to mask the taste of the ASBT inhibitor. The taste-masking agent can be a sweetener, a flavoring agent, or a combination thereof. The taste-masking agent typically provides up to about 0.1% or 5% by weight of the total pharmaceutical composition. In a preferred embodiment of the present invention, the composition includes both a sweetener and a flavoring agent.

[0223] Flavoring agents herein are substances capable of enhancing the taste or aroma of a composition. Suitable natural or synthetic flavoring agents can be selected from standard reference books, such as Fenaroli's Handbook of Flavor Ingredients, 3rd edition (1995).Non-limiting examples of flavoring and / or sweetening agents useful in the formulations described herein include, for example, acacia syrup, acesulfame K, alitame, anise, apple, aspartame, banana, bavarois cream, berry, blackcurrant, butterscotch, calcium citrate, camphor, caramel, cherry, cherry cream, chocolate, cinnamon, bubble gum, citrus, citrus punch, citrus cream, cotton candy, cocoa, cola, cool cherry, cool citrus, and the like. , cyclamate, cylamate, dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger, glycyrrhetinate, glycyrrhiza (licorice) syrup, grapes, grapefruit, honey, isomalt, lemon, lime, lemon cream, monoammonium glycyrrhizinate (MagnaSweet®), maltol, mannitol, maple, marshmallow, menthol, mint cream, mixed base Lee, Neohesperidin DC, Neotame, Orange, Pear, Peach, Peppermint, Peppermint Cream, Prosweet® Powder, Raspberry, Root Beer, Rum, Saccharin, Safrole, Sorbitol, Spearmint, Spearmint Cream, Strawberry, Strawberry Cream, Stevia, Sucralose, Sucrose, Sodium Saccharin, Saccharin, Aspartame, Acesulfame Potassium, Mannitol, Talin, Silitol, Sucralose, Sorbitol Tall, Swiss cream, tagatose, tangerine, thaumatin, tutti frutti, vanilla, walnut, watermelon, wild cherry, wintergreen, xylitol, or any combination of these flavoring ingredients, such as anise-menthol, cherry-anise, cinnamon-orange, cherry-cinnamon, chocolate-mint, honey-lemon, lemon-lime, lemon-mint, menthol-eucalyptus, orange-cream, vanilla-mint, and mixtures thereof. The flavoring agents may be used alone or in combination of two or more. In some embodiments, the aqueous liquid dispersion includes a sweetener or flavoring agent at a concentration ranging from 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 ranging from 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 ranging from 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 ranging from 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 ranging from about 0.01% to about 0.5% by volume of the aqueous dispersion.

[0224] In certain embodiments, the pediatric pharmaceutical compositions described herein contain one or more compounds described herein as active ingredients in the form of free acid or free base, or in the form of a pharma- ceutically acceptable salt. In some embodiments, the compounds described herein are utilized as N-oxides, or in crystalline or amorphous forms (i.e., polymorphs). In some situations, 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, where the solvated forms include any pharma- ceutically acceptable solvent, e.g., water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be described herein.

[0225] The "carrier" of the pediatric pharmaceutical composition, in some embodiments, comprises a pharma- ceutically acceptable excipient, selected based on compatibility with the compounds described herein, such as a compound of any of Formulas I-VI, and the release profile characteristics of the desired dosage form. Exemplary carrier materials include, for example, binders, suspending agents, disintegrants, fillers, surfactants, solubilizers, stabilizers, lubricants, wetting agents, diluents, and the like. See, e.g., Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. 1975; Liberman, HA and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999); all of which are incorporated by reference in their entireties for all purposes.

[0226] Furthermore, in certain embodiments, the pediatric pharmaceutical compositions described herein are formulated as dosage forms.Thus, in some embodiments, dosage forms are provided herein that contain the compounds described herein and are suitable for administration to individuals.In certain embodiments, suitable dosage forms include, by way of non-limiting examples, aqueous oral dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, solid oral dosage forms, aerosols, sustained release formulations, fast dissolving formulations, effervescent formulations, lyophilized formulations, tablets, powders, pills, dragees, capsules, delayed release formulations, sustained release formulations, pulsed release formulations, multiparticulate formulations, and mixed immediate release and controlled release formulations.

[0227] In certain embodiments, pediatric compositions or formulations comprising one or more compounds described herein are orally administered for ASBTI or for local delivery of the compounds described herein to the colon and / or rectum. Unit dosage forms of such compositions include pills, tablets or capsules formulated for enteral delivery to the colon.

[0228] In some embodiments, ASBTI, or other compounds described herein, are administered orally with a carrier suitable for delivery to the distal gastrointestinal tract (eg, the distal ileum, colon, and / or rectum).

[0229] In certain embodiments, the pediatric compositions described herein include ASBTI or other compounds described herein in association with a matrix (e.g., a matrix including hypermellose) that allows for controlled release of the active agent in the distal portion of the ileum and / or colon. In some embodiments, the compositions include a polymer that is pH sensitive (e.g., MMX™ matrix from Cosmo Pharmaceuticals) that allows for controlled release of the active agent in the distal portion of the ileum. Examples of such pH sensitive polymers suitable for controlled release include, but are not limited to, polyacrylic acid polymers (e.g., anionic polymers of methacrylic acid and / or methacrylic acid esters, e.g., Carbopol® polymers) that include acidic groups (e.g., -COOH, -SO3H) and swell at the basic pH of the intestine (e.g., a pH of about 7 to about 8). In some embodiments, the compositions suitable for controlled release in the distal ileum include a particulate active agent (e.g., a micronized active agent). In some embodiments, a non-enzymatically degrading poly(dl-lactide-co-glycolide) (PLGA) core is suitable for delivery of enteroendocrine peptide secretagogues to the distal ileum. In some embodiments, dosage forms containing enteroendocrine peptide secretagogues are coated with enteric polymers (e.g., Eudragit® S-100, cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, anionic polymers of methacrylic acid, methacrylic acid esters, etc.) for site-specific delivery to the distal ileum and / or colon. In some embodiments, a bacteria-activating system is suitable for targeted delivery to the distal portion of the ileum. Examples of microflora-activating systems include dosage forms containing pectin, galactomannan, and / or Azo hydrogels and / or glycoside conjugates of active agents (e.g., conjugates of D-galactosides, β-D-xylopyranosides, etc.). Examples of gut microflora enzymes include bacterial glycosidases, such as D-galactosidase, β-D-glucosidase, α-L-arabinofuranosidase, β-D-xylopyranosidase.

[0230] The pediatric pharmaceutical compositions described herein optionally include an additional therapeutic compound as described herein, as well as one or more pharma- ceutically acceptable additives, such as a compatible carrier, a binder, a filler, a suspending agent, a flavoring agent, a sweetener, a disintegrant, a dispersant, a surfactant, a lubricant, a coloring agent, a diluent, a solubilizer, a humectant, a plasticizer, a stabilizer, a permeation enhancer, a wetting agent, an antifoaming agent, an antioxidant, a preservative, or one or more combinations thereof. 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 Remington's Pharmaceutical Sciences, 20th Edition (2000). In one embodiment, the compound described herein is in the form of particles, and some or all of the particles of the compound are coated. In certain embodiments, some or all of the particles of the compound described herein are microencapsulated. In some embodiments, the particles of the compound described herein are not microencapsulated and are not coated.

[0231] Liquid dosage forms Liquid pharmaceutical dosage forms of the present invention can be prepared according to techniques well known in the art of pharmacy.

[0232] A solution refers to a liquid formulation in which the active ingredient is dissolved in a liquid. Pharmaceutical solutions of the present invention include syrups and elixirs. A suspension refers to a liquid formulation in which the active ingredient is precipitated in a liquid.

[0233] It is desirable for liquid dosage forms to have a particular pH and / or be maintained within a particular pH range. To control the pH, an appropriate buffer system can be used. Additionally, the buffer system must have sufficient capacity to maintain the desired pH range. Examples of buffer systems useful in the present invention include, but are not limited to, citrate buffer, phosphate buffer, or any other suitable buffer known in the art. Preferably, the buffer system includes 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 pH / pH range required for the liquid dosage form. In one embodiment, the concentration is in the range of 0.005-0.5 w / v% in the final liquid dosage form.

[0234] Pharmaceutical compositions, including liquid dosage forms of the present invention, may also contain suspending / stabilizing agents to prevent sedimentation of the active substance. Over time, sedimentation may cause the active substance to cake on the inner walls of the product pack, making redispersion and accurate dispensing difficult. Suitable stabilizers include, but are not limited to, polysaccharide stabilizers such as xanthan, guar and tragacanth gum, as well as cellulose derivatives HPMC (hydroxypropylmethylcellulose), methylcellulose and Aviccel RC-591 (microcrystalline cellulose / sodium carboxymethylcellulose). In another embodiment, polyvinylpyrrolidone (PVP) may also be used as a stabilizer.

[0235] In addition to the aforementioned ingredients, the ASBTI oral suspension formulation may optionally contain alternative solvents, flavoring agents, antioxidants, bulking agents, acidifiers, enzyme inhibitors, and other additives as described in Handbook of Pharmaceutical Excipients, Rowe et al., Eds., 4 th The composition may include other excipients commonly found in pharmaceutical compositions, such as those described in U.S. Pat. No. 6,313,311, the disclosure of which is incorporated herein by reference in its entirety for all purposes.

[0236] The addition of alternative solvents can help to increase the solubility of the active ingredient in the liquid dosage form, thereby increasing its absorption and bioavailability in the subject's body.Preferably, the alternative solvents include methanol, ethanol, or propylene glycol, etc.

[0237] In another aspect, the present invention provides a process for preparing a liquid dosage form. This process includes mixing ASBTI or a pharma- ceutically acceptable salt thereof with ingredients including glycerol or syrup or mixtures thereof, preservatives, buffer systems and suspending / stabilizing agents in a liquid medium. In general, the liquid dosage form is prepared by uniformly and homogeneously mixing these various ingredients in a liquid medium. For example, ingredients such as glycerol or syrup or mixtures thereof, preservatives, buffer systems and suspending / stabilizing agents can be dissolved in water to form an aqueous solution, and then the active ingredient can be dispersed in the aqueous solution to form a suspension.

[0238] In some embodiments, the liquid dosage forms provided herein may have a volume between about 0.1 ml and about 50 ml. In some embodiments, the liquid dosage forms provided herein may have a volume between about 0.2 ml and about 40 ml. In some embodiments, the liquid dosage forms provided herein may have a volume between about 0.5 ml and about 30 ml. In some embodiments, the liquid dosage forms provided herein may have a volume between about 1 ml and about 20 ml. In some embodiments, the liquid dosage forms provided herein may have a volume between about 0.1 ml and about 20 ml. In some embodiments, the liquid dosage forms provided herein may have a volume between about 0.1 ml and about 20 ml. In some embodiments, the liquid dosage forms provided herein may have a volume between about 0.1 ml and about 20 ml. In some embodiments, the liquid dosage forms provided herein may have a volume between about 0.1 ml and about 20 ml. In some embodiments, the amount of ASBTI may range 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, ASBTI may be in an amount ranging from about 1% to about 50% of the total volume. In some embodiments, ASBTI may be in an amount ranging from about 1% to about 40% of the total volume. In some embodiments, ASBTI may be in an amount ranging from about 1% to about 30% of the total volume. In some embodiments, ASBTI may be in an amount ranging from about 1% to about 20% of the total volume. In some embodiments, ASBTI may be in an amount ranging from about 1% to about 10% of the total volume. In some embodiments, ASBTI may be in an amount ranging from about 5% to about 70% of the total volume. In some embodiments, ASBTI may be in an amount ranging from about 5% to about 60% of the total volume. In some embodiments, ASBTI may be in an amount ranging from about 5% to about 50% of the total volume. In some embodiments, ASBTI may be in an amount ranging from about 5% to about 40% of the total volume. In some embodiments, ASBTI may be in an amount ranging from about 5% to about 30% of the total volume. In some embodiments, ASBTI may be in an amount ranging from about 5% to about 20% of the total volume. In some embodiments, the ASBTI can be in an amount ranging from about 5% to about 10% of the total volume.In some embodiments, ASBTI may be in an amount ranging from about 10% to about 50% of the total volume. In some embodiments, ASBTI may be in an amount ranging from about 10% to about 40% of the total volume. In some embodiments, ASBTI may be in an amount ranging from about 10% to about 30% of the total volume. In some embodiments, 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 has a liquid volume of 0.1 ml to 30 ml, preferably 0.1 ml to 20 ml, and the active ingredient is in an amount ranging from about 0.001 mg / ml to about 16 mg / ml, or from about 0.025 mg / ml to about 8 mg / ml, or from about 0.1 mg / ml to about 4 mg / ml, or in an amount of about 0.25 mg / ml, or about 0.5 mg / ml, or about 1 mg / ml, or about 2 mg / ml, or about 4 mg / ml, or about 5 mg / ml, or about 8 mg / ml, or about 9 mg / ml, or about 10 mg / ml, or about 12 mg / ml, or about 14 mg / ml, or about 16 mg / ml.

[0239] Bile acid sequestrants In certain embodiments, the oral formulation for use in any of the methods described herein is, for example, ASBTI with a labile bile acid sequestrant.A labile bile acid sequestrant is a bile acid sequestrant that has an unstable affinity for bile acid.In certain embodiments, the bile acid sequestrant described herein is an agent that sequesters (e.g., adsorbs or loads) bile acid and / or its salt.

[0240] In certain embodiments, the labile bile acid sequestrant sequester (e.g., adsorb or load) bile acids and / or their salts and releases at least a portion of the adsorbed or loaded bile acids and / or their salts in the distal digestive tract (e.g., colon, ascending colon, sigmoid colon, distal colon, rectum, or any combination thereof). In certain embodiments, the labile bile acid sequestrant is an enzyme-dependent bile acid sequestrant. In certain embodiments, the enzyme is a bacterial enzyme. In some embodiments, the enzyme is a bacterial enzyme found in higher concentrations in the human colon or rectum compared to concentrations found in the small intestine. Examples of microflora activation systems include dosage forms that include pectin, galactomannan, and / or Azo hydrogels and / or glycoside conjugates of active agents (e.g., conjugates of D-galactosides, β-D-xylopyranosides, etc.). Examples of gut microflora enzymes include bacterial glycosidases, such as, for example, D-galactosidase, β-D-glucosidase, α-L-arabinofuranosidase, β-D-xylopyranosidase. In some embodiments, the labile bile acid sequestrant is a time-dependent bile acid sequestrant (i.e., the bile acid sequestrant sequesters bile acids and / or their salts and releases at least a portion of the bile acids and / or their salts 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 bile acid sequestrants described herein are bile acid sequestrants that have a low affinity for bile acids and / or their salts, thereby allowing the bile acid sequestrant to continue to sequester bile acids and / or their salts in environments where the bile acids / salts and / or their salts are present in high concentrations and release them in environments where the bile acids / salts and / or their salts are present in lower relative concentrations. In some embodiments, the labile bile acid sequestrant has a high affinity for a primary bile acid and a lower affinity for a secondary bile acid, and the bile acid sequestrant sequesters the primary bile acid or salt thereof and subsequently releases the secondary bile acid or salt thereof as the primary bile acid or salt thereof is converted (e.g., metabolized) to the secondary bile acid or salt thereof.In some embodiments, the labile bile acid sequestrant is a pH-dependent bile acid sequestrant. 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 lower affinity for bile acids at a pH of greater than 6. In certain embodiments, the pH-dependent bile acid sequestrant decomposes at a pH of greater than 6.

[0241] In some embodiments, the labile bile acid sequestrants described herein include any compound, e.g., macrostructure compounds, that can sequester a bile acid / salt and / or its salt through any suitable mechanism. For example, in certain embodiments, the bile acid sequestrant sequesters a bile acid / salt and / or its salt through ionic interactions, polar interactions, static interactions, hydrophobic interactions, lipophilic interactions, hydrophilic interactions, steric interactions, etc. In certain embodiments, the macrostructure compounds sequester the bile acid / salt and / or sequestrant by trapping the bile acid / salt and / or its salt in a pocket of the macrostructure compound, and optionally through other interactions such as those described above. In some embodiments, bile acid sequestrants (e.g., labile bile acid sequestrants) include, by way of non-limiting example, lignin; modified lignin; polymers; polycationic polymers and copolymers; polymers and / or copolymers comprising any one or more of N-alkenyl-N-alkylamine residues, one or more N,N,N-trialkyl-N-(N'-alkenylamino)alkyl-azanium residues, one or more N,N,N-trialkyl-N-alkenyl-azanium residues, one or more alkenylamine residues, or combinations thereof; or any combination thereof.

[0242] Covalent binding of drug to carrier In some embodiments, strategies utilized for colon targeted delivery include, by way of non-limiting example, covalent attachment of ASBTI or other compounds described herein to a carrier, coating the formulation with a pH sensitive polymer for delivery upon reaching the pH environment of the colon, use of redox (oxidation-reduction) sensitive polymers, use of time-released formulations, use of coatings that are specifically degraded by colonic bacteria, use of bioadhesive systems, and use of osmotically controlled drug delivery systems.

[0243] In certain embodiments of such oral administration of compositions containing ASBTI or other compounds described herein, covalent bonds to carriers are included, and upon oral administration, the bound moieties remain intact in the stomach and small intestine. Upon entering the colon, the covalent bonds are cleaved by pH changes, enzymes, and / or degradation by intestinal microflora. In certain embodiments, the covalent bonds between ASBTI and carriers include, by way of non-limiting examples, azo bonds, glycoside conjugates, glucuronide conjugates, cyclodextrin conjugates, dextran conjugates, and amino acid conjugates (high hydrophilicity and long chain length of the carrier amino acid).

[0244] Coating with polymers: pH-sensitive polymers 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 a coating that remains intact in the low pH environment of the stomach, but dissolves readily when the optimum dissolution pH of the particular coating is reached, which depends on the chemical composition of the enteric coating. The thickness of the coating depends on the dissolution characteristics of the coating material. In certain embodiments, the thickness of the coating used in such formulations described herein ranges from about 25 μm to about 200 μm.

[0245] In certain embodiments, the compositions or formulations described herein are coated so that the ASBTI or other compounds described herein of the compositions or formulations are delivered to the colon and / or rectum without being absorbed in the upper part of the intestine. In certain embodiments, specific delivery to the colon and / or rectum is achieved by coating the formulation with a polymer that degrades only in the pH environment of the colon. In alternative embodiments, the compositions are coated with an enteric coat that dissolves at the pH of the intestine and an outer layer matrix that slowly erodes in the intestine. In some such embodiments, the matrix slowly erodes until only the core composition comprising the enteroendocrine peptide secretagogue (and, in some embodiments, the drug absorption inhibitor) remains, and the core is delivered to the colon and / or rectum.

[0246] In certain embodiments, the pH-dependent system takes advantage of the progressively increasing pH along the human gastrointestinal tract (GIT), from the stomach (pH 1-2, rising to 4 during digestion), to the small intestine at the site of digestion (pH 6-7), and to 7-8 at the distal ileum. In certain embodiments, dosage forms for oral administration of the compositions described herein are coated with a pH-sensitive polymer to provide delayed release and protect the enteroendocrine peptide secretagogue from gastric fluids. In certain embodiments, such polymers can tolerate the lower pH values ​​of the stomach and proximal portions of the small intestine, but disintegrate at the neutral or slightly alkaline pH of the terminal ileum and / or ileocecal region. Thus, in certain embodiments, provided herein are oral dosage forms comprising a coating, the coating comprising a pH-sensitive polymer. In some embodiments, polymers used for colon and / or rectal targeting include, 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, polyvinyl acetate phthalate, hydroxypropyl ethylcellulose phthalate, hydroxypropyl methylcellulose phthalate 50, hydroxypropyl methylcellulose phthalate 55, cellulose acetate trimellitate, cellulose acetate phthalate, and combinations thereof.

[0247] In certain embodiments, oral dosage forms suitable for delivery to the colon and / or rectum include a coating having a biodegradable and / or bacteriodegradable polymer(s) that are degraded by the microflora (bacteria) in the colon. In such biodegradable systems, suitable polymers include, by way of non-limiting example, azopolymers, linear segmented polyurethanes containing azo groups, polygalactomannans, pectins, glutaraldehyde cross-linked dextran, polysaccharides, amylose, guar gum, pectins, chitosan, inulin, cyclodextrins, chondroitin sulfate, dextran, locust bean gum, chondroitin sulfate, chitosan, poly(-caprolactone), polylactic acid, and poly(lactic-co-glycolic acid).

[0248] In certain embodiments of such oral administration of compositions comprising one or more ASBTIs or other compounds described herein, the compositions are delivered to the colon without being absorbed in the upper intestine by coating the formulation with a redox (oxidation-reduction) sensitive polymer that is degraded by the colonic microflora (bacteria). In such biodegradable systems, such polymers include, by way of non-limiting example, redox sensitive polymers that contain azo and / or disulfide bonds in the backbone.

[0249] In some embodiments, compositions formulated for delivery to the colon and / or rectum are formulated for time release, hi some embodiments, the time release formulation resists the acidic environment of the stomach, thereby delaying release of the enteroendocrine peptide secretagogue until the formulation enters the colon and / or rectum.

[0250] In certain embodiments, the time-release formulations described herein include a capsule (containing an enteroendocrine peptide secretagogue and an optional absorption inhibitor) with a hydrogel plug. In certain embodiments, the capsule and hydrogel plug are covered with a water-soluble cap, and the entire unit is coated with an enteric polymer. When the capsule enters the small intestine, the enteric coating dissolves, and the hydrogel plug swells and detaches from the capsule after a period of time, releasing the composition from the capsule. The amount of hydrogel is used to adjust the period of content release.

[0251] In some embodiments, oral dosage forms are provided herein that include multiple coatings, the coatings comprising different layers of polymers with different pH sensitivities. As the coated formulation moves along the GIT, the different layers dissolve depending on the pH encountered. Polymers used in such formulations include, by way of non-limiting example, polymethacrylates with suitable pH solubility properties, Eudragit® RL and Eudragit® RS (inner layer), and Eudragit® FS (outer layer). In other embodiments, the dosage form is an enteric coated tablet with an outer shell of hydroxypropyl cellulose or hydroxypropyl methylcellulose acetate succinate (HPMCAS).

[0252] In some embodiments, provided herein are oral dosage forms comprising a coating with cellulose butyrate phthalate, cellulose hydrogen phthalate, cellulose proprionate phthalate, polyvinyl acetate phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate, dioxypropyl methylcellulose succinate, carboxymethyl ethyl cellulose, hydroxypropyl methylcellulose acetate succinate; polymers and copolymers formed from acrylic acid, methacrylic acid, and combinations thereof.

[0253] Combination therapy In some embodiments, the methods provided herein include administering a compound (e.g., ASBTI) or composition described herein in combination with one or more additional agents. In some embodiments, the present invention also provides compositions comprising a compound (e.g., ASBTI) with one or more additional agents.

[0254] Fat-soluble vitamins In some embodiments, the methods provided herein further comprise administering one or more vitamins, in some embodiments, the vitamins are vitamin A, B1, B2, B3, B5, B6, B7, B9, B12, C, D, E, K, folic acid, pantothenic acid, niacin, riboflavin, thiamine, retinol, beta-carotene, pyridoxine, ascorbic acid, cholecalciferol, cyanocobalamin, tocopherol, phylloquinone, menaquinone.

[0255] In some embodiments, the vitamin is a fat-soluble vitamin such as vitamin A, D, E, K, retinol, beta-carotene, cholecalciferol, tocopherol, phylloquinone, etc. In a preferred embodiment, the fat-soluble vitamin is tocopherol polyethylene glycol succinate (TPGS).

[0256] ASBTI and PPAR agonists In various embodiments, the present invention provides methods of using a combination of ASBTI and a PPAR (peroxisome proliferator-activated receptor) agonist. In various embodiments, the PPAR agonist is a fibrate. In some embodiments, the fibrate is clofibrate, gemfibrozil, ciprofibrate, benzafibrate, fenofibrate, or various combinations thereof. In various embodiments, the PPAR agonist is aleglitazar, muraglitazar, tesaglitazar, saroglitazar, GW501516, GW-9662, a thiazolidinedione (TZD), an NSAID (e.g., IBUPROFEN), an indole, or various combinations thereof.

[0257] ASBTI and FXR Medications In various embodiments, the present invention provides methods of using a combination of an ASBTI and a farnesoid X receptor (FXR) targeted drug. In various embodiments, the FXR targeted drug is avermectin B1a, bepridil, fluticasone propionate, GW4064, gliquidone, nicardipine, triclosan, CDCA, ivermectin, chlorotrianisene, tribenoside, mometasone furoate, miconazole, amiodarone, butoconazole, bromocriptine mesylate, pizotifen malate, or various combinations thereof.

[0258] Partial External Biliary Diversion (PEBD) In some embodiments, the methods provided herein further include using partial external biliary drainage as a treatment for patients who have not yet developed cirrhosis. This treatment method helps to reduce bile acid / salt circulation in the liver to reduce complications and prevent the need for early transplant in many patients.

[0259] This surgical technique involves isolating a 10 cm long section of intestine from the rest of the intestine to be used as a biliary conduit (a passageway for the passage of bile). One end of the conduit is attached to the gallbladder, and the other end is brought out to the skin to form a stoma (a surgically constructed opening to allow the passage of waste). Partial external biliary stomy may be used in patients who do not respond to all medical treatments, especially older, larger patients. This technique may not be helpful in younger patients, such as infants. Partial external biliary stomy may reduce the intensity of itching and lower blood cholesterol levels.

[0260] ASBTI and Ursodiol In some embodiments, ASBTI is administered in combination with ursodiol or ursodeoxycholic acid, chenodeoxycholic acid, cholic acid, taurocholic acid, ursocholic acid, glycocholic acid, glycodeoxycholic acid, taurodeoxycholic acid, taurocholic acid, glycochenodeoxycholic acid, tauroursodeoxycholic acid. In some instances, increasing the concentration of bile acids / salts in the distal gut induces intestinal regeneration, reduces intestinal damage, reduces bacterial translocation, inhibits the release of free radical oxygen, inhibits the production of inflammatory cytokines, or any combination thereof.

[0261] In certain embodiments, a patient receives about or at least about 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 36 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 ... Ursodiol is administered at daily doses of 0 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1,000 mg, 1,250 mg, 1,500 mg, 1,750 mg, 2,000 mg, 2,250 mg, 2,500 mg, 2,750 mg, or 3,000 mg. In certain embodiments, a patient receives about 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 36 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg , 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1,000 mg, 1,250 mg, 1,500 mg, 1,750 mg, 2,000 mg, 2,250 mg, 2,500 mg, 2,750 mg, 3,000 mg, or 3,500 mg or less per day. In various embodiments, patients are administered ursodiol at a daily dose of about or at least about 3 mg to about 300 mg, about 30 mg to about 250 mg, about 36 mg to about 200 mg, about 10 mg to about 3000 mg, about 1000 mg to about 2000 mg, or about 1500 to about 1900 mg.

[0262] In various embodiments, the ursodiol is administered as a tablet. In various embodiments, the ursodiol is administered as a suspension. In various embodiments, the concentration of ursodiol in the suspension is about 10 mg / mL to about 200 mg / mL, about 50 mg / mL to about 150 mg / mL, about 10 mg / mL to about 500 mg / mL, or about 40 mg / mL to about 60 mg / mL. In various embodiments, the concentration of ursodiol in the suspension is about or at least about 20 mg / mL, 25 mg / mL, 30 mg / mL, 35 mg / mL, 40 mg / mL, 45 mg / mL, 50 mg / mL, 55 mg / mL, 60 mg / mL, 65 mg / mL, 70 mg / mL, 75 mg / mL, or 80 mg / mL. In various embodiments, the concentration of ursodiol in the suspension is about 25 mg / mL or less, 30 mg / mL or less, 35 mg / mL or less, 40 mg / mL or less, 45 mg / mL or less, 50 mg / mL or less, 55 mg / mL or less, 60 mg / mL or less, 65 mg / mL or less, 70 mg / mL or less, 75 mg / mL or less, 80 mg / mL or less, or 85 mg / mL or less.

[0263] The ASBTI and the second active ingredient are used such that the combination is present in a therapeutically effective amount. The therapeutically effective amount may result from the use of the combination of ASBTI and another active ingredient (e.g., ursodiol), each of which is used in a therapeutically effective amount, or each of which may be used in a subclinical therapeutically effective amount, i.e., an amount that would be less effective for the therapeutic purpose described herein if used alone, provided that the combination is therapeutically effective due to the additive or synergistic effects resulting from the combination. In some embodiments, the use of the combination of ASBTI and any other active ingredient described herein encompasses combinations 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 combination is therapeutically effective due to their additive or synergistic effects. As used herein, the term "additive effect" describes a combined effect of two (or more) pharmaceutically active agents that is equal to the sum of the effects of each agent given alone. A synergistic effect is an effect in which the combined effect of two (or more) pharmaceutically active agents is greater than the sum of the effects of each agent given alone. Any suitable combination of ASBTI with one or more of the other active ingredients discussed above, and optionally with one or more other pharmacologically active substances, is contemplated within the scope of the methods described herein.

[0264] In some embodiments, the specific selection of compounds depends on the diagnosis of the attending physician and the attending physician's judgment regarding the individual's condition and the appropriate treatment protocol. Compounds are optionally administered simultaneously (e.g., simultaneously, essentially simultaneously, or within the same treatment protocol) or sequentially, depending on the nature of the disease, disorder, or condition, the individual's condition, and the actual selection of compounds used. In certain instances, the determination of the order of administration and the number of repetitions of administration of each therapeutic agent during the treatment protocol is based on the evaluation of the disease being treated and the individual's condition.

[0265] In some embodiments, the therapeutically effective dosage changes when drugs are used in a therapeutic combination. Methods for experimentally determining the therapeutically effective dosages of drugs and other agents for use in combination therapy regimens are described in the literature.

[0266] In some embodiments of the combination therapy described herein, the dosage of the co-administered compound varies depending on the type of co-drug used, the specific drug used, the disease or condition being treated, etc. Furthermore, when co-administered with one or more biologically active agents, the compounds provided herein are optionally administered simultaneously or sequentially with the biologically active agents. In certain instances, when administered sequentially, the attending physician will determine the appropriate sequence of the therapeutic compounds described herein in combination with the additional therapeutic agent.

[0267] Multiple therapeutic agents (at least one of which is a therapeutic compound described herein) are optionally administered in any order or simultaneously. When administered simultaneously, multiple therapeutic agents are optionally provided in a single, integrated form, or in multiple forms (by way of example only, either as a single pill or two separate pills). In certain examples, one of the therapeutic agents is optionally given in multiple doses. In other examples, both are optionally given as multiple doses. If not simultaneously, the timing between the multiple doses is any suitable timing, for example, more than 0 weeks to less than 4 weeks. Furthermore, the combination methods, compositions and formulations are not limited to the use of only two agents; multiple therapeutic combinations are also envisioned (including those that include more than two compounds described herein).

[0268] In certain embodiments, the dosage regimen for treating, preventing or improving the condition that is sought to be alleviated is modified according to various factors.These factors include the disorder that the subject suffers from, as well as the age, weight, sex, diet and medical condition of the subject.Therefore, in various embodiments, the dosage regimen that is actually used varies and deviates from the dosage regimen described herein.

[0269] In some embodiments, the pharmaceutical agents constituting the combination therapy 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 constituting the combination therapy are administered sequentially, with either therapeutic compound being administered by a regimen requiring two-step administration. In some embodiments, the two-step administration regimen requires sequential administration of the active agents or spaced administration of the separate active agents. In certain embodiments, the period between the multiple administration steps varies from minutes to hours, depending on the properties of each pharmaceutical agent, such as, by way of non-limiting example, the potency, solubility, bioavailability, plasma half-life, and kinetic profile of the pharmaceutical agent.

[0270] In certain embodiments, combination therapy is provided herein. In certain embodiments, the composition described herein comprises an additional therapeutic agent. In some embodiments, the method described herein comprises administering a second dosage form comprising an additional therapeutic agent. In certain embodiments of combination therapy, the composition described herein is administered as part of a regimen. Thus, the additional therapeutic agent and / or additional pharmaceutical dosage form can be applied to the patient either directly or indirectly, simultaneously or sequentially with the composition and formulation described herein.

[0271] kit In another aspect, provided herein is a kit comprising a device for oral administration and a pharmaceutical composition as described herein. In certain embodiments, the kit comprises a prefilled sachet or bottle for oral administration. In certain embodiments, the kit comprises a prefilled syringe for oral or enema administration.

[0272] Release in the distal ileum and / or colon In certain embodiments, the dosage form comprises a matrix (e.g., a matrix comprising hypromellose) that allows for controlled release of the active agent in the distal jejunum, proximal ileum, distal ileum and / or colon. In some embodiments, the dosage form comprises a polymer that is pH sensitive (e.g., MMX™ matrix from Cosmo Pharmaceuticals) that 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 acid polymers (e.g., anionic polymers of methacrylic acid and / or methacrylic acid esters, e.g., Carbopol® polymers) that contain acidic groups (e.g., -COOH, -SC3H) and swell at the basic pH of the intestine (e.g., a pH of about 7 to about 8). In some embodiments, the dosage form suitable for controlled release in the distal ileum comprises a particulate active agent (e.g., a micronized active agent). In some embodiments, a non-enzymatically degrading poly(dl-lactide-co-glycolide) (PLGA) core is suitable for delivery of ASBTI to the distal ileum. In some embodiments, dosage forms containing ASBTI are coated with enteric polymers (e.g., Eudragit® S-100, cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, anionic polymers such as methacrylic acid and methacrylic acid esters) for site-specific delivery to the ileum and / or colon. In some embodiments, bacterial activation systems are suitable for targeted delivery to the ileum. Examples of microflora activation systems include dosage forms containing pectin, galactomannan, and / or Azo hydrogels and / or glycoside conjugates of active agents (e.g., conjugates of D-galactosides, β-D-xylopyranosides, etc.). Examples of gut microflora enzymes include bacterial glycosidases, such as D-galactosidase, β-D-glucosidase, α-L-arabinofuranosidase, β-D-xylopyranosidase.

[0273] The pharmaceutical solid dosage forms described herein optionally contain an additional therapeutic compound as described herein, as well as one or more pharma- ceutically acceptable additives, such as a compatible carrier, a binder, a filler, a suspending agent, a flavoring agent, a sweetener, a disintegrant, a dispersant, a surfactant, a lubricant, a coloring agent, a diluent, a solubilizer, a humectant, a plasticizer, a stabilizer, a permeation enhancer, a wetting agent, an antifoaming agent, an antioxidant, a preservative, or one or more combinations thereof. In some aspects, a film coating is provided around the formulation of ASBTI using standard coating procedures, such as those described in Remington's Pharmaceutical Sciences, 20th Edition (2000). In one embodiment, the compound described herein is in the form of particles, and some or all of the particles of the compound are coated. In certain embodiments, some or all of the particles of the compound described herein are microencapsulated. In some embodiments, the particles of the compound described herein are not microencapsulated and are not coated.

[0274] ASBT inhibitors can be used for the preparation of medicaments for the prophylactic and / or therapeutic treatment of cholestasis or cholestatic liver disease.The method for treating any of the diseases or conditions described herein in an individual who needs such treatment can comprise administering to said individual a therapeutically effective amount of a pharmaceutical composition comprising at least one ASBT inhibitor described herein, or its pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate. EXAMPLES

[0275] The following examples are provided to further illustrate some of the embodiments disclosed herein. The examples are intended to illustrate, but not limit, the disclosed embodiments.

[0276] Example 1. Administration of an apical sodium-dependent bile acid transporter inhibitor (ASBTI) in the fasted state minimizes gastrointestinal adverse effects while maintaining pharmacodynamic efficacy Apical sodium-dependent bile acid transporter inhibitors (ASBTIs), also known as ileal bile acid transporter inhibitors (IBATi), decrease the enterohepatic circulation of bile acids (BAs) by decreasing BA reabsorption and increasing fecal BA (fBA) excretion. ASBTIs, such as maralixibat (MRX; recently approved for the treatment of cholestatic pruritus in patients with Alagille syndrome [ALGS] aged >1 year) and vorixibat (VLX), decrease the toxic accumulation of BAs in the liver and alleviate cholestasis. GI adverse effects (AEs; diarrhea, abdominal pain) are potential side effects of ASBTIs, but MRX and VLX can be taken in the fasted state 30 min before a meal, which may minimize GIAEs. The objective of this analysis was to understand the impact of timing of ASBTI administration relative to mealtime on pharmacodynamic (PD) effects and gastrointestinal adverse events (GIAEs).

[0277] AE data from three separate Phase 1 clinical trials of MRX and VLX in healthy participants were compiled to evaluate the effect of ASBTI administration versus mealtime on GIAEs (Table 1, Figure 1). In each clinical trial, ASBTI was administered in both fed and fasted states and rates of GIAEs were compared. Separately, AE data from a placebo (PBO)-controlled study in ALGS patients in which MRX was administered 30 min prior to a meal allows for a comparison of GIAE rates with MRX versus PBO.

[0278] Across three Phase 1 clinical trials, there were lower rates of GI adverse events (AEs) when ASBTI was administered in the fasted state (0%, 0%, and 50% GIAEs reported in Studies 1, 2, and 3, respectively) compared with when administered in the fed state or with a meal (75%, 33%, and 100% in Studies 1, 2, and 3, respectively) (Figure 2). In a PBO-controlled study in ALGS patients where MRX was administered in the fasted state 30 min prior to a meal, diarrhea was reported with similar frequency in patients receiving the drug and those receiving PBO (43.6% for MRX and 44.4% for PBO).

[0279] The PD effect of time of administration of ASBTI relative to mealtime was examined in healthy dogs (Figure 3). In healthy dogs, MRX significantly increased fBA excretion regardless of time of administration relative to the daily meal (p<0.01 vs. pretreatment baseline by paired t-test). The greatest increase in fBA excretion was seen when administered 30 min before the meal (231% increase) to 4 h after the meal (229% increase), indicating flexibility in the timing of ASBTI administration relative to mealtime to maintain maximum PD effects (Figure 4). P<0.01 vs. pretreatment by paired one-tailed t-test. Data are presented as ± SEM (n=7-8). %=change compared to pretreatment values. Each group was administered at the indicated times. Fecal samples were collected 48 h before the start of treatment and for the last 72 h of the 7-day treatment period and analyzed for bile acid content.

[0280] The animal PD data demonstrated herein showed that there is flexibility in dosing ASBTI relative to food to increase fBA excretion. Optimal GI tolerability of ASBTI dosing in healthy individuals is achieved by dosing in the fasted state. The rate of GIAEs in ALGS patients administered MRX in the fasted state was similar to PBO. Future studies may allow for more detailed elucidation of the relationship between food, ASBTI dosing, GIAEs, and efficacy.

[0281] These data demonstrate improved GI tolerability when ASBTI is administered in the fasted state versus with a meal or immediately following food ingestion. Animal data show that PD efficacy is maintained regardless of time of administration relative to mealtime, suggesting efficacy can be maintained while minimizing GI effects.

[0282] [Table 1]

[0283] All references cited anywhere within this specification are incorporated herein by reference in their entirety for all purposes.

[0284] 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.

[0285] The recitation of ranges of values ​​herein, unless otherwise stated herein, is merely intended to serve as a shorthand method of referring individually to each separate value and each endpoint falling within the range, and each separate value and endpoint is incorporated herein as if they were individually recited herein.

[0286] Numerous variations, changes, and substitutions will occur to those skilled in the art without departing from the present invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in carrying out 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

Claim 1: A composition for use in a method for treating cholestatic liver disease in a subject in need thereof, comprising an apical sodium-dependent bile acid transporter inhibitor (ASBTI), wherein the ASBTI is 【Chemical 1】 or a pharmaceutically acceptable salt thereof, wherein the method comprises administering a therapeutically effective amount of ASBTI to a subject prior to ingestion of food, wherein the subject experiences a reduction in the frequency and / or severity of one or more side effects associated with administration of ASBTI, wherein the frequency and / or severity of the side effects is reduced compared to side effects when the ASBTI is administered after ingestion of food, simultaneously with food, or mixed with food.

2. 2. The composition of claim 1, wherein (i) the cholestatic liver disease is pediatric cholestatic liver disease, or (ii) the cholestatic liver disease is adult cholestatic liver disease.

3. The cholestatic liver disease includes 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 parenteral nutrition-associated cholestasis, paraneoplastic cholestasis, Stauffer's syndrome, intrahepatic cholestasis of pregnancy, and contraceptives.

2. The composition of claim 1, wherein the condition is selected from the group consisting of: cholestasis associated with liver cirrhosis, drug-related cholestasis, infection-related cholestasis, Dubin-Johnson syndrome, primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), cholelithiasis, Alagille syndrome, biliary atresia, biliary atresia after Kasai operation, biliary atresia after liver transplantation, cholestasis after liver transplantation, post-liver transplant-related liver disease, liver damage complicated with intestinal failure, bile acid-mediated liver injury, MRP2 deficiency syndrome, and neonatal sclerosing cholangitis.

4. 10. The composition of claim 1, wherein the one or more side effects are diarrhea, loose stools, nausea, gastrointestinal pain, abdominal pain, cramps, anorectal discomfort, or a combination thereof.

5. 10. The composition of claim 1, wherein the ASBTI is administered to the subject in a fasted state.

6. 10. The composition of claim 1, wherein the ASBTI is administered less than about 60 minutes before ingestion of food, or less than about 30 minutes before ingestion of food, or immediately before ingestion of food.

7. 10. The composition of claim 1, wherein the ASBTI is administered at least 4 hours after the last meal.

8. 10. The composition of claim 1, wherein the ASBTI is administered once daily or twice daily.

9. 10. The composition of claim 1, wherein the ASBTI is administered in an amount of about 0.1 mg to about 100 mg per dose, or in an amount of about 10 mg to about 100 mg per dose, or in an amount of about 20 mg to about 80 mg per dose.

10. 10. The composition of claim 1, wherein the ASBTI is administered in an amount of about 100 μg / kg / day to 1400 μg / kg / day, or about 400 μg / kg / day to about 800 μg / kg / day.

11. ASBTI is 【Chemistry 2】 The composition according to any one of claims 1 to 10,

12. The composition of any one of claims 1 to 10, wherein the ASBTI is vorixibat or a pharmaceutically acceptable salt thereof.

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

14. The composition of claim 13, wherein the one or more side effects are diarrhea, loose stools, nausea, gastrointestinal pain, abdominal pain, cramps, anorectal discomfort, or a combination thereof.

15. The composition described in claim 13 or 14, wherein the one or more side effects are improved by at least 10% compared to the side effects when ASBTI is administered after ingestion of food, simultaneously with food, or mixed with food.

16. The composition of claim 15, wherein the one or more side effects are improved by at least 20% compared to the side effects when ASBTI is administered after ingestion of food, simultaneously with food, or mixed with food.

17. The composition of claim 16, wherein the one or more side effects are improved by at least 50% compared to the side effects when ASBTI is administered after ingestion of food, simultaneously with food, or mixed with food.

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