Methods for treating cholestasis

Abstract

To provide methods for treating cholestasis in a subject having liver disease.SOLUTION: Methods include administering an Apical Sodium-dependent Bile Acid Transport Inhibitor (ASBTI) to a subject. More specifically, the present invention relates to methods for treating cholestasis in a subject, including administering the ASBTI to the subject at a dose of at least 10 μg / kg / day.SELECTED DRAWING: None

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional Application Nos. 62 / 804,523, filed February 12, 2019, 62 / 863,904, filed June 20, 2019, 62 / 908,431, filed September 30, 2019, and 62 / 932,015, filed November 7, 2019, which are hereby incorporated by reference in their entireties for all purposes. [Technical Field]

[0002] The present invention relates generally to methods of treating cholestasis in a subject having liver disease. More specifically, the present invention relates to methods of treating cholestasis in a subject comprising administering ASBTI to the subject at a dose of at least 10 μg / kg / day. [Background technology]

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

[0004] Neonatal respiratory distress syndrome and pneumonia are frequently associated with intrahepatic cholestasis of pregnancy. Aggressive treatment and prevention are limited. Currently, effective treatments for hypercholesterolemia and cholestatic liver disease include surgery, liver transplantation, and, rarely, ursodiol administration. Effective and safe pharmacologic therapies for hypercholesterolemia and cholestatic liver disease are needed. Summary of the Invention [Means for solving the problem]

[0005] Various non-limiting aspects and embodiments of the present invention are described below.

[0006] In one aspect, the present invention provides a method of treating cholestatic liver disease in a subject, comprising administering to the subject an apical sodium-dependent bile acid transporter inhibitor (ASBTI), wherein the ASBTI is administered in an amount of about 10 μg / kg / day to about 1400 μg / kg / day.

[0007] In some embodiments, the ASBTI is [ka] or a pharmaceutically acceptable salt thereof. In various embodiments, ASBTI is maralixibat, or a pharmaceutically acceptable salt thereof. In some embodiments, ASBTI is volixibat, or a pharmaceutically acceptable salt thereof. In certain embodiments, ASBTI is odevixibat, or a pharmaceutically acceptable salt thereof. In various embodiments, ASBTI is elobixibat, or a pharmaceutically acceptable salt thereof. In certain embodiments, ASBTI is GSK2330672, or a pharmaceutically acceptable salt thereof.

[0008] In some embodiments, cholestatic liver disease is pediatric cholestatic liver disease that causes below-normal growth, height or weight.In various embodiments, cholestatic liver disease is selected from progressive familial intrahepatic cholestasis (PFIC), Alagille syndrome (ALGS), primary sclerosing cholangitis (PSC), biliary atresia, intrahepatic cholestasis of pregnancy (ICP) or primary biliary cholangitis (PBC).In some embodiments, cholestatic liver disease is biliary atresia.In various embodiments, cholestatic liver disease is ICP.

[0009] In certain embodiments, the cholestatic liver disease is PFIC. In some embodiments, ASBTI is odevixibat. In certain embodiments, ASBTI is maralixibat. In certain embodiments, PFIC is selected from PFIC type 1, PFIC type 2, and PFIC type 3. In various embodiments, PFIC is PFIC type 2. In some embodiments, the subject has a non-truncating mutation in the ABCB11 gene. In various embodiments, the subject is a pediatric subject. In certain embodiments, ASBTI is administered once daily (QD).

[0010] In various embodiments, ASBTI is administered twice daily (BID). In some embodiments, ASBTI is administered in an amount of about 140 μg / kg / day to about 1400 μg / kg / day. In some embodiments, ASBTI is administered in an amount of about 280 μg / kg / day to about 1400 μg / kg / day.

[0011] In certain embodiments, administration of ASBTI results in a reduction in symptoms of cholestatic liver disease or a change in a disease-related laboratory measurement that is maintained for at least one year. In various embodiments, the reduction in symptoms or a change in a disease-related laboratory measurement includes a decrease in sBA concentration, an increase in serum 7α-hydroxy-4-cholesten-3-one (7αC4) concentration, an increase in the ratio of serum 7αC4 concentration to serum bile acid (sBA) concentration (7αC4:sBA), a reduction in pruritus (itch), an increase in quality of life inventory score, an increase in quality of life inventory score for fatigue, an increase in growth, or a combination thereof. In various embodiments, the reduction in symptoms or a change in a disease-related laboratory measurement is determined compared to baseline levels. In certain embodiments, the reduction in symptoms or a change in a disease-related laboratory measurement includes an increase in growth. In various embodiments, the increase in growth of a pediatric subject is measured as an increase in height Z-score or weight Z-score.

[0012] In certain embodiments, administration of ASBTI results in an increase in serum 7αC4 concentration. In some embodiments, the serum 7αC4 concentration is increased by about 1.5-fold to about 40-fold over baseline. In various embodiments, the serum 7αC4 concentration is increased by at least 100% over baseline. In some embodiments, administration of ASBTI results in an increase in the ratio of serum 7αC4 concentration to sBA concentration (7αC4:sBA). In certain embodiments, 7αC4:sBA is increased by about 2-fold to about 5000-fold over baseline.

[0013] In various embodiments, the method further comprises administering a second dose of ASBTI, the second dose being greater than the first dose, if 7αC4:sBA is not maintained at a value greater than about 2-fold above the baseline ratio after administration of the first dose of ASBTI. In some embodiments, the method further comprises administering a second dose of ASBTI, the second dose being greater than the first dose, if 7αC4:sBA initially increases to a value greater than at least 2-fold above the baseline ratio and then begins to decrease and return to the baseline ratio.

[0014] In various embodiments, administration of ASBTI results in a decrease in sBA concentrations of at least about 70% relative to baseline. In certain embodiments, administration of ASBTI results in a reduction in the severity of pruritus. In various embodiments, a reduction in the severity of pruritus is measured as a decrease in the observer-reported Itch Reported Outcome (ITCHRO(OBS)) score of at least 1.0 compared to baseline. In some embodiments, administration of ASBTI results in an ITCHRO(OBS) score of 1 or greater. In various embodiments, administration of ASBTI results in an increase in a quality of life scale score or a quality of life scale score for fatigue. In certain embodiments, the quality of life scale score is a health-related quality of life (HRQoL) score for fatigue. In various embodiments, the quality of life scale score is a pediatric quality of life scale (PedsQL) score, and the PedsQL score increases by at least 10% relative to baseline.

[0015] In some embodiments, serum bilirubin concentrations are at about pre-administration baseline levels about 4 months after the first administration of ASBTI. In some embodiments, serum alanine aminotransferase (ALT) concentrations are at about pre-administration baseline levels about 4 months after the first administration of ASBTI. In certain embodiments, serum aspartate aminotransferase (AST) concentrations and serum bilirubin concentrations are within the normal range about 4 months after the first administration of ASBTI. In various embodiments, administration of ASBTI results in serum ALT concentrations that are reduced by at least about 10% relative to baseline.

[0016] In some embodiments, the cholestatic liver disease is ALGS. In various embodiments, the subject is a pediatric subject.

[0017] In certain embodiments, ASBTI is administered once daily (QD). In various embodiments, ASBTI is administered twice daily (BID). In some embodiments, ASBTI is administered in an amount of about 140 μg / kg / day to about 1400 μg / kg / day. In some embodiments, ASBTI is administered in an amount of about 280 μg / kg / day to about 1400 μg / kg / day.

[0018] In certain embodiments, administration of ASBTI results in a reduction in symptoms of cholestatic liver disease or a change in disease-related laboratory measurements that is maintained for at least 6 months. In various embodiments, the reduction in symptoms or the change in disease-related laboratory measurements includes a decrease in sBA concentration, an increase in serum 7αC4 concentration, a reduction in pruritus, an increase in quality of life scale scores, an increase in quality of life scale scores for fatigue, a decrease in xanthomas score, an increase in growth, or a combination thereof. In some embodiments, the reduction in symptoms or the change in disease-related laboratory measurements is determined compared to baseline levels. In various embodiments, the reduction in symptoms or the change in disease-related laboratory measurements includes an increase in growth. In some embodiments, the increase in growth of a pediatric subject is measured as an increase in height Z score or weight Z score. In certain embodiments, the reduction in symptoms or the change in disease-related laboratory measurements is maintained for at least 2 years.

[0019] In various embodiments, administration of ASBTI results in a reduction in the intensity of pruritus. In some embodiments, the subject's ITCHRO(OBS) score is reduced by at least 40% compared to baseline. In certain embodiments, the subject's CSS score is reduced by at least 50% compared to baseline. In various embodiments, the subject has an ITCHRO(OBS) score of 1 or less on at least 50% of days after 6 months. In certain embodiments, administration of ASBTI results in a sustained, progressive reduction in the severity and frequency of pruritus over time.

[0020] In some embodiments, administration of ASBTI results in a reduction of sBA concentration by at least 30% by 18 weeks. In various embodiments, administration of ASBTI results in a reduction of sBA concentration by at least 50%. In certain embodiments, administration of ASBTI is consistent with a positive correlation between the reduction of sBA concentration and the reduction of pruritus severity. In some embodiments, administration results in a reduction of the subject's xanthomas score by at least 25%.

[0021] In various embodiments, administration of ASBTI results in an increase in quality of life scale score. In some embodiments, the quality of life scale score is a health-related quality of life (HRQoL) score. In particular embodiments, the quality of life scale score is a pediatric quality of life scale (PedsQL) score, and the PedsQL score increases by at least 10% over baseline. In some embodiments, administration of ASBTI results in a decrease in serum cholesterol concentration of at least 15% by 18 weeks. In some embodiments, administration of ASBTI results in an increase in serum 7αC4 concentration of at least 50% by about 18 weeks.

[0022] In certain embodiments, ASBTI is administered for a period of up to 3 years. In various embodiments, ASBTI is administered for a period of up to 4 years.

[0023] In various embodiments, the cholestatic liver disease is PSC and the ASBTI is vorixibat or a pharmaceutically acceptable salt thereof. In some embodiments, the subject is an adult. In some embodiments, the ASBTI is administered once daily (QD). In various embodiments, the ASBTI is administered twice daily (BID). In various embodiments, the ASBTI is administered in an amount of about 0.5 mg / day to about 100 mg / day.

[0024] In some embodiments, the administration of ASBTI results in the alleviation of symptoms of cholestatic liver disease or the change of disease-related laboratory measurements, which lasts for at least 4 weeks.In various embodiments, the alleviation of symptoms or the change of disease-related laboratory measurements comprises the reduction of sBA concentration, the increase of serum 7αC4 concentration, the decrease of serum autotaxin concentration, the alleviation of pruritus, the increase of quality of life scale score, the increase of quality of life scale score for fatigue, or a combination thereof.In certain embodiments, the alleviation of symptoms or the change of disease-related laboratory measurements is determined by comparing with baseline level.

[0025] In some embodiments, the degree of symptom relief or change in disease-related laboratory measurements is positively correlated with the subject's baseline ITCHRO score. In certain embodiments, the degree of symptom relief or change in disease-related laboratory measurements is greater when the subject has a baseline ITCHRO score of at least 4 than when the subject has a baseline ITCHRO score of less than 4.

[0026] In various embodiments, administration of ASBTI results in a reduction in the severity of pruritus. In various embodiments, the subject's ITCHRO score is reduced by at least 40% relative to baseline by 14 weeks. In some embodiments, the subject's ITCHRO score is reduced by at least 60% relative to a baseline ITCHRO score of 4 or greater.

[0027] In certain embodiments, administration of ASBTI results in a decrease in sBA concentration of at least 30% relative to baseline. In some embodiments, if the subject has a baseline ITCHRO score of at least 4, the sBA concentration is decreased by at least 45% relative to baseline. In various embodiments, administration of ASBTI results in a decrease in total serum cholesterol concentration of at least 10 mg / dL. In some embodiments, if the subject has a baseline ITCHRO score of at least 4, the decrease in total serum cholesterol concentration is at least 12.5 mg / dL.

[0028] In certain embodiments, administration of ASBTI results in a decrease in serum LDL cholesterol concentration of at least 5%. In various embodiments, administration of ASBTI results in a decrease in serum LDL cholesterol concentration of at least 10 mg / dL. In some embodiments, administration of ASBTI results in an increase in serum 7αC4 concentration of at least 30% relative to baseline.

[0029] In certain embodiments, administration of ASBTI results in a decrease in serum autotaxin concentration of at least 50% when the subject has a baseline ITCHRO score of at least 4. In various embodiments, administration of ASBTI results in a decrease in serum autotaxin concentration of at least 10% by week 6 and at least 20% by week 14. In various embodiments, administration of ASBTI results in no significant change from baseline in serum conjugated bilirubin concentration when the subject has a baseline ITCHRO score of at least 4. In various embodiments, administration of ASBTI results in no significant change from baseline in serum bilirubin concentration, serum AST concentration, serum ALT concentration, serum alkaline phosphatase concentration, or some combination thereof.

[0030] In some embodiments, by day 28 of administration, the subject's fecal bile acid (fBA) excretion is increased by at least 250 μmol. In certain embodiments, by day 7 of administration, the subject's fBA excretion is increased by at least 1,000 μmol. In some embodiments, by day 7 of administration of ASBTI, the subject's fBA excretion is increased by at least 1.5-fold over baseline. In various embodiments, administration of ASBTI results in an increase in fBA excretion of at least 4-fold over baseline. In some embodiments, administration of ASBTI results in a dose-dependent increase in fBA excretion.

[0031] These and other aspects of the present invention will become apparent to those skilled in the art after reading the following detailed description of the invention, including the appended claims. [Brief explanation of the drawings]

[0032] [Figure 1] FIG. 1 shows a schematic diagram summarizing the physiological effects of maralixibat administration in patients. [Figure 2] Schematic diagram outlining the dosing regimen used in the INDIGO Phase 2, open-label, safety and efficacy clinical trial of maralixibat in children with PFIC (INDIGO clinical trial) is shown. [Figure 3A] We provide a quantitative summary of response measures measured for a responder (a 3-year-old girl) who participated in the INDIGO clinical trial. [Figure 3B] We provide a quantitative summary of response measures measured for a responder (a 10-year-old boy) who participated in the INDIGO clinical trial. [Figure 3C] We provide a quantitative summary of response measures measured for a responder (a 6-year-old girl, sister of a 10-year-old boy) who participated in the INDIGO clinical trial. [Figure 3D] We provide a quantitative summary of response measures measured for a responder (a 4-year-old girl) who participated in the INDIGO clinical trial. [Figure 3E] We provide a quantitative summary of response measures measured for a responder (a 3-year-old boy) who participated in the INDIGO clinical trial. [Figure 3F] We provide a quantitative summary of response measures measured for responders (1-year-old girls) who participated in the INDIGO clinical trial. [Figure 4] Scatter plots depicting the change in height Z-score from baseline over time for responders and non-responders in the INDIGO clinical trial. [Figure 5A] Scatter plots of serum bile acid (sBA) concentrations over time for patients enrolled in the INDIGO clinical trial and for patients with non-truncating bile salt export pump (BSEP, encoded by the ABCB11 gene) mutations. [Figure 5B]Scatter plots of serum bile acid (sBA) concentrations over time for patients participating in the INDIGO clinical trial. sBA concentrations over time for patients with truncating BSEP mutations. [Figure 6] Scatter plots plotting the mean weekly scores of the Observer-Reported Itch Reported Outcome (ITCHRO(OBS)) for patients with non-truncating BSEP mutations participating in the INDIGO clinical trial. [Figure 7] Scatter plot of mean serum 7α-hydroxy-4-cholesten-3-one (7αC4 or C4) concentrations over time for patients with non-truncating BSEP mutations participating in the INDIGO clinical trial. [Figure 8] Scatter plots showing the time course of the ratio of 7αC4 concentration to sBA concentration (7αC4:sBA) for patients with non-truncating BSEP mutations who participated in the INDIGO clinical trial are shown. [Figure 9] Provides bar graphs showing the mean change from baseline to days 6 and 7 in fecal bile acid (fBA) excretion with the indicated doses of maralixibat, vorixibat, and placebo for a Phase 1, blinded, placebo-controlled, dose-ranging clinical trial (NCT02475317). [Figure 10] 1 provides a bar graph showing the mean change from baseline to day 7 in serum 7αC4 concentrations by the indicated doses of maralixibat, vorixibat, and placebo. [Figure 11] 1 provides a bar graph showing the mean ITCHRO weekly total score in the overall population of participants in a 14-week, single-arm, open-label, early Phase 2a, proof-of-concept trial of maralixibat (CAMEO clinical trial) with itch at baseline and in participants with an ITCHRO daily score ≥ 4 at baseline. [Figure 12] Bar graphs of sBA concentrations (left panel) and 7αC4 concentrations (right panel) are shown for the overall population participating in the CAMEO clinical trial and for participants with an ITCHRO daily score of ≧4 at baseline. [Figure 13]Bar graphs of serum autotaxin concentrations (left panel) and serum low-density lipoprotein cholesterol (LDL-C) concentrations (right panel) are shown for the overall population participating in the CAMEO clinical trial and for participants with an ITCHRO daily score ≥4 at baseline. [Figure 14] Bar graphs of the percentage change from baseline to week 14 or early discontinuation in efficacy measures including ITCHRO score (1–10 daily score), sBA concentration, and serum autotaxin concentration are shown for six participants in the CAMEO clinical trial who had an ITCHRO daily score ≥4 at baseline. [Figure 15] 1 is a diagram summarizing the clinical trial design of a double-blind, randomized, placebo-controlled drug treatment withdrawal study (ICONIC clinical trial) that included an extended open-label treatment period of maralixibat 400 μg / kg QD. [Figure 16] This is a diagram summarizing the disposition of participants in the ICONIC clinical trial. [Figure 17A] 1 shows significant improvements in sBA levels compared to baseline and placebo in participants in the ICONIC clinical trial. A graph plotting the mean change in sBA concentrations from baseline to week 48 for all participants is shown. [Figure 17B] Figure 1 shows significant improvement in sBA levels compared to baseline and placebo in participants in the ICONIC clinical trial. Figure 2 shows a bar graph depicting the mean change in sBA from weeks 18 to 22 in sBA responders during the randomized treatment discontinuation period. [Figure 18] 1 shows plots of mean sBA concentrations for participants in the ICONIC clinical trial during the core study (first 48 weeks) and extension (period after 48 weeks). [Figure 19] 1 shows a bar graph depicting the mean change from baseline (BL) in sBA levels observed in the ICONIC clinical trial. [Figure 20A]This shows that improvements in ITCHRO(Obs) scores were maintained during the randomized treatment discontinuation period in maralixibat-treated participants in the ICONIC clinical trial. This shows the mean change from baseline in participants' ITCHRO(OBS) scores over time. [Figure 20B] Figure 1 shows that improvements in ITCHRO(Obs) scores were maintained during the randomized treatment discontinuation period in maralixibat-treated participants in the ICONIC clinical trial. Figure 2 shows a plot of ITCHRO(OBS) scores for participants during the placebo-controlled treatment discontinuation period. [Figure 21A]

[0023] Figure 1 shows improvement from baseline in Clinician Scratch Scale (CSS) scores across the ICONIC clinical trial. The percentage of all patients with the specified CSS scores at baseline, 18 weeks, and 48 weeks are shown. [Figure 21B] Figure 1 shows the improvement from baseline in Clinician Scratch Scale (CSS) scores across the ICONIC clinical trial. Figure 2 shows the percentage of patients with a specified CSS score at week 22 for all patients receiving maralixibat or placebo during the placebo-controlled withdrawal period. [Figure 22] Figure 1 shows the change from baseline (BL) in CSS scores for participants in the ICONIC clinical trial at 48 and 191 weeks. [Figure 23A] 1 shows a plot of the average weekly ITCHRO(OBS) scores over time for participants in the ICONIC clinical trial during the core study and extension. 2 provides a scatter plot showing the progress of the average ITCHRO(OBS) scores over time. [Figure 23B] Figure 1 shows a plot of the average weekly ITCHRO(OBS) scores over time for participants in the ICONIC clinical trial during the core study and extension, demonstrating that itch reduction was maintained in the long-term extension. [Figure 23C] Plot of weekly mean ITCHRO(OBS) scores over time for participants in the ICONIC clinical trial during the core and extension studies, showing that itch reduction was maintained with maralixibat but not with crossover to placebo treatment withdrawal periods. [Figure 23D]Plot of weekly mean ITCHRO(OBS) scores over time for participants in the ICONIC clinical trial during the core and extension studies, showing that itch reduction was maintained with maralixibat but not with crossover to placebo treatment withdrawal periods. [Figure 24] Figure 1 shows the change from baseline (BL) in ITCHRO(OBS) scores at 48 and 193 weeks for participants in the ICONIC clinical trial. [Figure 25] 1 shows a bar graph depicting the percentage of study days with an ITCHRO(OBS) score ≦1 for all participants in the ICONIC clinical trial on placebo and on maralixibat. [Figure 26] Figure 1 shows a plot of HRQoL scores over time for patients participating in the ICONIC clinical trial. [Figure 27] 1 shows a bar graph depicting the change from baseline (BL) in PEDSQL fatigue scale score (scale of 0-100) at weeks 48 and 191 for participants in the ICONIC clinical trial. [Figure 28] 1 shows a plot of Clinician Xanthomas Scale scores over time for patients participating in the ICONIC clinical trial. [Figure 29] 1 provides bar graphs showing the change from baseline (BL) in Clinician Xanthomas Scale scores for participants in the ICONIC clinical trial at 48 and 191 weeks. [Figure 30] 1 provides a scatter plot showing the time course of serum concentrations of indicators of liver function in participants in the ICONIC clinical trial. [Figure 31] 1 shows a plot of percent change from baseline in sBA against change from baseline in ITCHRO(OBS) morning weekly mean score at 48 weeks for participants in the ICONIC clinical trial. [Figure 32A] Lattice plots for each participant in the ICONIC clinical trial (identified by subject number above each plot) are shown through 48 weeks. [Figure 32B]Lattice plots for each participant in the ICONIC clinical trial (identified by subject number above each plot) are shown through 48 weeks. [Figure 32C] Lattice plots for each participant (identified by subject number above each plot) in the ICONIC clinical trial through week 48 are shown. [Figure 32D] Lattice plots for each participant in the ICONIC clinical trial (identified by subject number above each plot) are shown through 48 weeks. [Figure 32E] Lattice plots for each participant in the ICONIC clinical trial (identified by subject number above each plot) are shown through 48 weeks. [Figure 32F] Lattice plots for each participant in the ICONIC clinical trial (identified by subject number above each plot) are shown through 48 weeks. [Figure 32G] Lattice plots for each participant in the ICONIC clinical trial (identified by subject number above each plot) are shown through 48 weeks. [Figure 32H] Lattice plots for each participant in the ICONIC clinical trial (identified by subject number above each plot) are shown through 48 weeks. [Figure 33] Scatter plots depicting the mean change from baseline in height Z-score over time for all participants in the ICONIC clinical trial. [Figure 34] A scatterplot showing the mean change from baseline in height Z-score over time for ICONIC trial participants who agreed to the long-term extension of the ICONIC trial and remained in the trial for approximately 4 years (n=15). [Figure 35] Scatter plots depicting the mean change from baseline in weight Z-score over time for all participants in the ICONIC clinical trial (n=31). [Figure 36] A scatterplot showing the mean change from baseline in height Z-score over time for participants in the ICONIC clinical trial who agreed to a long-term extension of the ICONIC clinical trial and remained in the trial for approximately 4 years (n=15). DETAILED DESCRIPTION OF THE INVENTION

[0033] Detailed embodiments of the present invention are disclosed herein. However, it should be understood that the disclosed embodiments are merely exemplary of the invention, which may be embodied in various forms. Furthermore, each of the examples given in connection with various embodiments of the present invention is intended to be illustrative and 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 how to variously use the present invention.

[0034] Figure 1 shows a schematic diagram summarizing the physiological effects of maralixibat administration in patients. CYP7A1, cholesterol 7α-hydroxylase; FGF, fibroblast growth factor; FXR, farnesoid X receptor.

[0035] Figure 2 shows a schematic outlining the dosing regimen used in the INDIGO Phase 2 open-label safety and efficacy clinical trial of maralixibat in children with PFIC (INDIGO clinical trial). The clinical trial investigated long-term exposure to maralixibat.

[0036] Figures 3A–3F provide a quantitative summary of the response indices measured for the six responders who participated in the INDIGO clinical trial. The six responders were a 3-year-old girl (Figure 3A), a 10-year-old boy (Figure 3B), a 6-year-old girl (the younger sister of the 10-year-old boy) (Figure 3C), a 4-year-old girl (Figure 3D), a 3-year-old boy (Figure 3E), and a 1-year-old girl (Figure 3F). Figures 3A–3F provide three scatterplots plotting sBA levels, pruritus severity scores, and Pediatric Quality of Life Inventory (PEDSQL) scores against study week. Pruritus severity scores were measured according to the clinical scratch score (CSS) and Itch Reported Outcome (ITCHRO) scores. Each of Figures 3A-3F also provides a summary of the changes observed in ALT (alanine aminotransferase) and AST (aspartate aminotransferase) levels, bilirubin levels, and C4 levels for each responder.

[0037] Figure 4 shows a scatterplot depicting the change in height Z-score from baseline over time for responders and non-responders in the INDIGO clinical trial. The decrease in mean height Z-score at 60 weeks is due to one patient not having a measurement at that time point.

[0038] Figures 5A and 5B show scatter plots of serum bile acid (sBA) concentrations over time for patients participating in the INDIGO clinical trial. Figure 5A plots sBA concentrations over time for patients with nontruncating bile salt export pump (BSEP, encoded by the ABCB11 gene) mutations. Figure 5B plots sBA concentrations over time for patients with truncating BSEP mutations. Figures 5A and 5B show that sBA responses differ by BSEP mutation status. Black filled circles indicate the end of treatment. White filled circles indicate the start of BID dosing (280 μg / kg BID). In Figures 5A and 5B, lines corresponding to nonresponders are marked with an asterisk.

[0039] Figure 6 shows a scatterplot plotting the average weekly scores of the observer-reported itch response outcome (ITCHRO(OBS)) for patients with non-truncating BSEP mutations participating in the INDIGO clinical trial. Figure 6 demonstrates that the ITCHRO(OBS) response was sustained over the years, with >50% (10 / 19) of patients showing a reduction in ITCHRO(OBS) score of ≥1.0. Filled black circles indicate completion. Filled white circles indicate initiation of BID dosing (280 μg / kg BID). The ITCHRO(OBS) scale ranges from 0 to 4. In Figure 6, lines corresponding to non-responders are marked with an asterisk.

[0040] Figure 7 shows a scatter plot of mean serum 7α-hydroxy-4-cholesten-3-one (7αC4 or C4) concentrations over time for patients with non-truncating BSEP mutations who participated in the INDIGO clinical trial. Figure 7 demonstrates that non-truncating BSEP mutation responders showed a significant increase in 7αC4 concentrations. Black filled circles indicate the end of treatment. White filled circles indicate the start of BID dosing (280 μg / kg BID). The ITCHRO (OBS) scale ranges from 0 to 4. In Figure 7, lines corresponding to non-responders are marked with an asterisk.

[0041] Figure 8 shows a scatterplot depicting the time course of the 7αC4 to sBA ratio (7αC4:sBA) for patients with non-truncating BSEP mutations who participated in the INDIGO clinical trial. Figure 8 demonstrates that non-truncating BSEP mutation responders had significantly different 7αC4:sBA ratios than non-responders. Two non-truncating BSEP mutation responders showed an increase in the 7αC4:sBA ratio after dose escalation. Black filled circles indicate the end of treatment, while white filled circles indicate the start of BID dosing (280 μg / kg BID). The ITCHRO (OBS) scale ranges from 0 to 4. In Figure 8, the lines corresponding to non-responders are marked with an asterisk.

[0042] Figure 9 provides a bar graph showing the mean change from baseline to days 6 and 7 in fecal bile acid (fBA) excretion with the indicated doses of maralixibat, vorixibat, and placebo for the Phase 1, blinded, placebo-controlled, dose-ranging clinical trial (NCT02475317). BID, twice daily; QD, once daily; SE, standard error.

[0043] Figure 10 provides a bar graph showing the mean change from baseline to day 7 in serum 7αC4 concentrations by the indicated doses of maralixibat, vorixibat, and placebo. BID, twice daily; fBA, fecal bile acids; QD, once daily; SE, standard error.

[0044] Figure 11 provides a bar graph showing the mean ITCHRO weekly total score in the overall population of participants in a 14-week, single-arm, open-label, early Phase 2a, proof-of-concept trial of maralixibat (CAMEO clinical trial) with itch at baseline and in participants with an ITCHRO daily score of ≥ 4 at baseline.

[0045] FIG. 12 shows bar graphs of sBA concentrations (left panel) and 7αC4 concentrations (right panel) in the overall population participating in the CAMEO clinical trial and in participants with a baseline ITCHRO daily score of ≧4.

[0046] Figure 13 shows bar graphs of serum autotaxin concentrations (left panel) and serum low-density lipoprotein cholesterol (LDL-C) concentrations (right panel) in the overall population participating in the CAMEO clinical trial and in participants with an ITCHRO daily score of ≥4 at baseline.

[0047] Figure 14 shows bar graphs of the percentage change from baseline to week 14 or early discontinuation in efficacy measures including ITCHRO score (1-10 daily score), sBA concentration, and serum autotaxin concentration in six participants in the CAMEO clinical trial who had an ITCHRO daily score ≥ 4 at baseline.

[0048] FIG. 15 is a diagram summarizing the clinical trial design of a double-blind, randomized, placebo-controlled drug withdrawal study (ICONIC clinical trial) that included an extended open-label treatment period of maralixibat 400 μg / kg QD.

[0049] Figure 16 is a diagram summarizing the disposition of participants in the ICONIC clinical trial.

[0050] Figures 17A and 17B show significant improvements in sBA levels compared to baseline and placebo in participants in the ICONIC clinical trial. Figure 17A shows a graph plotting the mean change in sBA concentrations from baseline to week 48 for all participants. Figure 17B shows a bar graph depicting the mean change in sBA from weeks 18 to 22 in sBA responders during the randomized treatment withdrawal period.

[0051] Figure 18 shows a plot of the mean sBA concentrations of participants in the ICONIC clinical trial during the core study (first 48 weeks) and extension (period after 48 weeks). MRX = maralixibat; PLA = placebo.

[0052] FIG. 19 shows a bar graph depicting the mean change from baseline (BL) in sBA levels observed in the ICONIC clinical trial.

[0053] Figures 20A and 20B show that improvements in ITCHRO(Obs) scores were maintained during the randomized treatment withdrawal period in maralixibat-treated participants in the ICONIC clinical trial. Figure 20A shows the mean change from baseline in participants' ITCHRO(OBS) scores over time. Figure 20B shows a plot of participants' ITCHRO(OBS) scores during the placebo-controlled treatment withdrawal period.

[0054] Figures 21A and 21B show the improvement from baseline in Clinician Scratch Scale (CSS) scores across the ICONIC clinical trial. Figure 21A shows the percentage of all patients with a specified CSS score at baseline, Week 18, and Week 48. Figure 21B shows the percentage of patients with a specified CSS score at Week 22 for all patients who received maralixibat or placebo during the placebo-controlled withdrawal period.

[0055] Figure 22 shows the change from baseline (BL) in CSS scores for participants in the ICONIC clinical trial at 48 and 191 weeks.

[0056] Figures 23A-23D show plots of the weekly mean ITCHRO(OBS) scores over time for participants in the ICONIC clinical trial during the core study and extension. Figure 23A provides a scatterplot showing the mean ITCHRO(OBS) scores over time. Figure 23B shows that itch relief was maintained in the long-term extension. Each line represents an individual patient's ITCHRO(OBS) score. Figures 23C and 23D show that itch relief was maintained with maralixibat but not with the switch to placebo treatment withdrawal period (indicated by the boxed area in the plot). Each line represents an individual patient's ITCHRO(OBS) score. MRX = maralixibat; PLA = placebo. N = number of participants measured at the specified time point.

[0057] FIG. 24 shows the change from baseline (BL) in ITCHRO(OBS) scores at 48 and 193 weeks for participants in the ICONIC clinical trial.

[0058] FIG. 25 shows a bar graph depicting the percentage of study days with an ITCHRO(OBS) score of ≦1 for all participants in the ICONIC clinical trial while receiving placebo and while receiving maralixibat.

[0059] Figure 26 shows a plot of HRQoL scores over time for patients participating in the ICONIC clinical trial. HRQoL scores were measured as PEDSQL scores.

[0060] Figure 27 shows a bar graph depicting the change from baseline (BL) in PEDSQL Fatigue Scale score (scale of 0 to 100) at weeks 48 and 191 for participants in the ICONIC clinical trial. n = number of participants represented at the indicated time point.

[0061] FIG. 28 shows a plot of Clinician Xanthomas Scale scores over time for patients participating in the ICONIC clinical trial.

[0062] FIG. 29 provides a bar graph showing the change from baseline (BL) in Clinician Xanthomas Scale scores for participants in the ICONIC clinical trial at 48 and 191 weeks.

[0063] Figure 30 provides a scatter plot showing the time course of serum concentrations of indicators of liver function in participants in the ICONIC clinical trial: GGT, gamma-glutamyl transpeptidase;

[0064] FIG. 31 shows a plot of percent change from baseline in sBA against change from baseline in ITCHRO(OBS) morning weekly mean score at 48 weeks for participants in the ICONIC clinical trial.

[0065] Figures 32A-32H show lattice plots for each participant in the ICONIC clinical trial through week 48 (identified by subject number above each plot). Figures 32A-32H show lattice plots of sBA concentrations (blue; left axis; μmol / L) and average weekly ITCHRO(OBS) scores (red; right axis) for each participant in the ICONIC clinical trial over time (bottom axis). Figures 32A and 32D show lattice plots for patients in the MRX-MRX-MRX study group, which includes only patients who received maralixibat before, during, and after the placebo-controlled withdrawal period in the ICONIC clinical trial. Figures 32E and 32H show lattice plots for patients in the MRX-placebo-MRX study group, which includes only patients who received maralixibat before, placebo during, and again after the placebo-controlled withdrawal period. Patient 090004 did not have a post-baseline assessment, so their baseline data point is not shown in the plot.

[0066] Figure 33 shows a scatter plot of the mean change from baseline in height Z-score over time for all participants in the ICONIC clinical trial. The number of patients (N) measured at each data point is indicated below the x-axis. BL = baseline.

[0067] Figure 34 shows a scatter plot of the mean change from baseline in height Z-score over time for ICONIC clinical trial participants who agreed to the long-term extension of the ICONIC clinical trial and remained in the trial for approximately 4 years (n=15). The number of patients (N) measured at each data point is indicated below the x-axis. BL = baseline.

[0068] Figure 35 shows a scatter plot of the mean change from baseline in body weight Z-score over time for all participants (n=31) in the ICONIC clinical trial. The number of patients (N) measured at each data point is indicated below the x-axis. BL = baseline.

[0069] Figure 36 shows a scatter plot of the mean change from baseline in height Z-score over time for participants in the ICONIC clinical trial who agreed to a long-term extension of the ICONIC clinical trial and remained in the trial for approximately 4 years (n=15). The number of patients (N) measured at each data point is indicated below the x-axis. BL = baseline.

[0070] 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 through 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 attached to the end of the chain. The most common bile acids are cholic acid and chenodeoxycholic acid ("primary bile acids"). Before leaving hepatocytes 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). Conjugated bile acids, called bile salts, are more efficient surfactants than bile acids due to their amphiphilic nature. Bile salts, rather than bile acids, are found in bile.

[0071] Bile salts are secreted by hepatocytes into the bile canaliculi to form bile. The bile canaliculi empty into the left and right hepatic ducts, and 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 returned to the liver via the portal vein. Bile salts often undergo multiple enterohepatic circulations before being excreted via feces. A small proportion of bile salts can be absorbed in the proximal intestine by either passive or carrier-mediated transport. 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 movement of bile acids / salts into the portal circulation. Completion of the enterohepatic circulation occurs at the basolateral surface of hepatocytes through 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.

[0072] In the intestinal lumen, the concentration of bile acids varies depending on the large amount of reuptake that occurs in the distal intestine. Described herein are specific compositions and methods for controlling the concentration of bile acids in the intestinal lumen, thereby controlling hepatocellular damage caused by bile acid accumulation in the liver.

[0073] Types 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.

[0074] Cholestatic liver disease can be divided clinicopathologically into two major categories: obstructive, often extrahepatic, cholestasis, and nonobstructive, or intrahepatic, cholestasis. In the former, cholestasis occurs when bile flow is mechanically blocked, such as by gallstones or tumors, or as in extrahepatic biliary atresia.

[0075] The latter group, with nonobstructive intrahepatic cholestasis, is further divided into two major subgroups. In the first subgroup, cholestasis occurs when the processes of bile secretion and modification or bile component synthesis are secondary to hepatocellular injury so severe that nonspecific impairment of many functions, including those supporting 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 bile component synthesis is constitutively impaired. Such cholestasis is considered primary.

[0076] Thus, provided herein are methods and compositions for stimulating epithelial proliferation and / or regeneration of the intestinal lining and / or enhancing adaptive processes in the intestine 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.

[0077] Elevated bile acid levels, as well as elevated levels of AP (alkaline phosphatase), LAP (leukocyte alkaline phosphatase), γGT (γ-glutamyl transpeptidase), and 5'-nucleotidase, are biochemical hallmarks of cholestasis and cholestatic liver disease. 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 elevated levels of AP (alkaline phosphatase), LAP (leukocyte alkaline phosphatase), γGT (γ-glutamyl transpeptidase or GGT), and / or 5'-nucleotidase. In some such embodiments, the method comprises increasing the bile acid concentration in the intestinal lumen. Further 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.

[0078] 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 among individuals (i.e., some individuals are more sensitive to elevated levels of bile acids / salts).

[0079] 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 epithelial proliferation and / or intestinal lining regeneration and / or enhancing intestinal adaptive processes in individuals with pruritus.In some 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 acids in feces.

[0080] Another symptom of hypercholesterolemia and cholestatic liver disease is increased serum levels of conjugated bilirubin. Elevated serum levels of conjugated bilirubin result in jaundice and dark urine. Because no relationship has been established between serum levels of conjugated bilirubin and the severity of hypercholesterolemia and cholestatic liver disease, the magnitude of the increase is not diagnostically significant. Conjugated bilirubin levels rarely exceed 30 mg / dL. Accordingly, provided herein are methods and compositions for stimulating epithelial proliferation and / or regeneration of the intestinal lining and / or enhancing adaptive processes in the intestine in individuals with elevated serum levels of conjugated bilirubin. In some such embodiments, the method includes increasing bile acid concentrations in the intestinal lumen. Also provided herein are methods and compositions for treating elevated serum levels of conjugated bilirubin, including reducing overall serum bile acid load by excreting bile acids in the feces.

[0081] Increased serum concentrations of unconjugated bilirubin are 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 biliproteins). This fraction can account for a large proportion of total bilirubin in patients with cholestatic jaundice. The presence of large amounts of δ-bilirubin indicates prolonged cholestasis. δ-bilirubin in umbilical cord blood or neonatal blood is an indicator of prenatal cholestasis / cholestatic liver disease. Thus, provided herein are methods and compositions for stimulating epithelial proliferation and / or regeneration of the intestinal lining and / or enhanced adaptive processes in individuals with elevated serum concentrations of unconjugated bilirubin or δ-bilirubin. In some such embodiments, the method comprises increasing bile acid concentrations 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.

[0082] Cholestasis and cholestatic liver disease cause hypercholesterolemia. During metabolic cholestasis, hepatocytes retain bile salts. Bile salts reflux from hepatocytes into the serum, resulting in increased bile salt concentrations in the peripheral circulation. Furthermore, uptake of bile salts entering the liver through portal blood is inefficient, resulting in bile salt spillover into the peripheral circulation. Therefore, provided herein are methods and compositions for stimulating epithelial proliferation and / or regeneration of the intestinal lining and / or enhancing adaptive processes in the intestine in individuals with hypercholesterolemia. In some such embodiments, the method includes increasing bile acid concentrations in the intestinal lumen. Also provided herein are methods and compositions for treating hypercholesterolemia, including reducing overall serum bile acid load by excreting bile acids in the feces.

[0083] Hyperlipidemia is a hallmark of some, but not all, cholestatic disorders. 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 function. Furthermore, because bile salts are metabolic products of cholesterol, decreased cholesterol metabolism leads to decreased bile acid / salt synthesis. Serum cholesterol levels observed in children with cholestasis range from about 1,000 mg / dL to about 4,000 mg / dL. Accordingly, provided herein are methods and compositions for stimulating epithelial proliferation and / or regeneration of the intestinal lining and / or enhancing adaptive processes in the intestine in individuals with hyperlipidemia. In some such embodiments, the method comprises increasing bile acid concentrations in the intestinal lumen. Further provided herein are methods and compositions for treating hyperlipidemia, including reducing overall serum bile acid load by excreting bile acids in the feces.

[0084] 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 first develop 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. Accordingly, provided herein are methods and compositions for stimulating epithelial proliferation and / or regeneration of the intestinal lining and / or enhancing adaptive processes in the intestine in individuals with xanthomas. In some such embodiments, the method includes increasing bile acid concentrations in the intestinal lumen. Also provided herein are methods and compositions for treating xanthomas, including reducing overall serum bile acid load by excreting bile acids in the feces.

[0085] 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 fat digestion and absorption and reduced vitamin intake (vitamins E, D, K, and A are all malabsorbed in cholestasis). Furthermore, delivery of fat to the colon can cause colonic secretions and diarrhea. Treatments for failure to thrive include dietary substitution and supplementation with long-chain triglycerides, medium-chain triglycerides, and vitamins. Ursodeoxycholic acid, used to treat some cholestatic conditions, does not form mixed micelles and does not affect fat absorption. Therefore, provided herein are methods and compositions for stimulating epithelial proliferation and / or regeneration of the intestinal lining and / or enhancing adaptive processes in the intestine in individuals (e.g., children) with growth failure. 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.

[0086] Primary biliary cirrhosis (PBC) Primary biliary cirrhosis (PBC) is an autoimmune disease of the liver characterized by the destruction of bile canaliculi. Damage to the bile canaliculi leads to the accumulation of bile in the liver (i.e., cholestasis). Bile accumulation in the liver can damage liver tissue, potentially leading to scarring, fibrosis, and cirrhosis. PBC typically develops in adulthood (e.g., over 40 years of age). Individuals with PBC often present with fatigue, pruritus, and / or jaundice. PBC is diagnosed when individuals have elevated AP concentrations, elevated γGT levels, serum antimitochondrial antibodies (AMA) (>1:40), and florid bile duct lesions for at least 6 months. Serum ALT, AST, and conjugated bilirubin may also be elevated, but these are not considered pathognomonic for the disease. PBC-associated cholestasis has been treated or ameliorated with the 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.

[0087] Progressive familial intrahepatic cholestasis (PFIC) PFIC is a rare genetic disorder that causes progressive liver disease, usually leading to liver failure. In individuals with PFIC, liver cells are impaired in their ability to secrete bile. The resulting accumulation of bile leads to liver disease in affected individuals. Signs and symptoms of PFIC usually begin during infancy. Patients experience severe itching, jaundice, failure to grow at the expected rate (failure to thrive), and increasing liver dysfunction (liver failure). The disease is estimated to affect one in every 50,000 to 100,000 births in the United States and Europe. Six genetically identified types of PFIC have been identified, all of which are similarly characterized by impaired bile flow and progressive liver disease.

[0088] PFIC1 PFIC1 (also known as Byler disease or FIC1 deficiency) is associated with mutations in the ATP8B1 gene (also called FIC1). This gene, encoding a P-type ATPase, is located on human chromosome 18 and is also mutated in 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 is primarily expressed in cholangiocytes within the liver. The P-type ATPase appears to be an aminophospholipid transporter responsible for maintaining the enrichment of phosphatidylserine and phosphatidylethanolamine in the inner leaflet of the plasma membrane compared with 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 hepatocellular bile acid overload.

[0089] PFIC1 typically presents in infants (e.g., 6–18 months of age). Infants may exhibit 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 lack bile duct proliferation. Most individuals with PFIC1 develop end-stage liver disease by age 10. No treatment has proven beneficial for the long-term treatment of PFIC1. Children are often given medium-chain triglycerides and fat-soluble vitamins to alleviate extrahepatic symptoms (e.g., malnutrition and growth failure). Ursodiol has not been proven effective in individuals with PFIC1.

[0090] PFIC2 PFIC2 (also known as Byler syndrome or 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 the 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, resulting in reduced bile flow and intrahepatic bile salt accumulation, accompanied by ongoing severe hepatocellular damage.

[0091] PFIC2 typically presents in infants (e.g., 6–18 months of age). Infants may exhibit 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 vein inflammation and giant cell hepatitis. Additionally, individuals often develop hepatocellular carcinoma. No treatment has proven beneficial for the long-term treatment of PFIC2. To alleviate extrahepatic symptoms (e.g., malnutrition and growth failure), children are often administered medium-chain triglycerides and fat-soluble vitamins. PFIC2 patients account for approximately 60% of the PFIC population.

[0092] PFIC3 PFIC3 (also known as MDR3 deficiency) is caused by a genetic defect in the ABCB4 gene (also known as 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) across the canalicular membrane of hepatocytes. PFIC3 results from bile toxicity, in which detergent bile salts are not inactivated by phospholipids, causing damage to the bile canaliculi and bile duct epithelium.

[0093] PFIC3 also develops in early childhood. In contrast to PFIC1 and PFIC2, individuals have elevated γGT levels. Individuals also have portal vein inflammation, fibrosis, cirrhosis, and extensive bile duct proliferation. Individuals may also develop intrahepatic cholelithiasis. Ursodiol is effective in treating or ameliorating PFIC3.

[0094] Benign recurrent intrahepatic cholestasis (BRIC) BRIC1 BRIC1 is caused by a genetic defect in the FIC1 protein in the bile canalicular membrane of hepatocytes. BRIC1 is usually 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, the majority of patients do not progress to chronic liver disease. During attacks, patients develop severe jaundice and experience pruritus, steatorrhea, and weight loss. Some patients also have kidney stones, pancreatitis, and diabetes.

[0095] BRIC2 BRIC2 is caused by mutations in ABCB11, leading to defective BSEP expression and / or function in the bile canalicular membrane of hepatocytes.

[0096] BRIC3 BRIC3 is associated with defective MDR3 expression and / or function in the canalicular membrane of hepatocytes. Patients with MDR3 deficiency typically exhibit elevated serum gamma-glutamyl transpeptidase levels in the presence of normal or slightly elevated bile acid levels.

[0097] Dubin-Johnson syndrome (DJS) DJS is characterized by conjugated hyperbilirubinemia due to inherited dysfunction of MRP2. Liver function is preserved in affected individuals. Several different mutations have been associated with the condition, resulting in either a complete absence of immunohistochemically detectable MRP2 in affected individuals or impaired protein maturation and sorting.

[0098] 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 small bile ducts.

[0099] Primary sclerosing cholangitis (PSC) PSC is a chronic inflammatory liver disorder that slowly progresses to end-stage liver failure in most affected patients. PSC inflammation is characterized by fibrosis and obstruction of large and medium-sized intrahepatic and extrahepatic bile ducts.

[0100] PSC is characterized by progressive cholestasis, which often leads to severe pruritus and significantly impairs quality of life.

[0101] Intrahepatic cholestasis of pregnancy (ICP) ICP is characterized by the development of transient cholestasis or cholestatic liver disease in pregnant women, usually occurring during the third trimester of pregnancy when circulating levels of estrogen are high. ICP is associated with pruritus of varying severity and biochemical cholestasis or cholestatic liver disease, which constitutes a risk factor for prematurity and intrauterine fetal death. Based on strong regional clustering, a higher prevalence in female family members of ICP patients, and the susceptibility of ICP patients to developing intrahepatic cholestasis or cholestatic liver disease in the setting of other hormonal ingestion, such as oral contraceptives, a genetic predisposition has been suspected. The heterogeneous state of MDR3 gene deficiency may represent a genetic predisposition.

[0102] cholelithiasis Cholelithiasis is one of the most common and costly of all gastrointestinal diseases, with a prevalence of up to 17% in Caucasian 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.

[0103] Drug-induced cholestasis Drug-induced inhibition of BSEP function is an important mechanism of drug-induced cholestasis, leading to hepatic accumulation of bile salts and subsequent hepatocellular injury. Several drugs have been implicated in BSEP inhibition. Most of these drugs, such as rifampicin, cyclosporine, glibenclamide, and troglitazone, directly inhibit ATP-dependent taurocholate transport in a competitive manner through cis-inhibition, whereas estrogen and progesterone metabolites indirectly inhibit BSEP through trans-inhibition after secretion into the bile canaliculi by Mrp2. Alternatively, drug-mediated stimulation of MRP2 may promote cholestasis or cholestatic liver disease by altering bile composition.

[0104] Total parenteral nutrition-associated cholestasis TPNAC represents one of the most serious clinical scenarios, characterized by the rapid onset of cholestasis or cholestatic liver disease and a high risk of early death. Infants, usually premature and those who have undergone intestinal resection, rely on TPN for growth and frequently develop cholestasis or cholestatic liver disease, which rapidly progresses to fibrosis, cirrhosis, and portal hypertension, usually before the age of 6 months. The extent of cholestasis or cholestatic liver disease and the likelihood of survival in these infants are related to the number of sepsis episodes, likely initiated by repeated bacterial translocation across the intestinal mucosa. While cholestatic effects from intravenous preparations may also play a role in these infants, sepsis mediators likely contribute most to altered liver function.

[0105] Alagille Syndrome (ALGS) Alagille syndrome is a genetic disorder affecting 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 and is caused by mutations in JAG1 (>90% of cases) or NOTCH2. The estimated incidence of ALGS is 1 in 30,000 or 1 in 50,000 live births in the United States and Europe. In patients with ALGS, mutations can affect multiple organ systems, including the liver, heart, kidneys, and central nervous system. Bile acid accumulation prevents the liver from properly functioning and removing waste products from the bloodstream, leading to progressive liver disease and ultimately requiring a liver transplant in 15% to 47% of patients. Signs and symptoms resulting from liver damage in ALGS include jaundice, pruritus, xanthomas, and reduced growth. The pruritus experienced by patients with ALGS is the most severe form of chronic liver disease and is present in most affected children by the first three years of life.

[0106] ALGS often manifests during infancy (e.g., 6–18 months) or early childhood (e.g., 3–5 years) and may stabilize after age 10. Symptoms may include chronic progressive cholestasis, bile ductopenia, 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, rifampin, and phenobarbital. Due to a reduced ability to absorb fat-soluble vitamins, individuals with Alagille syndrome are additionally administered high-dose multivitamins.

[0107] biliary atresia Biliary atresia is a life-threatening condition in infants whose bile ducts, either inside or outside the liver, lack normal openings. 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 eventually fails, and the infant requires a liver transplant to survive. Two types of biliary atresia are fetal and perinatal. Fetal biliary atresia manifests while the baby is in the womb. Perinatal biliary atresia is more common and does not become apparent until 2 to 4 weeks after birth.

[0108] Biliary atresia after Kasai operation Biliary atresia is treated with a surgical procedure called the Kasai procedure or a liver transplant. The Kasai procedure is usually the first treatment for biliary atresia. During the Kasai procedure, a pediatric surgeon removes the infant's damaged bile ducts and replaces them with a loop of intestine. While the Kasai procedure can restore biliary flow and correct many problems caused by biliary atresia, the procedure does not cure the disease. If the Kasai procedure is unsuccessful, the infant usually requires a liver transplant within one to two years. Even after successful surgery, most infants with biliary atresia 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.

[0109] Biliary atresia after liver transplantation Once complete atresia occurs, 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. Also, donor livers may become unavailable. Furthermore, in some patients, liver transplantation may not be successful in curing biliary atresia.

[0110] xanthomas Xanthomas are a skin condition associated with cholestatic liver disease, in which certain fats accumulate beneath 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 LDL receptors to deliver cholesterol to cells throughout the body like normal LDL. Lipoprotein X increases hepatic cholesterol production fivefold and blocks the liver's normal removal of lipoprotein particles from the blood.

[0111] 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.

[0112] 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.

[0113] As used herein, the term "baseline" or "pre-administration baseline" refers to information collected at the beginning of a study or a known initial value used for comparison with subsequent data. A baseline is an initial measurement of a measurable condition obtained 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 representing the normal or starting level of a measurable condition and is used for comparison with values ​​representing a response to an intervention or environmental stimulus. A baseline is time "zero," before study participants receive an experimental drug or intervention or 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.

[0114] As used herein, the terms "level" and "concentration" are used interchangeably. For example, "high serum bilirubin level" may alternatively be expressed as "high serum bilirubin concentration."

[0115] As used herein, the term "normalized" or "normal range" refers to an age-specific value within a range appropriate for healthy individuals (i.e., a normal or normalized value). For example, the phrase "serum bilirubin concentration normalized within 3 weeks" means that the serum bilirubin concentration fell within a range known in the art to be appropriate for healthy individuals (i.e., within the normal range, not, for example, an elevated range) within 3 weeks. In various embodiments, a normalized serum bilirubin concentration is between about 0.1 mg / dL and about 1.2 mg / dL. In various embodiments, a normalized serum bile acid concentration is between about 0 μmol / L and about 25 μmol / L.

[0116] 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 and older. Thus, when the ITCHRO(OBS) scale is referred to in relation to an adult patient, the ITCHRO scale is the indicated scale. Similarly, when the ITCHRO scale is referred to in relation to a pediatric patient, the ITCHRO(OBS) scale is usually the indicated scale (although some older children were 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.

[0117] As used herein, the term "bile acid(s)" includes steroid acids (and / or their carboxylate anions) and their salts found in animal (e.g., human) bile, including, but not limited to, 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-beta-methylcholic acid, methyllithocholic acid, chenodeoxycholate, lithocholic acid, lithocholate, and the like. Taurocholic acid and / or taurocholate are referred to herein as TCAs. As used herein, any reference to a bile acid includes a 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 / salts" are used interchangeably herein unless otherwise specified. Any reference to a bile acid as used herein includes a reference to a bile acid or its salt. Additionally, pharmaceutically acceptable bile acid esters are optionally utilized as "bile acids" herein, e.g., bile acids / salts conjugated to an amino acid (e.g., glycine or taurine). Other bile acid esters include, for example, substituted or unsubstituted alkyl esters, substituted or unsubstituted heteroalkyl esters, substituted or unsubstituted aryl esters, substituted or unsubstituted heteroaryl esters, and the like. For example, the term "bile acid" includes cholic acid conjugated with 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, as used herein, a plurality of references to elements includes a reference to one and only one, one or more, or at least one of such elements unless otherwise stated.

[0118] 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; livestock 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.

[0119] As used herein, the term "about" includes any value within 10% of the stated value.

[0120] As used herein, the term "composition" includes disclosure of both compositions and compositions administered in the methods described herein. Furthermore, in some embodiments, the compositions of the present invention are or comprise a "formulation," oral dosage form, or rectal dosage form, as described herein.

[0121] The terms "treat," "treating," or "treatment," and other grammatical equivalents used herein, include alleviating, suppressing, or alleviating symptoms; reducing or inhibiting the severity of a disease or condition; reducing the occurrence of a disease or condition; reducing or inhibiting the recurrence of a disease or condition; delaying the onset of a disease or condition; delaying the recurrence of a disease or condition; alleviating 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 conditions caused by a disease or condition; or halting the symptoms of a disease or condition. These terms further include achieving a therapeutic benefit. Therapeutic benefit refers to eradication or amelioration of the underlying disease being treated and / or eradication or amelioration of one or more physiological symptoms associated with the underlying disease such that an improvement is observed in the patient.

[0122] As used herein, the term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of at least one agent (e.g., a therapeutically active substance) being administered to achieve a desired result in a subject or individual, e.g., an amount sufficient to alleviate 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 described herein required to provide a clinically significant alleviation of the disease. The appropriate "effective" amount in any individual case can be 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.

[0123] As used herein, the terms "administer," "administering," "administration," and the like refer to methods that can be used to deliver an agent or composition to the site where a biological effect is desired. These methods include, but are not limited to, oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular, or infusion), topical administration, and rectal administration. Administration techniques that can be 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.

[0124] 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).

[0125] The phrase "pharmaceutically 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 tolerable and do not normally produce adverse reactions when administered to a mammal (e.g., a human). Preferably, as used herein, the term "pharmaceutically acceptable" means approved by a federal or state regulatory agency or listed in the United States Pharmacopoeia or other generally recognized pharmacopoeias for use in mammals, more specifically, humans.

[0126] In various embodiments, pharmaceutically 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, pharmaceutically acceptable salts include, by way of non-limiting example, alkaline earth metal salts (e.g., calcium or magnesium), alkali metal salts (e.g., sodium or potassium), ammonium salts, etc.

[0127] bile acids Bile contains water, electrolytes, and numerous organic molecules (such as bile acids, cholesterol, phospholipids, and bilirubin). It is secreted from the liver and stored in the gallbladder. When the gallbladder contracts due to the ingestion of a fatty meal, bile passes through the bile ducts and enters 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 stages. 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 bile flows through the bile ducts, it is modified by the addition of a watery, bicarbonate-rich secretion from bile duct epithelial cells. Bile is typically concentrated fivefold during storage in the gallbladder.

[0128] Bile flow is lowest during fasting, with most of it being directed to the gallbladder for concentration. When the chyme from a ingested meal enters the small intestine, acid and partially digested fat and protein 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 potent stimulus for the release of cholecystokinin is the presence of fat in the duodenum. Secretin, a hormone secreted in response to acid in the duodenum, stimulates cholangiocytes to secrete bicarbonate and water, thereby increasing bile volume and its outflow to the intestine.

[0129] Bile acids / salts are derivatives of cholesterol. Cholesterol ingested as part of the diet or derived from liver synthesis is converted to bile acids / salts in hepatocytes. Examples of such bile acids / salts include cholic acid and chenodeoxycholic acid, which are then 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 cholic acid and deoxycholic acid, which are typically conjugated with either glycine or taurine to produce glycocholate or taurocholate, respectively.

[0130] Free cholesterol is virtually insoluble in aqueous solutions but becomes 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. Therefore, secretion into bile is the primary pathway for cholesterol elimination. Although a large amount of bile acids / salts is secreted into the intestine each day, relatively little is lost from the body. This is because approximately 95% of bile acids / salts delivered to the duodenum are absorbed back into the blood in the ileum through a process known as the "enterohepatic circulation."

[0131] Venous blood from the ileum enters the portal vein and thus passes through the hepatic sinusoids. Hepatocytes extract bile acids / salts from sinusoidal blood very efficiently, with very little escaping into the systemic circulation from a healthy liver. The bile acids / salts are then transported across hepatocytes and re-secreted into the bile canaliculi. The net effect of this enterohepatic circulation is that each bile salt molecule is recycled approximately 20 times, often 2–3 times during a single digestive cycle. Bile biosynthesis represents the major metabolic fate of cholesterol, accounting for more than half of the approximately 800 mg / day of cholesterol consumed by the average adult during metabolic processes. In comparison, steroid hormone biosynthesis consumes only approximately 50 mg of cholesterol per day. Much more than 400 mg of bile salts are required per day and secreted into the intestine, which is achieved by recycling the bile salts. Most of the bile salts secreted into the upper region of the small intestine are absorbed at the lower end of the small intestine along with the dietary lipids they emulsify. 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.

[0132] Bile acids / salts are amphiphilic; cholesterol-derived moieties contain both hydrophobic (lipid-soluble) and polar (hydrophilic) moieties, whereas amino acid conjugates are generally polar and hydrophilic. This amphiphilicity allows bile acids / salts to perform two important functions: emulsification of lipid aggregates and solubilization and transport of lipids into aqueous environments. Bile acids / salts have a detergent effect on dietary fat particles, 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 lipid droplets. Furthermore, 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.

[0133] As used herein, the terms "non-systemic" or "minimally absorbed" refer 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 systemically (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 administered dose. In some embodiments, the systemic absorption of the non-systemic compound is less than 10% (<10%) of the administered dose. In some embodiments, the systemic absorption of the non-systemic compound is less than 15% (<15%) of the administered dose. In some embodiments, the systemic absorption of the non-systemic compound is less than 25% (<25%) of the administered dose. In another approach, the non-systemic ASBTI is a compound that has a lower systemic bioavailability compared to the systemic bioavailability of a 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 a systemic ASBTI (e.g., Compounds 100A, 100C).

[0134] In another alternative approach, the compositions described herein are formulated to systemically deliver less than 10% of the dosage of ASBTI. In some embodiments, the compositions described herein are formulated to systemically deliver less than 20% of the dosage of ASBTI. In some embodiments, the compositions described herein are formulated to systemically deliver less than 30% of the dosage of ASBTI. In some embodiments, the compositions described herein are formulated to systemically deliver less than 40% of the dosage of ASBTI. In some embodiments, the compositions described herein are formulated to systemically deliver less than 50% of the dosage of ASBTI. In some embodiments, the compositions described herein are formulated to systemically deliver less than 60% of the dosage of ASBTI. In some embodiments, the compositions described herein are formulated to systemically deliver less than 70% of the dosage of ASBTI. In some embodiments, systemic absorption is determined by any suitable method, including total circulating amount, amount cleared after administration, etc.

[0135] The term "optionally substituted" or "substituted" means that the referenced group is substituted with one or more additional groups. In certain embodiments, the one or more additional groups are individually and independently selected from amido, ester, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, ester, alkylsulfone, arylsulfone, cyano, halo, alkoyl, alkoyloxo, isocyanato, thiocyanato, isothiocyanato, nitro, haloalkyl, haloalkoxy, fluoroalkyl, amino, alkylamino, dialkylamino, and amido.

[0136] An "alkyl" group refers to an aliphatic hydrocarbon group. Reference to an alkyl group includes "saturated alkyl" and / or "unsaturated alkyl." Alkyl groups include branched, straight-chain, or cyclic groups, whether saturated or unsaturated. By way of example only, alkyl includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, neopentyl, and hexyl. In some embodiments, alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, ethenyl, propenyl, butenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. A "lower alkyl" is a C1-C6 alkyl. A "heteroalkyl" group is one in which any one of the carbons of an alkyl group is replaced with a heteroatom (e.g., an NH or O group in place of a CH2 group) to which an appropriate number of hydrogen atoms are attached.

[0137] The term "alkylene" refers to a divalent alkyl radical. Any of the monovalent alkyl groups described above can become an alkylene by abstraction of a second hydrogen atom from the alkyl. In one aspect, an alkylene is a C1-C 10 In another aspect, the alkylene is a C1-C6 alkylene. Typical alkylene groups include, but are not limited to, -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, and the like.

[0138] An "alkoxy" group refers to a (alkyl)O- group, where alkyl is as defined herein.

[0139] The term "alkylamine" refers to -N(alkyl) x H yrefers to the group, where alkyl is as defined herein and x and y are selected from the group x=1, y=1 and x=2, y=0. When x=2, the alkyl groups, together with the nitrogen to which they are attached, optionally form a cyclic ring system.

[0140] An "amide" is a chemical moiety having the formula -C(O)NHR or -NHC(O)R, where R is selected from alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon), and heteroalicyclic (bonded through a ring carbon).

[0141] The term "ester" refers to a chemical moiety having the formula -C(=O)OR, where R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, and heteroalicyclic.

[0142] As used herein, the term "aryl" refers to an aromatic ring in which each atom forming the ring is a carbon atom. The aryl rings described herein include rings having 5, 6, 7, 8, 9, or more than 9 carbon atoms. The aryl group can be optionally substituted. Examples of aryl groups include, but are not limited to, phenyl and naphthalenyl.

[0143] The term "aromatic" refers to a planar ring having a delocalized π-electron system containing 4n+2 π-electrons, where n is an integer. An aromatic ring can be formed from 5, 6, 7, 8, 9, 10, or more than 10 atoms. An aromatic can be optionally substituted. The term "aromatic" includes both carbocyclic aryl ("aryl", e.g., phenyl) and heterocyclic aryl (or "heteroaryl" or "heteroaromatic") groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings that share adjacent pairs of carbon atoms) groups.

[0144] The term "cycloalkyl" refers to a monocyclic or polycyclic non-aromatic radical, wherein each atom forming the ring (i.e., skeletal atom) is a carbon atom. In various embodiments, the cycloalkyl is saturated or partially unsaturated. In some embodiments, the cycloalkyl is fused to an aromatic ring. Cycloalkyl groups include groups having 3 to 10 ring atoms. Illustrative examples of cycloalkyl groups include, but are not limited to, the following moieties: [ka] Monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0145] The term "heterocyclo" refers to heteroaromatic (or heteroaromatic) and heteroalicyclic (or heteroalicyclic) groups containing 1 to 4 ring heteroatoms, respectively, selected from O, S, and N. In certain instances, each heterocyclyl (or heterocyclic) group has 4 to 10 atoms in its ring system, provided that the ring of the group does not contain two adjacent O or S atoms. Non-aromatic heterocyclic groups include groups having 3 atoms in their ring system, while aromatic heterocyclic groups must have at least 5 atoms in their ring system. Heterocyclic groups include benzo-fused ring systems. An example of a 3-membered heterocyclic group is aziridinyl (derived from aziridine). An example of a 4-membered heterocyclic group is azetidinyl (derived from azetidine). An example of a 5-membered heterocyclic group is thiazolyl. An example of a 6-membered heterocyclic group is pyridyl, and an example of a 10-membered heterocyclic group is quinolinyl. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2-dihydro-2-methyl- ... , 2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl, and quinolizinyl.Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl.

[0146] The term "heteroaryl" or, alternatively, "heteroaromatic (or heteroaromatic)" refers to an aryl group containing one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur. An N-containing "heteroaromatic" or "heteroaryl" moiety refers to an aromatic group in which at least one of the skeletal atoms of the ring is a nitrogen atom. In certain embodiments, heteroaryl groups are monocyclic or polycyclic. Illustrative examples of heteroaryl groups include the following moieties, etc.: [ka]

[0147] A "heteroalicyclic (or heteroalicyclic)" group, or alternatively a "heterocyclo" group, refers to a cycloalkyl group in which at least one skeletal ring atom is a heteroatom selected from nitrogen, oxygen, and sulfur. In various embodiments, the radical has an aryl or heteroaryl. Illustrative examples of heterocyclo groups, also referred to as non-aromatic heterocycles, include the following: [ka] The term heteroalicyclic also includes all ring forms of the carbohydrates, including but not limited to monosaccharides, disaccharides and oligosaccharides.

[0148] The term "halo" or alternatively "halogen" means fluoro, chloro, bromo and iodo.

[0149] The terms "haloalkyl" and "haloalkoxy" include alkyl and alkoxy structures substituted with one or more halogens. In embodiments where a group contains more than one halogen, the halogens are the same or different. The terms "fluoroalkyl" and "fluoroalkoxy" include haloalkyl and haloalkoxy groups, respectively, where halo is fluorine.

[0150] The term "heteroalkyl" includes optionally substituted alkyl, alkenyl, and alkynyl radicals having one or more skeletal atoms selected from atoms other than carbon, such as oxygen, nitrogen, sulfur, phosphorus, silicon, or combinations thereof. In certain embodiments, the heteroatom is placed at any interior position of the heteroalkyl group. Examples include, but are not limited to, -CH2-O-CH3, -CH2-CH2-O-CH3, -CH2-NH-CH3, -CH2-CH2-NH-CH3, -CH2-N(CH3)-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2,-S(O)-CH3, -CH2-CH2-S(O)-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, and -CH=CH-N(CH3)-CH3. In some embodiments, up to two heteroatoms are consecutive, such as, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3.

[0151] A "cyano" group refers to a -CN group.

[0152] An "isocyanato" group refers to a --NCO group.

[0153] A "thiocyanato" group refers to a -CNS group.

[0154] An "isothiocyanato" group refers to a -NCS group.

[0155] "Alkoyloxy" refers to the group RC(=O)O-.

[0156] "Alkoyl" refers to the group RC(=O)-.

[0157] As used herein, the term "modulate" refers to having some effect (eg, increasing, enhancing, or maintaining a particular level).

[0158] The term "optionally substituted" or "substituted" means that the referenced group may be substituted with one or more additional groups individually and independently selected from C-C alkyl, C-C cycloalkyl, aryl, heteroaryl, C-C heteroalicyclic, hydroxy, C-C alkoxy, aryloxy, arylalkoxy, aralkyloxy, arylalkyloxy, C-C alkylthio, arylthio, C-C alkylsulfoxide, arylsulfoxide, C-C alkylsulfone, arylsulfone, cyano, halo, C-C acyl, C-C acyloxy, nitro, C-C haloalkyl, C-C fluoroalkyl, and amino (including C-C alkylamino), and protected derivatives thereof. By way of example, an optional substituent is L s R s where each L s is independently selected from a bond, -O-, -C(=O)-, -S-, -S(=O)-, -S(=O)2-, -NH-, -NHC(=O)-, -C(=O)NH-, S(=O)2NH-, -NHS(=O)2-, -OC(=O)NH-, -NHC(=O)O-, -(C1-C6 alkyl)-, or -(C2-C6 alkenyl)-; each R sare independently selected from H, (C1-C4 alkyl), (C3-C8 cycloalkyl), heteroaryl, aryl, and C1-C6 heteroalkyl. An optionally substituted non-aromatic group may be substituted with one or more oxo (=O). Protecting groups that may form the protective derivatives of the above substituents are known to those of skill in the art and can be found in references such as Greene and Wuts, above. In some embodiments, the alkyl groups described herein are optionally substituted with O attached to two adjacent carbon atoms (i.e., forming an epoxide).

[0159] ASBT inhibitors In various embodiments of the methods of the present invention, an ASBT inhibitor is administered to a subject. The ASBT inhibitor (ASBTI) reduces or inhibits bile acid recycling in the distal gastrointestinal tract (GI), including the distal ileum, colon, and / or rectum. Inhibition of the apical sodium-dependent bile acid transporter disrupts the enterohepatic circulation of bile acids, resulting in greater bile acid excretion in the feces (see FIG. 1), leading to reduced bile acid levels systemically, 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 described herein is not systemically absorbed. In some embodiments, the ASBTI described herein is modified or substituted to be non-systemic (e.g., with an -LK group). In certain embodiments, any ASBT inhibitor may be modified or substituted with one or more charged groups (e.g., K) and, optionally, one or more linkers (e.g., L), where L and K are as defined herein.

[0160] In some embodiments, the ASBTI suitable for the methods described herein is a compound of Formula I, and salts, solvates, and physiologically functional derivatives thereof: [ka] During the ceremony, R 1 is a linear C1-6 is an alkyl group; R 2 is a linear C 1-6 is an alkyl group; R 3 is hydrogen or a group OR 11 where R 11 is hydrogen, optionally substituted C 1-6 Alkyl or C 1-6 is an alkylcarbonyl group; R 4 is pyridyl or optionally substituted phenyl or -L z -K z where z is 1, 2, or 3; each L is independently substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aminoalkyl group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; each K is a moiety that prevents systemic absorption; R 5 , R 6 , R 7 , and R 8 are the same or different and represent hydrogen, halogen, cyano, and R 5 -acetylide, OR 15 , optionally substituted C 1-6 Alkyl, COR 15 , CH(OH)R 15 , S(O) n R 15 , P(O)(OR 15 )2, OCOR 15 , OCF3, OCN, SCN, NHCN, CH2OR 15 , CHO, (CH2) p CN, CONR 12 R 13 , (CH2) p CO2R 15 , (CH2) p NR 12 R 13 , CO2R 15 , NHCOCF3, NHSO2R 15 , OCH2OR 15, OCH=CHR 15 , O(CH2CH2O) n R 15 , O(CH2) p SO3R 15 , O(CH2) p NR 12 R 13 , O(CH2) p N + R 12 R 13 R 14 , and -WR 31 where W is O or NH and R 31 teeth, [ka] where p is an integer from 1 to 4, n is an integer from 0 to 3, and R 12 , R 13 , R 14 and R 15 is hydrogen and optionally substituted C 1-6 alkyl; or R 6 and R 7 is linked to the base [ka] where R 12 and R 13 is as previously described, and m is 1 or 2; R 9 and R 10 are the same or different and are hydrogen or C 1-6 alkyl.

[0161] In some embodiments of the method, the compound of formula I is R 1 is a linear C 1-6 is an alkyl group; R 2 is a linear C 1-6 is an alkyl group; R 3 is hydrogen or a group OR 11 where R11 is hydrogen, optionally substituted C 1-6 Alkyl or C 1-6 is an alkylcarbonyl group; R 4 is optionally substituted phenyl; R 5 , R 6 and R 8 C, which is substituted by hydrogen and optionally fluorine 1-4 Alkyl, C 1-4 independently selected from alkoxy, halogen, or hydroxy; R 7 But halogen, cyan, R 15 -acetylide, OR 15 , optionally substituted C 1-6 Alkyl, COR 15 , CH(OH)R 15 , S(O) n R 15 , P(O)(OR 15 )2, OCOR 15 , OCF3, OCN, SCN, HNCN, CH2OR 15 , CHO, (CH2) p CN, CONR 12 R 13 , (CH2) p CO2R 15 , (CH2) p NR 12 R 13 , CO2R 15 , NHCOCF3, NHSO2R 15 , OCH2OR 15 , OCH=CHR 15 , O(CH2CH2O) p R 15 , O(CH2) p SO3R 15 , O(CH2) p NR 12 R 13 , and O(CH2) p N + R 12 R 13 R 14 where n, p, and R 12 From R 15is as defined above; However, R 5 ~R 8 at least two of the are not hydrogen; compounds, their salts, solvates and physiologically functional derivatives.

[0162] In some embodiments of the methods described herein, the compound of formula I is R 1 is a linear C 1-6 is an alkyl group; R 2 is a linear C 1-6 is an alkyl group; R 3 is hydrogen or a group OR 11 where R 11 is hydrogen, optionally substituted C 1-6 Alkyl or C 1-6 is an alkylcarbonyl group; R 4 is unsubstituted phenyl; R 5 is hydrogen or halogen; R 6 and R 8 C, which is substituted by hydrogen and optionally fluorine 1-4 Alkyl, C 1-4 independently selected from alkoxy, halogen, or hydroxy; R 7 But, OR 15 , S(O) n R 15 ,OCOR 15 , OCF3, OCN, SCN, CHO, OCH2OR 15 , OCH=CHR 15 , O(CH2CH2O)nR 15 , O(CH2) p SO3R 15 , O(CH2) p NR 12 R 13 , and O(CH2) p N + R 12 R 13 R 14where p is an integer from 1 to 4, n is an integer from 0 to 3, and R 12 , R 13 , R 14 , and R 15 is hydrogen and optionally substituted C 1-6 independently selected from alkyl; R 9 and R 10 are the same or different and are hydrogen or C 1-6 selected from alkyl; compounds, as well as salts, solvates and physiologically functional derivatives thereof.

[0163] In some embodiments of the method, the compound of formula I is R 1 is methyl, ethyl or n-propyl; R 2 is methyl, ethyl, n-propyl, n-butyl or n-pentyl; R 3 is hydrogen or a group OR 11 where R 11 is hydrogen, optionally substituted C 1-6 Alkyl, or C 1-6 is an alkylcarbonyl group; R 4 is unsubstituted phenyl; R 5 is hydrogen; R 6 and R 8 C, which is substituted by hydrogen and optionally fluorine 1-4 Alkyl, C 1-4 independently selected from alkoxy, halogen, or hydroxy; R 7 But, OR 15 , S(O) n R 15 ,OCOR 15 , OCF3, OCN, SCN, CHO, OCH2OR 15 , OCH=CHR 15 , O(CH2CH2O)nR 15 , O(CH2) p SO3R15 , O(CH2) p NR 12 R 13 , and O(CH2) p N + R 12 R 13 R 14 where p is an integer from 1 to 4, n is an integer from 0 to 3, and R 12 , R 13 , R 14 and R 15 is hydrogen and optionally substituted C 1-6 independently selected from alkyl; R 9 and R 10 are the same or different and each is hydrogen or C 1-6 selected from alkyl; compounds, as well as salts, solvates and physiologically functional derivatives thereof.

[0164] In some embodiments of the method, the compound of formula I is R 1 is methyl, ethyl or n-propyl; R 2 is methyl, ethyl, n-propyl, n-butyl or n-pentyl; R 3 is hydrogen or a group OR 11 where R 11 is hydrogen, optionally substituted C 1-6 Alkyl, or C 1-6 is an alkylcarbonyl group; R 4 is unsubstituted phenyl; R 5 is hydrogen; R 6 But C 1-4 is alkoxy, halogen, or hydroxy; R 7 OR 15 where R 15 is hydrogen or optionally substituted C 1-6 is alkyl; R8 is hydrogen or halogen; R 9 and R 10 are the same or different and are hydrogen or C 1-6 selected from alkyl; compounds, as well as salts, solvates and physiologically functional derivatives thereof.

[0165] In some embodiments of the method, the compound of formula I is (3R,5R)-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,4-benzothiazepine 1,1-dioxide; (3R,5R)-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,4-benzothiazepin-4-ol 1,1-dioxide; (±)-trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,4-benzothiazepine 1,1-dioxide; (±)-trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,4,-benzothiazepin-4-ol 1,1-dioxide; (3R,5R)-7-Bromo-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepine 1,1-dioxide; (3R,5R)-7-Bromo-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepin-4-ol 1,1-dioxide; (3R,5R)-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-7,8-diol 1,1-dioxide; (3R,5R)-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepin-7-ol 1,1-dioxide; (3R,5R)-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-1,4-benzothiazepin-8-ol 1,1-dioxide; (±)-trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepine 1,1-dioxide; (±)-trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-8-ol 1,1-dioxide; (±)-trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-4,8-diol; (±)-trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-8-thiol 1,1-dioxide; (±)-trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-8-sulfonic acid 1,1-dioxide; (±)-trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8,9-dimethoxy-5-phenyl-1,4-benzothiazepine 1,1-dioxide; (3R,5R)-3-butyl-7,8-diethoxy-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine 1,1-dioxide; (±)-trans-3-butyl-8-ethoxy-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine 1,1-dioxide; (±)-trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-isopropoxy-5-phenyl-1,4-benzothiazepine 1,1-dioxide hydrochloride; (±)-trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-8-carbaldehyde-1,1-dioxide; 3,3-Diethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,4-benzothiazepine 1,1-dioxide; 3,3-Diethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepine 1,1-dioxide; 3,3-Diethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazupine-4,8-diol 1,1-dioxide; (RS)-3,3-Diethyl-2,3,4,5-tetrahydro-4-hydroxy-7,8-dimethoxy-5-phenyl-1,4-benzothiazepine 1,1-dioxide; (±)-trans-3-butyl-8-ethoxy-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-4-ol-1-dioxide; (±)-trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-isopropoxy-5-phenyl-1,4-benzothiazepin-4-ol 1,1-dioxide; (±)-trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8,9-trimethoxy-5-phenyl-1,4-benzothiazepin-4-ol 1,1-dioxide; (3R,5R)-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-4,7,8-triol 1,1-dioxide; (±)-trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-4,7,8-trimethoxy-5-phenyl-1,4-benzothiazepine 1,1-dioxide; 3,3-Diethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-8-ol 1,1-dioxide; 3,3-Diethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-1,4-benzothiazepin-8-ol 1,1-dioxide; 3,3-dibutyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-8-ol 1,1-dioxide; (±)-trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-1,1-dioxo-5-phenyl-1,4-benzothiazepin-8-yl hydrogen sulfate; or 3,3-Diethyl-2,3,4,5-tetrahydro-1,1-dioxo-5-phenyl-1,4-benzothiazepin-8-yl hydrogen sulfate.

[0166] In some embodiments, the compound of formula I is [ka] [ka] is.

[0167] In some embodiments of the method, the compound of formula I is [ka] is.

[0168] In some embodiments, the compound of formula I is [ka] Rather than the structure shown in In the formula, m represents an integer of 1 or 2, and R 3 and R 4 may be different from each other, and each represents an alkyl group having 1 to 5 carbon atoms.

[0169] In some embodiments, the ASBTI suitable for the methods described herein is a compound of formula II, or a pharmaceutically acceptable salt, solvate, or prodrug thereof: [ka] During the ceremony, q is an integer from 1 to 4; n is an integer from 0 to 2; R 1 and R2 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl; wherein alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl are optionally selected from the group consisting of OR 9 , N.R. 9 R 10 , N + R 9 R 10 R w A - , S.R. 9 , S + R 9 R 10 A - , P + R 9 R 10 R 11 A - , S(O)R 9 , SO2R 9 , SO3R 9 , CO2R 9 , CN, halogen, oxo, and CONR 9 R 10 may be substituted with one or more substituents selected from the group consisting of: Alkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl, (polyalkyl)aryl, and cycloalkyl optionally have one or more carbons selected from O, NR 9 , N + R 9 R 10 A - ,S,SO,SO2,S + R 9 A - , P + R 9 R 10 A - or optionally replaced by phenylene; where R 9 , R10 , and R w is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocyclyl, ammonium alkyl, aryl alkyl, and alkylammonium alkyl; or R 1 and R 2 together with the carbon to which they are attached, form C3 to C 10 Forming a cycloalkyl; R 3 and R 4 is H, alkyl, alkenyl, alkynyl, acyloxy, aryl, heterocycle, OR 9 , N.R. 9 R 10 , S.R. 9 , S(O)R 9 , SO2R 9 , and SO3R 9 where R 9 and R 10 is as defined above; or R 3 and R 4 together, =O, =NOR 11 , =S, =NNR 11 R 12 , =NR 9 , or =CR 11 R 12 and where R 11 and R 12 is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR 9 , N.R. 9 R 10 , S.R. 9 , S(O)R 9 , SO2R 9 , SO3R 9 , CO2R 9 , CN, halogen, oxo, and CONR 9 R 10where R 9 and R 10 is as defined above, where R 3 and R 4 cannot both be OH, NH2, and SH, or R 11 and R 12 form a cyclic ring together with the nitrogen or carbon atom to which they are attached; R 5 and R 6 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, quaternary heteroaryl, OR 9 , S.R. 9 , S(O)R 9 , SO2R 9 , SO3R 9 , and -L z -K z independently selected from the group consisting of: wherein z is 1, 2, or 3; each L is independently substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aminoalkyl group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; each K is a moiety that prevents systemic absorption; Here, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, and quaternary heteroaryl are alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, halogen, oxo, R 15 , OR 13 , OR 13 R 14 , N.R. 13 R 14 , S.R. 13 , S(O)R 13 , SO2R 13 , SO3R 13 , N.R. 13 OR 14 , N.R.13 NR 14 R 15 , NO2, CO2R 13 , CN, OM, SO2OM, SO2NR 13 R 14 , C(O)NR 13 R 14 , C(O)OM, CR 13 , P(O)R 13 R 14 , P + R 13 R 14 R 15 A - , P(OR 13 ) OR 14 , S + R 13 R 14 A - , and N + R 9 R 11 R 12 A - and optionally substituted with one or more substituents independently selected from the group consisting of: where: A - is a pharmaceutically acceptable anion, M is a pharmaceutically acceptable cation, and said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle are each independently selected from the group consisting of OR 7 , N.R. 7 R 8 , S(O)R 7 , SO2R 7 , SO3R 7 , CO2R 7 , CN, Oxo, CONR 7 R 8 , N + R 7 R 8 R 9 A - , alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P(O)R 7 R 8 , P + R 7 R 8 R 9 A -, and P(O)(OR 7 ) OR 8 may be further substituted with one or more substituents selected from the group consisting of: The alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle may optionally have one or more carbons selected from O, NR 7 , N + R 7 R 8 A - ,S,SO,SO2,S + R 7 A - , PR 7 , P(O)R 7 , P + R 7 R 8 A - or phenylene, R 13 , R 14 , and R 15 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, aryl, arylalkyl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, quaternary heteroarylalkyl, and -GTVW; wherein alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, and polyalkyl optionally have one or more carbons selected from O, NR 9 , N + R 9 R 10 A - ,S,SO,SO2,S + R 9 A - , P.R., P. + R 9 R 10 A - , P(O)R 9 phenylene, carbohydrate, C2-C7 polyol, amino acid, peptide, or polypeptide; G, T and V are each independently a bond, -O-, -S-, -N(H)-, substituted or unsubstituted alkyl, -O-alkyl, -N(H)-alkyl, -C(O)N(H)-, -N(H)C(O)-, -N(H)C(O)N(H)-, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted alkenylalkyl, alkynylalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycle, substituted or unsubstituted carboxyalkyl, substituted or unsubstituted carboalkoxyalkyl, or substituted or unsubstituted cycloalkyl; W is a quaternary heterocycle, a quaternary heteroaryl, a quaternary heteroarylalkyl, N + R 9 R 11 R 12 A - , P + R 9 R 10 R 11 A - , OS(O)2OM, or S + R 9 R 10 A - and R 13 , R 14 and R 15 is optionally sulfoalkyl, quaternary heterocycle, quaternary heteroaryl, OR 9 , N.R. 9 R 10 , N + R 9 R 11 R 12 A - , S.R. 9 , S(O)R 9 , SO2R 9 , SO3R 9 , oxo, CO2R 9 , CN, halogen, CONR 9 R 10 , SO2OM, SO2NR 9 R 10 , PO(OR 16 ) OR 17 , P + R 9 R 10 R11 A - , S + R 9 R 10 A - and C(O)OM, where R 16 and R 17 is R 9 and independently selected from the substituents comprising M; or R 14 and R 15 are taken together with the nitrogen atom to which they are attached to form a cyclic ring; and are selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammonium alkyl, alkylammonium alkyl, and aryl alkyl; R 7 and R 8 are independently selected from the group consisting of hydrogen and alkyl; One or more R x is H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halogen, haloalkyl, cycloalkyl, heterocycle, heteroaryl, polyether, quaternary heterocycle, quaternary heteroaryl, OR 13 , N.R. 13 R 14 , S.R. 13 , S(O)R 13 , S(O)2R 13 , SO3R 13 , S + R 13 R 14 A - , N.R. 13 OR 14 , N.R. 13 NR 14 R 15 , NO2, CO2R 13 , CN, OM, SO2OM, SO2NR 13 R 14 , N.R. 14 C(O)R 13 , C(O)NR 13 R 14 , N.R. 14 C(O)R13 , C(O)OM, COR 13 , OR 18 , S(O) n NR 18 , N.R. 13 R 18 , N.R. 18 R 14 , N + R 9 R 11 R 12 A - , P + R 9 R 11 R 12 A - independently selected from the group consisting of: amino acids, peptides, polypeptides, and carbohydrates; where alkyl, alkenyl, alkynyl, cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy, arylalkyl, haloalkyl, polyether, quaternary heterocycle, and quaternary heteroaryl are OR 9 , N.R. 9 R 10 , N + R 9 R 11 R 12 A - , S.R. 9 , S(O)R 9 , SO2R 9 , SO3R 9 , oxo, CO2R 9 , CN, halogen, CONR 9 R 10 , SO2OM, SO2NR 9 R 10 , PO(OR 16 ) OR 17 、 P + R 9 R 11 R 12 A - 、 S + R 9 R 10 A - or may be further substituted by C(O)M; R 18is selected from the group consisting of acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, and alkyl; wherein acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, quaternary heterocycle, and quaternary heteroaryl are optionally selected from the group consisting of OR 9 , N.R. 9 R 10 , N + R 9 R 11 R 12 A - , S.R. 9 , S(O)R 9 , SO2R 9 , SO3R 9 , Oxo, CO3R 9 , CN, halogen, CONR 9 R 10 , SO3R 9 , SO2OM, SO2NR 9 R 10 , PO(OR 16 ) OR 17 and C(O)OM, R x In the formula, one or more carbons are optionally O, NR 13 , N + R 13 R 14 A - ,S,SO,SO2,S + R 13 A - , PR 13 , P(O)R 13 , P + R 13 R 14 A - , phenylene, amino acid, peptide, polypeptide, carbohydrate, polyether, or polyalkyl; In the polyalkyl, phenylene, amino acid, peptide, polypeptide, and carbohydrate, one or more carbons may optionally be O, NR 9 , R 9 R 10 A - ,S,SO,SO2,S+ R 9 A - , PR 9 , P + R 9 R 10 A - , or P(O)R 9 may be replaced by; wherein the quaternary heterocycle and quaternary heteroaryl are optionally selected from alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR 13 , N.R. 13 R 14 , S.R. 13 , S(O)R 13 , SO2R 13 , SO3R 13 , N.R. 13 OR 14 , N.R. 13 NR 14 R 15 , NO2, CO2R 13 , CN, OM, SO2OM, SO2NR 13 R 14 , C(O)NR 13 R 14 , C(O)OM, COR 13 , P(O)R 13 R 14 、 P + R 13 R 14 R 15 A - , P(OR 13 ) OR 14 , S + R 13 R 14 A - , and N + R 9 R 11 R 12 A - may be substituted with one or more groups selected from the group consisting of: however, R 5 and R 6 cannot both be hydrogen or SH; R 5or R 6 If is phenyl, R 1 or R 2 Only one of them is H; q=1 and R x If is styryl, anilide, or anilinocarbonyl, R 5 or R 6 provided that only one of is alkyl.

[0170] In some embodiments of the method, the compound of formula II is q is an integer from 1 to 4; n is 2; R 1 and R 2 are independently selected from the group consisting of H, alkyl, alkoxy, dialkylamino, and alkylthio; wherein alkyl, alkoxy, dialkylamino, and alkylthio are optionally selected from the group consisting of OR 9 , N.R. 9 R 10 , S.R. 9 , SO2R 9 , CO2R 9 , CN, halogen, oxo, and CONR 9 R 10 may be substituted with one or more substituents selected from the group consisting of: Each R 9 and R 10 are each independently selected from the group consisting of H, alkyl, cycloalkyl, aryl, acyl, heterocycle, and arylalkyl; R 3 and R 4 H, alkyl, acyloxy, OR 9 , N.R. 9 R 10 , S.R. 9 , and SO2R 9 where R 9 and R 10 is as defined above; R 11 and R 12is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR 9 , N.R. 9 R 10 , S.R. 9 , S(O)R 9 , SO2R 9 , SO3R 9 , CO2R 9 , CN, halogen, oxo, and CONR 9 R 10 where R 9 and R 10 is as defined above, where R 3 and R 4 cannot both be OH, NH2, and SH; or R 11 and R 12 but together with the nitrogen or carbon atom to which they are attached form a cyclic ring; R 5 and R 6 is H, alkyl, aryl, cycloalkyl, heterocycle, and -L z -K z wherein z is 1 or 2; each L is independently substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; each K is a moiety that prevents systemic absorption; Here, alkyl, aryl, cycloalkyl, and heterocycle are alkyl, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, halogen, oxo, OR 13 , OR 13 R 14 , N.R. 13 R 14 , S.R. 13 , SO2R 13 , N.R. 13 NR14 R 15 , NO2, CO2R 13 , CN, OM, and CR 13 and optionally substituted with one or more substituents independently selected from the group consisting of: where: A - is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation; R 13 , R 14 , and R 15 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, aryl, arylalkyl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, and quaternary heteroarylalkyl; R 13 , R 14 and R 15 is optionally a quaternary heterocycle, a quaternary heteroaryl, OR 9 , N.R. 9 R 10 , N + R 9 R 11 R 12 A - , S.R. 9 , S(O)R 9 , SO2R 9 , SO3R 9 , oxo, CO2R 9 , CN, halogens, and CONR 9 R 10 or may be substituted with one or more groups selected from the group consisting of: R 14 and R 15 taken together with the nitrogen atom to which they are attached form a cyclic ring; selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammonium alkyl, alkylammonium alkyl, and aryl alkyl; R 7 and R 8 are independently selected from the group consisting of hydrogen and alkyl; One or more R xis H, alkyl, acyloxy, aryl, arylalkyl, halogen, haloalkyl, cycloalkyl, heterocycle, heteroaryl, OR 13 , N.R. 13 R 14 , S.R. 13 , S(O)2R 13 , N.R. 13 NR 14 R 15 , NO2, CO2R 13 , CN, SO2NR 13 R 14 , N.R. 14 C(O)R 13 , C(O)NR 13 R 14 , N.R. 14 C(O)R 13 , and C.O.R. 13 independently selected from the group consisting of: however, R 5 and R 6 cannot both be hydrogen; R 5 or R 6 If is phenyl, R 1 or R 2 Only one of them is H; q=1 and R x If is styryl, anilide, or anilinocarbonyl, R 5 or R 6 Only one of the is alkyl; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0171] In some embodiments, the compound of formula II is q is 1; n is 2; R x is N(CH3)2; R 7 and R 8 are independently H; R 1 and R 2 is alkyl; R 3 is H and R4 is OH; R 5 is H and R 6 is alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, quaternary heteroaryl, OR 9 , S.R. 9 , S(O)R 9 , SO2R 9 , SO3R 9 , and -L z -K z selected from the group consisting of: wherein z is 1, 2, or 3; each L is independently substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aminoalkyl group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; each K is a moiety that prevents systemic absorption; Here, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, and quaternary heteroaryl are alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, halogen, oxo, R 15 , OR 13 , OR 13 R 14 , N.R. 13 R 14 , S.R. 13 , S(O)R 13 , SO2R 13 , SO3R 13 , N.R. 13 OR 14 , N.R. 13 NR 14 R 15 , NO2, CO2R 13 , CN, OM, SO2OM, SO2NR 13 R 14 , C(O)NR 13 R 14 , C(O)OM, CR 13 , P(O)R 13 R 14 , P+ R 13 R 14 R 15 A - , P(OR 13 ) OR 14 , S + R 13 R 14 A - , and N + R 9 R 11 R 12 A - and optionally substituted with one or more substituents independently selected from the group consisting of: where A - is a pharmaceutically acceptable anion, M is a pharmaceutically acceptable cation, and said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle are each independently selected from the group consisting of OR 7 , N.R. 7 R 8 , S(O)R 7 , SO2R 7 , SO3R 7 , CO2R 7 , CN, Oxo, CONR 7 R 8 , N + R 7 R 8 R 9 A - , alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P(O)R 7 R 8 , P + R 7 R 8 R 9 A - , and P(O)(OR 7 ) OR 8 may be further substituted with one or more substituents selected from the group consisting of: wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle optionally have one or more carbons selected from O, NR 7 , N + R7 R 8 A - ,S,SO,SO2,S + R 7 A - , PR 7 , P(O)R 7 , P + R 7 R 8 A - or phenylene, R 13 , R 14 , and R 15 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, aryl, arylalkyl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, quaternary heteroarylalkyl, and -GTVW; wherein alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, and polyalkyl optionally have one or more carbons selected from O, NR 9 , N + R 9 R 10 A - ,S,SO,SO2,S + R 9 A - , P.R., P. + R 9 R 10 A - , P(O)R 9 phenylene, carbohydrate, C2-C7 polyol, amino acid, peptide, or polypeptide; G, T and V are each independently a bond, -O-, -S-, -N(H)-, substituted or unsubstituted alkyl, -O-alkyl, -N(H)-alkyl, -C(O)N(H)-, -N(H)C(O)-, -N(H)C(O)N(H)-, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted alkenylalkyl, alkynylalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycle, substituted or unsubstituted carboxyalkyl, substituted or unsubstituted carboalkoxyalkyl, or substituted or unsubstituted cycloalkyl; W is a quaternary heterocycle, a quaternary heteroaryl, a quaternary heteroarylalkyl, N + R 9 R 11 R 12 A - , P + R 9 R 10 R 11 A - , OS(O)2OM, or S + R 9 R 10 A - and R 9 and R 10 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammonium alkyl, aryl alkyl, and alkylammonium alkyl; R 11 and R 12 is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR 9 , N.R. 9 R 10 , S.R. 9 , S(O)R 9 , SO2R 9 , SO3R 9 , CO2R 9 , CN, halogen, oxo, and CONR 9 R 10 where R 9 and R 10 is as defined above, where R 3 and R 4 cannot both be OH, NH2, and SH; or R 11 and R 12 together with the nitrogen or carbon atom to which they are attached form a cyclic ring; R 13 , R 14 and R 15is optionally sulfoalkyl, quaternary heterocycle, quaternary heteroaryl, OR 9 , N.R. 9 R 10 , N + R 9 R 11 R 12 A - , S.R. 9 , S(O)R 9 , SO2R 9 , SO3R 9 , oxo, CO2R 9 , CN, halogen, CONR 9 R 10 , SO2OM, SO2NR 9 R 10 , PO(OR 16 ) OR 17 , P + R 9 R 10 R 11 A - , S + R 9 R 10 A - and C(O)OM, where R 16 and R 17 is R 9 and the substituents comprising M; or R 14 and R 15 are taken together with the nitrogen atom to which they are attached to form a cyclic ring; and are selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammonium alkyl, alkylammonium alkyl, and aryl alkyl; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0172] In some embodiments, the compound of formula II is q is 1; n is 2; R x is N(CH3)2; R 7and R 8 are independently H; R 1 and R 2 are independently C1-C4 alkyl; R 3 is H and R 4 is OH; R 5 is H and R 6 is alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, halogen, oxo, R 15 , OR 13 , OR 13 R 14 , N.R. 13 R 14 , S.R. 13 , S(O)R 13 , SO2R 13 , SO3R 13 , N.R. 13 OR 14 , N.R. 13 NR 14 R 15 , NO2, CO2R 13 , CN, OM, SO2OM, SO2NR 13 R 14 , C(O)NR 13 R 14 , C(O)OM, CR 13 , P(O)R 13 R 14 , P + R 13 R 14 R 15 A - , P(OR 13 ) OR 14 , S + R 13 R 14 A - , and N + R 9 R 11 R 12 A - and is aryl substituted with one or more substituents independently selected from the group consisting of: where A -is a pharmaceutically acceptable anion, M is a pharmaceutically acceptable cation, and said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle are each independently selected from the group consisting of OR 7 , N.R. 7 R 8 , S(O)R 7 , SO2R 7 , SO3R 7 , CO2R 7 , CN, Oxo, CONR 7 R 8 , N + R 7 R 8 R 9 A - , alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P(O)R 7 R 8 , P + R 7 R 8 R 9 A - , and P(O)(OR 7 ) OR 8 may be further substituted with one or more substituents selected from the group consisting of wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle optionally have one or more carbons selected from O, NR 7 , N + R 7 R 8 A - ,S,SO,SO2,S + R 7 A - , PR 7 , P(O)R 7 , P + R 7 R 8 A - or phenylene, R 13 , R 14 , and R 15are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, aryl, arylalkyl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, quaternary heteroarylalkyl, and -GTVW; wherein alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, and polyalkyl optionally have one or more carbons selected from O, NR 9 , N + R 9 R 10 A - ,S,SO,SO2,S + R 9 A - , P.R., P. + R 9 R 10 A - , P(O)R 9 phenylene, carbohydrate, C2-C7 polyol, amino acid, peptide, or polypeptide; G, T and V are each independently a bond, -O-, -S-, -N(H)-, substituted or unsubstituted alkyl, -O-alkyl, -N(H)-alkyl, -C(O)N(H)-, -N(H)C(O)-, -N(H)C(O)N(H)-, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted alkenylalkyl, alkynylalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycle, substituted or unsubstituted carboxyalkyl, substituted or unsubstituted carboalkoxyalkyl, or substituted or unsubstituted cycloalkyl; W is a quaternary heterocycle, a quaternary heteroaryl, a quaternary heteroarylalkyl, N + R 9 R 11 R 12 A - , P + R 9 R 10 R 11 A - , OS(O)2OM, or S + R 9 R 10 A -and R 9 and R 10 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammonium alkyl, aryl alkyl, and alkylammonium alkyl; R 11 and R 12 is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR 9 , N.R. 9 R 10 , S.R. 9 , S(O)R 9 , SO2R 9 , SO3R 9 , CO2R 9 , CN, halogen, oxo, and CONR 9 R 10 where R 9 and R 10 is as defined above, where R 3 and R 4 cannot both be OH, NH2, and SH; or R 11 and R 12 but together with the nitrogen or carbon atom to which they are attached form a cyclic ring; R 13 , R 14 and R 15 optionally sulfoalkyl, quaternary heterocycle, quaternary heteroaryl, OR 9 , N.R. 9 R 10 , N + R 9 R 11 R 12 A - , S.R. 9 , S(O)R 9 , SO2R 9 , SO3R 9 , oxo, CO2R 9 , CN, halogen, CONR9 R 10 , SO2OM, SO2NR 9 R 10 , PO(OR 16 ) OR 17 , P + R 9 R 10 R 11 A - , S + R 9 R 10 A - and C(O)OM, where R 16 and R 17 is R 9 and the substituents comprising M; or R 14 and R 15 together with the nitrogen atom to which they are attached form a cyclic ring; selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammonium alkyl, alkylammonium alkyl, and aryl alkyl; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0173] In some embodiments of the method, the compound of formula II is R 5 and R 6 is independently selected from the group consisting of H, aryl, heterocycle, quaternary heterocycle, and quaternary heteroaryl; wherein aryl, heteroaryl, quaternary heterocycle and quaternary heteroaryl are optionally selected from alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR 13 , OR 13 R 14 , N.R. 13 R 14 , S.R. 13 , S(O)R 13 , SO2R 13 , SO3R13 , N.R. 13 OR 14 , N.R. 13 NR 14 R 15 , NO2, CO2R 13 , CN, OM, SO2OM, SO2NR 13 R 14 , C(O)NR 13 R 14 , C(O)OM, COR 13 , P(O)R 13 R 14 、 P + R 13 R 14 R 15 A - , P(OR 13 ) OR 14 , S + R 13 R 14 A - , N + R 9 R 11 R 12 A - , and L z -K z optionally substituted with one or more groups selected from the group consisting of It is a compound.

[0174] In some embodiments of the method, the compound of formula II is R 5 or R 6 -Ar-(R y ) t and t is an integer from 0 to 5; Ar is selected from the group consisting of phenyl, thiophenyl, pyridyl, piperazinyl, piperonyl, pyrrolyl, naphthyl, furanyl, anthracenyl, quinolinyl, isoquinolinyl, quinoxalinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrimidinyl, thiazolyl, triazolyl, isothiazolyl, indolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, and benzisothiazolyl; One or more R yis alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR 13 , OR 13 R 14 , N.R. 13 R 14 , S.R. 13 , S(O)R 13 , SO2R 13 , SO3R 13 , N.R. 13 OR 14 , N.R. 13 NR 14 R 15 , NO2, CO2R 13 , CN, OM, SO2OM, SO2NR 13 R 14 , C(O)NR 13 R 14 , C(O)OM, COR 13 , P(O)R 13 R 14 、 P + R 13 R 14 R 15 A - , P(OR 13 ) OR 14 , S + R 13 R 14 A - , N + R 9 R 11 R 12 A - , and -L z -K z independently selected from the group consisting of: wherein the alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle are selected from the group consisting of OR 13 , N.R. 13 R 14 , S.R. 13 , S(O)R 13 , SO2R 13 , SO3R 13 , N.R. 13 OR 14 , N.R. 13 NR14 R 15 , NO2, CO2R 13 , CN, Oxo, CONR 7 R 8 , N + R 7 R 8 R 9 A - , alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P(O)R 7 R 8 , P + R 7 R 8 A - , and P(O)(OR 7 ) OR 8 and / or phenylene; The alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle may optionally have one or more carbons selected from O, NR 7 , N + R 7 R 8 A - ,S,SO,SO2,S + R 7 A - , PR 7 , P(O)R 7 , P + R 7 R 8 A - or phenylene; It is a compound.

[0175] In some embodiments of the method, the compound of formula II is R 5 or R 6 but, [ka] It is a compound in which

[0176] In some embodiments of the method, the compound of formula II is a compound where n is 1 or 2. In some embodiments of the method, the compound of formula II is a compound where R 1 and R 2 are independently H or C 1-7 In some embodiments of the method, the compound of formula II is a compound where each C 1-7 In some embodiments of the method, the compound of formula II is a compound where R 3 and R 4 are independently H or OR 9 In some embodiments of the method, the compound of formula II is a compound wherein R 9 is a compound where

[0177] In some embodiments of the method, the compound of formula II comprises one or more R x is at the 7-, 8-, or 9-position of the benzo ring of formula II. In some embodiments of this method, the compound of formula II is x is at the 7-position of the benzo ring of formula II. In some embodiments of the method, the compound of formula II is x OR 13 and N.R. 13 R 14 are compounds independently selected from

[0178] In some embodiments of the method, the compound of formula II is q is 1 or 2; n is 2; R 1 and R 2 are each alkyl; R 3 is hydroxy; R 4 and R 6 is hydrogen; R 5 is the formula [ka] having; During the ceremony, t is an integer from 0 to 5; One or more R y is OR 13 OR 13 R 14 and; R 13 and R 14 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, aryl, arylalkyl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, and quaternary heteroarylalkyl; wherein said alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, and polyalkyl groups optionally have one or more carbons selected from O, NR 9 , N + R 9 R 10 A - ,S,SO,SO2,S + R 9 A - , PR 9 , P + R 9 R 10 A - , P(O)R 9 , phenylene, carbohydrate, amino acid, peptide, or polypeptide; R 13 and R 14 is optionally sulfoalkyl, quaternary heterocycle, quaternary heteroaryl, OR 9 , N.R. 9 R 10 , N + R 9 R 11 R 12 A - , S.R. 9 , S(O)R 9 , SO2R 9 , SO3R 9 , oxo, CO2R 9 , CN, halogen, CONR 9 R 10 , SO2OM, SO2NR9 R 10 , PO(OR 16 ) OR 17 , P + R 9 R 10 R 11 A - , S + R 9 R 10 A - and C(O)OM; wherein A is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation; R 9 and R 10 is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammonium alkyl, aryl alkyl, and alkylammonium alkyl; R 11 and R 12 is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR 9 , N.R. 9 R 10 , S.R. 9 , S(O)R 9 , SO2R 9 , SO3R 9 , CO2R 9 , CN, halogen, oxo, and CONR 9 R 10 where R 9 and R 10 is as defined above, where R 3 and R 4 cannot both be OH, NH2, and SH; or R 11 and R 12 together with the nitrogen or carbon atom to which they are attached form a cyclic ring; R 16 and R17 is R 9 and independently selected from the substituents comprising M; R 7 and R 8 is hydrogen; One or more R x is alkoxy, alkylamino and dialkylamino, and -WR 31 wherein W is O or NH; and R 31 teeth, [ka] Selected from: or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0179] In some embodiments, the compound of formula II is [ka] And so on.

[0180] In some embodiments of the method, the compound of formula II is [ka] is.

[0181] In certain embodiments, the ASBTI suitable for the methods described herein is a non-systemic analog of Compound 100C. Certain compounds provided herein are Compound 100C analogs modified or substituted to include a charged group. In certain embodiments, the Compound 100C analog is modified or substituted with a charged group that is an ammonium group (e.g., a cyclic or acyclic ammonium group). In certain embodiments, the ammonium group is an aprotic ammonium group containing a quaternary nitrogen.

[0182] In some embodiments, the compound of formula II is [ka] is.

[0183] In some embodiments, the compound of Formula II is 1-[[5-[[3-[(3S,4R,5R)-3-butyl-7-(dimethylamino)-3-ethyl-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxide-1-benzothiepin-5yl]phenyl]amino]-5-oxopentyl]amino]-1-deoxy-D-glucitol or SA HMR1741 (also known as BARI-1741).

[0184] In some embodiments, the compound of formula II is [ka] is.

[0185] In some embodiments, the compound of Formula II is potassium ((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) sulfate ethanolate, hydrate, or SAR548304B (also known as SAR-548304).

[0186] In some embodiments, an ASBTI suitable for the methods described herein is a compound of formula III, or a pharmaceutically acceptable prodrug thereof: [ka] During the ceremony, Each R 1 , R 2 are independently H, hydroxy, alkyl, alkoxy, -C(=X)YR 8 , -YC(=X)R 8, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkyl-aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkyl-cycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl-heteroaryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted alkyl-heterocycloalkyl, or -LK; or R 1 and R 2 together with the nitrogen to which they are attached, optionally R 8 forming a 3- to 8-membered ring substituted by; Each R 3 , R 4 are independently H, hydroxy, alkyl, alkoxy, -C(=X)YR 8 , -YC(=X)R 8 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkyl-aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkyl-cycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl-heteroaryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted alkyl-heterocycloalkyl, or -LK; R 5 is H, hydroxy, alkyl, alkoxy, -C(=X)YR 8 , -YC(=X)R 8 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkyl-aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkyl-cycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl-heteroaryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted alkyl-heterocycloalkyl; Each R 6 , R 7 are independently H, hydroxy, alkyl, alkoxy, -C(=X)YR 8 , -YC(=X)R 8, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkyl-aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkyl-cycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl-heteroaryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted alkyl-heterocycloalkyl, or -LK; or R 6 and R 7 come together to form a bond; each X is independently NH, S, or O; each Y is independently NH, S, or O; R 8 is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkyl-aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkyl-cycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl-heteroaryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted alkyl-heterocycloalkyl, or -LK; L is A n and Each A is independently 1 , S(O) m , O, C(═X)Y, Y(C═X), substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; where each m is independently 0 to 2; n is 0 to 7; K is the moiety that prevents systemic absorption; However, R 1 , R 2 , R 3 , or R 4 At least one of is -LK.

[0187] In some embodiments of the compound of Formula III, R 1 and R 3is -LK. In some embodiments, R 1 , R 2 and R 3 is -LK.

[0188] In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 At least one of R 5 , R 6 , R 7 is H and R 1 , R 2 , R 3 and R 4 is alkyl, aryl, alkylaryl, or heteroalkyl. In some embodiments, R 1 and R 2 is H. In some embodiments, R 1 , R 2 , R 5 , R 6 and R 7 is H. In some embodiments, R 6 and R 7 together form a bond. In certain embodiments, R 5 , R 6 and R 7 is H, alkyl or O-alkyl.

[0189] In some embodiments, R 1 and R 3 is -LK. In some embodiments, R 1 , R 2 and R 3 is -LK. In some embodiments, R 3 and R 4 In some embodiments, R 1 and R 2 are taken together with the nitrogen to which they are attached to form a 3-8 membered ring, and the ring is substituted with -LK.1 or R 2 or R 3 or R 4 is aryl optionally substituted with -LK. In some embodiments, R 1 or R 2 or R 3 or R 4 is alkyl optionally substituted with -LK. In some embodiments, R 1 or R 2 or R 3 or R 4 is alkyl-aryl optionally substituted with -LK. In some embodiments, R 1 or R 2 or R 3 or R 4 is heteroalkyl optionally substituted by -LK.

[0190] In some embodiments, L is C1-C7 alkyl. In some embodiments, L is heteroalkyl. In particular embodiments, L is C1-C7 alkyl-aryl. In some embodiments, L is C1-C7 alkyl-aryl-C1-C7 alkyl.

[0191] In certain embodiments, K is an aprotic charged group. In some particular embodiments, each K is an ammonium group. In some embodiments, each K is a cyclic aprotic ammonium group. In some embodiments, each K is an acyclic aprotic ammonium group.

[0192] In certain embodiments, each K has the structure: [ka] is a cyclic aprotic ammonium group;

[0193] In certain embodiments, each K has the structure: [ka] is an acyclic aprotic ammonium group; In these formulas, p, q, R 9 , R 10 and Z are as defined above. In certain embodiments, p is 1. In other embodiments, p is 2. In further embodiments, p is 3. In some embodiments, q is 0. In other embodiments, q is 1. In some other embodiments, q is 2.

[0194] The compound is Cl - , Br - , I - , R 11 SO3 - , (SO3 - -R 11 -SO3 - ), R 11 CO2 - , (CO2 - -R 11 -CO2 - ), (R 11 )2(P=O)O - and (R 11 )(P=O)O2 2- wherein R 11 is as defined above. In some embodiments, the counter ion is Cl - , Br - , I - , CH2CO2 - , CH3SO3 - , or C6H5SO3 - or CO2 - -(CH2)2-CO2 - In some embodiments, the compound of formula III has one K group and one counterion. In other embodiments, the compound of formula III has one K group and two molecules of the compound of formula III have one counterion. In still other embodiments, the compound of formula III has two K groups and two counterions. In some other embodiments, the compound of formula III has one K group containing two ammonium groups and two counterions.

[0195] Also described herein are compounds having formula IIIA: [ka] During the ceremony: Each R 1 , R 2 are independently H, substituted or unsubstituted alkyl, or -LK; or R 1 and R 2 together with the nitrogen to which they are attached, optionally R 8 forming a 3- to 8-membered ring substituted by; R 3 , R 4 , R 8 , L, and K are as defined above.

[0196] In some embodiments of the compound of Formula IIIA, L is A n where each A is substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl, and n is 0 to 7. In certain embodiments of compounds of formula IIIA, R 1 is H. In some embodiments of Formula IIIA, R 1 and R 2 taken together with the nitrogen to which they are attached form a 3- to 8-membered ring optionally substituted by -LK.

[0197] Also described herein are compounds having formula IIIB: [ka] During the ceremony: Each R 3 , R 4 is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkyl-aryl, or -LK; R 1 , R 2 , L, and K are as defined above.

[0198] In certain embodiments of Formula IIIB, R 3 is H. In certain embodiments, R 3 and R 4 and each is -LK. In some embodiments, R 3 is H and R 4 is a substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkyl-aryl containing one or two -LK groups.

[0199] In some embodiments, the ASBTI suitable for the methods described herein is a compound of formula IIIC, or a pharmaceutically acceptable salt thereof: [ka] During the ceremony: Each R 1 , R 2 are independently H, hydroxy, alkyl, alkoxy, -C(=X)YR 8 , -YC(=X)R 8 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkyl-aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkyl-cycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl-heteroaryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted alkyl-heterocycloalkyl, or -LK; or R 1 and R 2 together with the nitrogen to which they are attached, optionally R 8 forming a 3- to 8-membered ring substituted by; Each R 3 , R 4 are independently H, hydroxy, alkyl, alkoxy, -C(=X)YR 8 , -YC(=X)R 8, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkyl-aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkyl-cycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl-heteroaryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted alkyl-heterocycloalkyl, or -LK; R 5 is H, hydroxy, alkyl, alkoxy, -C(=X)YR 8 , -YC(=X)R 8 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkyl-aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkyl-cycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl-heteroaryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted alkyl-heterocycloalkyl; Each R 6 , R 7 are independently H, hydroxy, alkyl, alkoxy, -C(=X)YR 8 , -YC(=X)R 8 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkyl-aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkyl-cycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl-heteroaryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted alkyl-heterocycloalkyl, or -LK; or R 6 and R 7 come together to form a bond; each X is independently NH, S, or O; each Y is independently NH, S, or O; R 8is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkyl-aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkyl-cycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl-heteroaryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted alkyl-heterocycloalkyl, or -LK; L is A n where Each A is independently NR 1 , S(O) m , O, C(═X)Y, Y(C═X), substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; where each m is independently 0 to 2; n is 0 to 7; K is the moiety that prevents systemic absorption.

[0200] In some particular embodiments of Formula I, II, or III, K is [ka] is selected from.

[0201] In some embodiments, the ASBTI suitable for the methods described herein is a compound of formula IV, and salts thereof: [ka] During the ceremony, R 1 is a linear C 1-6 is an alkyl group; R 2 is a linear C 1-6 is an alkyl group; R 3 is hydrogen or a group OR 11 where R 11 is hydrogen, optionally substituted C 1-6 Alkyl or C1-6 is an alkylcarbonyl group; R 4 is pyridyl or optionally substituted phenyl; R 5 , R 6 , and R 8 are the same or different and each represents hydrogen, halogen, cyano, or R 15 -acetylide, OR 15 , optionally substituted C 1-6 Alkyl, COR 15 , CH(OH)R 15 , S(O) n R 15 , P(O)(OR 15 )2, OCOR 15 ,OCF3,OCN,SCN,NHCN,CH2OR 15 , CHO, (CH2) p CN, CONR 12 R 13 , (CH2) p CO2R 15 , (CH2) p NR 12 R 13 , CO2R 15 , NHCOCF3, NHSO2R 15 , OCH2OR 15 , OCH=CHR 15 , O(CH2CH2O) n R 15 , O(CH2) p SO3R 15 , O(CH2) p NR 12 R 13 , and O(CH2) p N + R 12 R 13 R 14 is selected from, where: p is an integer from 1 to 4, n is an integer from 0 to 3, R 12 , R 13 , R 14 and R 15 is hydrogen and optionally substituted C 1-6 independently selected from alkyl; R 7 is a group of the formula: [ka] where the hydroxyl group is acetyl, benzyl, or -(C1-C6)-alkyl-R 17 may be substituted with wherein the alkyl group may be substituted with one or more hydroxyl groups; R 16 is -COOH, -CH2-OH, -CH2-O-acetyl, -COOMe, or -COOEt; R 17 is H, -OH, -NH2, -COOH, or COOR 18 and; R 18 is (C1-C4)-alkyl, or -NH-(C1-C4)-alkyl; X is -NH- or -O-; R 9 and R 10 are the same or different and each is hydrogen or C1-C6 alkyl.

[0202] In some embodiments, the compound of formula IV has the structure of formula IVA or formula IVB: [ka]

[0203] In some embodiments, the compound of formula IV has the structure of formula IVC: [ka]

[0204] In some embodiments of Formula IV, X is O and R 7 teeth, [ka] is selected from.

[0205] In some embodiments, the compound of formula IV is [ka] is.

[0206] In some embodiments, an ASBTI suitable for the methods described herein is a compound of formula V: or a pharmaceutically acceptable salt thereof, or an in vivo hydrolyzable ester or amide formed on an available carboxy or hydroxy group: [ka] During the ceremony: R v is hydrogen or C 1-6 alkyl; R 1 and R 2 One of the groups is hydrogen or C 1-6 alkyl, and the other is selected from C 1-6 alkyl; R x and R y is hydrogen, hydroxy, amino, mercapto, C 1-6 Alkyl, C 1-6 Alkoxy, N-(C 1-6 alkyl)amino, N,N-(C 1-6 Alkyl)2amino, C 1-6 AlkylS(O) a where a is 0 to 2; R z is halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkanoyl, C 1-6 Alkanoyloxy, N-(C 1-6 alkyl)amino, N,N-(C 1-6 Alkyl)2amino, C 1-6Alkanoylamino, N-(C 1-6 alkyl)carbamoyl, N,N-(C 1-6 Alkyl)2carbamoyl, C 1-6 AlkylS(O) a (a is 0 to 2), C 1-6 Alkoxycarbonyl, N-(C 1-6 -alkyl)sulfamoyl, and N,N-(C 1-6 alkyl)2sulfamoyl; n is 0 to 5; R 4 and R 5 one of which is a group of formula (VA): [ka] R 3 and R 6 , and R 4 and R 5 The other of these is hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkanoyl, C 1-6 Alkanoyloxy, N-(C 1-6 alkyl)amino, N,N-(C 1-6 Alkyl)2amino, C 1-6 Alkanoylamino, N-(C 1-6 alkyl)carbamoyl, N,N-(C 1-6 Alkyl)2carbamoyl, C 1-6 AlkylS(O) a (a is 0 to 2), C 1-6 Alkoxycarbonyl, N-(C 1-6 alkyl)sulfamoyl, and N,N-(C 1-6 alkyl)2sulfamoyl; where R 3 and R 6 , and R 4 and R 5The other of these may optionally be one or more R 17 may be substituted on carbon by; X is -O-, -N(R a )-, -S(O) b - or -CH(R a )-and; where R a is hydrogen or C 1-6 alkyl, and b is 0 to 2; Ring A is aryl or heteroaryl; wherein ring A is optionally R 18 may be substituted on carbon by one or more substituents selected from: R 7 is hydrogen, C 1-6 is alkyl, carbocyclyl, or heterocyclyl; where R 7 Optionally, R 19 and when said heterocyclyl contains an -NH- group, the nitrogen may optionally be substituted on the carbon by one or more substituents selected from R 20 may be substituted by a group selected from R 8 is hydrogen or C 1-6 - is alkyl; R 9 is hydrogen or C 1-6 is alkyl; R 10 is hydrogen, halo, nitro, cyano, hydroxy, amino, carbamoyl, mercapto, sulfamoyl, hydroxyaminocarbonyl, C 1-10 Alkyl, C 2-10 Alkynyl, C 2-10 Alkynyl, C 1-10 Alkoxy, C 1-10 Alkanoyl, C 1-10 Alkanoyloxy, N-(C 1-10 alkyl)amino, N,N-(C 1-10 alkyl)2amino, N,N,N-(C 1-10 Alkyl)3ammonio, C 1-10 Alkanoylamino, N-(C 1-10alkyl)carbamoyl, N,N-(C 1-10 Alkyl)2carbamoyl, C 1-10 AlkylS(O) a (where a is 0 to 2), N-(C 1-10 alkyl)sulfamoyl, N,N-(C 1-10 alkyl)2sulfamoyl, N-(C 1-10 alkyl)sulfamoylamino, N,N-(C 1-10 Alkyl)2sulfamoylamino, C 1-10 Alkoxycarbonylamino, carbocyclyl, carbocyclyl C 1-10 Alkyl, heterocyclyl, heterocyclylC 1-10 Alkyl, carbocyclyl-(C 1-10 alkylene) p -R 21 -(C 1-10 alkylene) q - or heterocyclyl-(C 1-10 alkylene) r -R 22 -(C 1-10 alkylene) s - where R 10 Optionally, R 23 and when said heterocyclyl contains an -NH- group, the nitrogen may optionally be substituted on the carbon by one or more substituents selected from R 24 or R 10 is a group of formula (VB): [ka] During the ceremony, R 11 is hydrogen or C 1-6 - is alkyl; R 12 and R 13 is hydrogen, halo, carbamoyl, sulfamoyl, C 1-10 Alkyl, C 2-10 Alkynyl, C 2-10 Alkynyl, C 1-10 Alkanoyl, N-(C 1-10alkyl)carbamoyl, N,N-(C 1-10 Alkyl)2carbamoyl, C 1-10 AlkylS(O) a (where a is 0 to 2), N-(C 1-10 alkyl)sulfamoyl, N,N-(C 1-10 alkyl)2sulfamoyl, N-(C 1-10 alkyl)sulfamoylamino, N,N-(C 1-10 alkyl)2sulfamoylamino, carbocyclyl, or heterocyclyl; 12 and R 13 are independently and optionally R 25 and when said heterocyclyl contains an -NH- group, the nitrogen may optionally be substituted on the carbon by one or more substituents selected from R 26 may be substituted by a group selected from R 14 is hydrogen, halo, carbamoyl, sulfamoyl, hydroxyaminocarbonyl, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkanoyl, N-(C 1-10 alkyl)carbamoyl, N,N-(C 1-10 Alkyl)2carbamoyl, C 1-10 AlkylS(O) a (where a is 0 to 2), N-(C 1-10 alkyl)sulfamoyl, N,N-(C 1-10 alkyl)2sulfamoyl, N-(C 1-10 alkyl)sulfamoylamino, N,N-(C 1-10 Alkyl)2sulfamoylamino, carbocyclyl, carbocyclyl C 1-10 Alkyl, heterocyclyl, heterocyclylC 1-10 Alkyl, carbocyclyl-(C 1-10 Alkylene)PR 27 -(C 1-10 alkylene) q - or heterocyclyl-(C 1-10 alkylene) r -R28 -(C 1-10 alkylene) s - selected from; where R 14 Optionally, R 29 and when said heterocyclyl contains an -NH- group, the nitrogen may optionally be substituted on the carbon by one or more substituents selected from R 30 or R 14 is a group of formula (VC): [ka] R 15 is hydrogen or C 1-6 alkyl; R 16 is hydrogen or C 1-6 alkyl; where R 16 Optionally, R 31 may be substituted on carbon by one or more groups selected from: Alternatively, R 15 and R 16 together with the nitrogen to which they are attached form a heterocyclyl; wherein said heterocyclyl optionally contains one or more R 37 when said heterocyclyl contains an -NH- group, the nitrogen may optionally be substituted on carbon by R 38 may be substituted by a group selected from m is 1 to 3; where R 7 The values ​​of can be the same or different; R 17 , R 18 , R 19 , R 23 , R 25 , R 29 , R 31 and R 37 are independently halo, nitro, cyano, hydroxy, amino, carbamoyl, mercapto, sulfamoyl, hydroxyaminocarbonyl, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, C1-10 Alkanoyl, C 1-10 Alkanoyloxy, N-(C 1-10 alkyl)amino, N,N-(C 1-10 alkyl)2amino, N,N,N-(C 1-10 Alkyl)3ammonio, C 1-10 Alkanoylamino, N-(C 1-10 alkyl)carbamoyl, N,N-(C 1-10 Alkyl)2carbamoyl, C 1-10 AlkylS(O) a (where a is 0 to 2), N-(C 1-10 alkyl)sulfamoyl, N,N-(C 1-10 alkyl)2sulfamoyl, N-(C 1-10 alkyl)sulfamoylamino, N,N-(C 1-10 Alkyl)2sulfamoylamino, C 1-10 Alkoxycarbonylamino, carbocyclyl, carbocyclyl C 1-10 Alkyl, heterocyclyl, heterocyclylC 1-10 Alkyl, carbocyclyl-(C 1-10 alkylene) p -R 32 -(C 1-10 alkylene) q - or heterocyclyl-(C 1-10 alkylene) r -R 33 -(C 1-10 alkylene) s - selected from; where R 17 , R 18 , R 19 , R 23 , R 25 , R 29 , R 31 and R 37 independently and optionally, one or more R 34 when said heterocyclyl contains an -NH- group, the nitrogen may optionally be substituted on carbon by R 35 may be substituted by a group selected from R 21 , R 22 , R 27 , R28 , R 32 , or R 33 are independently -O-, -NR 36 -, -S(O) x -, -NR 36 C(O)NR 36 -, -NR 36 C(S)NR 36 -, -OC(O)N=C-, -NR 36 C(O)- or -C(O)NR 36 - selected from; where R 36 is hydrogen or C 1-6 alkyl, where x is 0 to 2; p, q, r, and s are independently selected from 0 to 2; R 34 is selected from halo, hydroxy, cyano, carbamoyl, ureido, amino, nitro, carbamoyl, mercapto, sulfamoyl, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy, ethoxy, vinyl, allyl, ethynyl, formyl, acetyl, formamido, acetylamino, acetoxy, methylamino, dimethylamino, N-methylcarbamoyl, N,N-dimethylcarbamoyl, methylthio, methylsulfinyl, mesyl, N-methylsulfamoyl, N,N-dimethylsulfamoyl, N-methylsulfamoylamino and N,N-dimethylsulfamoylamino; R 20 , R 24 , R 26 , R 30 , R 35 and R 38 independently, C 1-6 Alkyl, C 1-6 Alkanoyl, C 1-6 Alkylsulfonyl, C 1-6 Alkoxycarbonyl, carbamoyl, N-(C 1-6 alkyl)carbamoyl, N,N-(C 1-6 alkyl)carbamoyl, benzyl, benzyloxycarbonyl, benzoyl, and phenylsulfonyl; wherein "heteroaryl" is a fully unsaturated monocyclic or bicyclic ring containing 3 to 12 atoms, at least one atom of which is selected from nitrogen, sulfur, and oxygen, and the heteroaryl may be linked at either carbon or nitrogen, unless otherwise specified; wherein "heterocyclyl" is a saturated, partially saturated or unsaturated monocyclic or bicyclic ring containing 3 to 12 atoms, at least one atom of which is selected from nitrogen, sulfur and oxygen, and the heterocyclyl may be linked at a carbon or nitrogen unless otherwise specified, and wherein a -CH2- group may optionally be replaced by a -C(O)- group, and ring sulfur atoms may optionally be oxidized to form S-oxides; Here, "carbocyclyl" is a saturated, partially saturated or unsaturated monocyclic or bicyclic carbon ring containing 3 to 12 atoms; wherein a -CH2- group can optionally be replaced by a -C(O) group.

[0207] In some embodiments, the compound of formula V is 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((R)-1)-carboxy-2-methylthio-ethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxy-2-(R)-hydroxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxy-2-methylpropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxybutyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxypropyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxy-2-(R)-hydroxypropyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-(2-sulfoethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxyethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((R)-1-carboxy-2-methylthioethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-{(S)-1-[N-((S)-2-hydroxy-1-carboxyethyl)carbamoyl]propyl}carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxy-2-methylpropyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-{(R)-α-carboxy4-hydroxybenzyl}carbamoylmethoxy]-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; or 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-(carboxymethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine, or a salt thereof.

[0208] In some embodiments, the compound of formula V is [ka] is.

[0209] In some embodiments, the ASBTI suitable for the methods described herein is a compound of formula VI, or a pharmaceutically acceptable salt, solvate, or solvate of such a salt thereof, or an in vivo hydrolyzable ester formed on an available carboxy or hydroxy thereof, or an in vivo hydrolyzable amide formed on an available carboxy thereof: [ka] During the ceremony: R v and R w are independently hydrogen or C 1-6 alkyl; R 1 and R 2 One of them is hydrogen or C 1-6 alkyl, and the other is selected from C 1-6 alkyl; R x and R y are independently hydrogen or C 1-6 alkyl, or R x and R y One of them is hydrogen or C 1-6 alkyl and the other is hydroxy or C 1-6 is alkoxy; R z is halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkanoyl, C 1-6 Alkanoyloxy, N-(C 1-6 alkyl)amino, N,N-(C 1-6 Alkyl)2amino, C 1-6 Alkanoylamino, N-(C 1-6 alkyl)carbamoyl, N,N-(C 1-6 Alkyl)2carbamoyl, C 1-6 AlkylS(O) a(where a is 0 to 2), C 1-6 Alkoxycarbonyl, N-(C 1-6 alkyl)sulfamoyl, and N,N-(C 1-6 alkyl)2sulfamoyl; n is 0 to 5; R 4 and R 5 one of which is a group of formula (VIA): [ka] R 3 and R 6 , and R 4 and R 5 and the other of the two is independently hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkanoyl, C 1-6 Alkanoyloxy, N-(C 1-6 alkyl)amino, N,N-(C 1-6 Alkyl)2amino, C 1-6 Alkanoylamino, N-(C 1-6 alkyl)carbamoyl, N,N-(C 1-6 Alkyl)2carbamoyl, C 1-6 AlkylS(O) a (where a is 0 to 2), C 1-6 Alkoxycarbonyl, N-(C 1-6 alkyl)sulfamoyl, and N,N-(C 1-6 alkyl)2sulfamoyl; 3 and R 6 , and R 4 and R 5 The other of these may optionally be one or more R 17 may be substituted on carbon by; X is -O-, -N(R a )-, -S(O) b - or -CH(Ra )-where R a is hydrogen or C 1-6 alkyl, and b is 0 to 2; Ring A is aryl or heteroaryl; wherein Ring A optionally contains R 18 may be substituted on carbon by one or more substituents selected from: R 7 is hydrogen, C 1-6 alkyl, carbocyclyl, or heterocyclyl; where R 7 Optionally, R 19 and when said heterocyclyl contains an -NH- group, the nitrogen may optionally be substituted on the carbon by one or more substituents selected from R 20 may be substituted by a group selected from R 8 is hydrogen or C 1-6 is alkyl; R 9 is hydrogen or C 1-6 is alkyl; R 10 is hydrogen, halo, nitro, cyano, hydroxy, amino, carbamoyl, mercapto, sulfamoyl, hydroxyaminocarbonyl, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, C 1-10 Alkanoyl, C 1-10 Alkanoyloxy, N-(C 1-10 alkyl)amino, N,N-(C 1-10 alkyl)2amino, N,N,N-(C 1-10 Alkyl)3ammonio, C 1-10 Alkanoylamino, N-(C 1-10 alkyl)carbamoyl, N,N-(C 1-10 Alkyl)2carbamoyl, C 1-10 AlkylS(O) a (where a is 0 to 2), N-(C 1-10 alkyl)sulfamoyl, N,N-(C 1-10 alkyl)2sulfamoyl, N-(C1-10 alkyl)sulfamoylamino, N,N-(C 1-10 Alkyl)2sulfamoylamino, C 1-10 Alkoxycarbonylamino, carbocyclyl, carbocyclyl C 1-10 Alkyl, heterocyclyl, heterocyclylC 1-10 Alkyl, carbocyclyl-(C 1-10 alkylene) p -R 21 -(C 1-10 alkylene) q - or heterocyclyl-(C 1-10 alkylene) r -R 22 -(C 1-10 alkylene) s - where R 10 Optionally, R 23 and when said heterocyclyl contains an -NH- group, the nitrogen may optionally be substituted on the carbon by one or more substituents selected from R 24 or R 10 is a group of formula (VIB): [ka] During the ceremony: R 11 is hydrogen or C 1-6 is alkyl; R 12 and R 13 are independently hydrogen, halo, nitro, cyano, hydroxy, amino, carbamoyl, mercapto, sulfamoyl, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, C 1-10 Alkanoyl, C 1-10 Alkanoyloxy, N-(C 1-10 alkyl)amino, N,N-(C 1-10 Alkyl)2amino, C 1-10 Alkanoylamino, N-(C 1-10 alkyl)carbamoyl, N,N-(C 1-10Alkyl)2carbamoyl, C 1-10 AlkylS(O) a (where a is 0 to 2), N-(C 1-10 alkyl)sulfamoyl, N,N-(C 1-10 alkyl)2sulfamoyl, N-(C 1-10 alkyl)sulfamoylamino, N,N-(C 1-10 alkyl)2sulfamoylamino, carbocyclyl, or heterocyclyl; 12 and R 13 are independently and optionally R 25 and when said heterocyclyl contains an -NH- group, the nitrogen may optionally be substituted on the carbon by one or more substituents selected from R 26 may be substituted by a group selected from R 14 is hydrogen, halo, nitro, cyano, hydroxy, amino, carbamoyl, mercapto, sulfamoyl, hydroxyaminocarbonyl, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, C 1-10 Alkanoyl, C 1-10 Alkanoyloxy, N-(C 1-10 alkyl)amino, N,N-(C 1-10 alkyl)2amino, N,N,N-(C 1-10 Alkyl)3ammonio, C 1-10 Alkanoylamino, N-(C 1-10 alkyl)carbamoyl, N,N-(C 1-10 Alkyl)2carbamoyl, C 1-10 AlkylS(O) a (where a is 0 to 2), N-(C 1-10 alkyl)sulfamoyl, N,N-(C 1-10 alkyl)2sulfamoyl, N-(C 1-10 alkyl)sulfamoylamino, N,N-(C 1-10 Alkyl)2sulfamoylamino, C 1-10 Alkoxycarbonylamino, carbocyclyl, carbocyclyl C1-10 Alkyl, heterocyclyl, heterocyclylC 1-10 Alkyl, carbocyclyl-(C 1-10 alkylene) p -R 27 -(C 1-10 alkylene) q - or heterocyclyl-(C 1-10 alkylene) r -R 28 -(C 1-10 alkylene) s - selected from; where R 14 Optionally, R 29 and when said heterocyclyl contains an -NH- group, the nitrogen may optionally be substituted on the carbon by one or more substituents selected from R 30 or R 14 is a group of formula (VIC): [ka] R 15 is hydrogen or C 1-6 is alkyl; R 16 is hydrogen or C 1-6 alkyl; where R 16 Optionally, R 31 may be substituted on carbon by one or more groups selected from: n is 1 to 3; where R 7 The values ​​of can be the same or different; R 17 , R 18 , R 19 , R 23 , R 25 , R 29 or R 31 are independently halo, nitro, cyano, hydroxy, amino, carbamoyl, mercapto, sulfamoyl, hydroxyaminocarbonyl, amidino, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, C 1-10Alkanoyl, C 1-10 Alkanoyloxy, (C 1-10 alkyl) 3 silyl, N-(C 1-10 alkyl)amino, N,N-(C 1-10 alkyl)2amino, N,N,N-(C 1-10 Alkyl)3ammonio, C 1-10 Alkanoylamino, N-(C 1-10 alkyl)carbamoyl, N,N-(C 1-10 Alkyl)2carbamoyl, C 1-10 AlkylS(O) a (where a is 0 to 2), N-(C 1-10 alkyl)sulfamoyl, N,N-(C 1-10 alkyl)2sulfamoyl, N-(C 1-10 alkyl)sulfamoylamino, N,N-(C 1-10 Alkyl)2sulfamoylamino, C 1-10 Alkoxycarbonylamino, carbocyclyl, carbocyclyl C 1-10 Alkyl, heterocyclyl, heterocyclylC 1-10 Alkyl, carbocyclyl-(C 1-10 alkylene) p -R 32 -(C 1-10 alkylene) q - or heterocyclyl-(C 1-10 alkylene) r -R 33 -(C 1-10 alkylene) s - selected from; where R 17 , R 18 , R 19 , R 23 , R 25 , R 29 or R 31 independently and optionally, one or more R 34 when said heterocyclyl contains an -NH- group, the nitrogen may optionally be substituted on carbon by R 35 may be substituted by a group selected from R 21 , R 22 , R 27 , R 28, R 32 , or R 33 are independently -O-, -NR 36 -, -S(O) x -, -NR 36 C(O)NR 36 -, -NR 36 C(S)NR 36 -, -OC(O)N=C-, -NR 36 C(O)- or -C(O)NR 36 - selected from; where R 36 is hydrogen or C 1-6 alkyl, where x is 0 to 2; p, q, r, and s are independently selected from 0 to 2; R 34 is selected from halo, hydroxy, cyano, carbamoyl, ureido, amino, nitro, carbamoyl, mercapto, sulfamoyl, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy, ethoxy, vinyl, allyl, ethynyl, formyl, acetyl, formamido, acetylamino, acetoxy, methylamino, dimethylamino, N-methylcarbamoyl, N,N-dimethylcarbamoyl, methylthio, methylsulfinyl, mesyl, N-methylsulfamoyl, N,N-dimethylsulfamoyl, N-methylsulfamoylamino and N,N-dimethylsulfamoylamino; R 20 , R 24 , R 26 , R 30 or R 35 independently, C 1-6 Alkyl, C 1-6 Alkanoyl, C 1-6 Alkylsulfonyl, C 1-6 Alkoxycarbonyl, carbamoyl, N-(C 1-6 alkyl)carbamoyl, N,N-(C 1-6 alkyl), carbamoyl, benzyl, benzyloxycarbonyl, benzoyl and phenylsulfonyl.

[0210] In some embodiments, the compound of formula VI has the structure of formula VID, or a pharmaceutically acceptable salt thereof: [ka] During the ceremony: R 1 and R 2 independently, C 1-6 alkyl; R 4 and R 5 one of which is a group of formula (VIE): [ka] R 3 and R 6 , and R 4 and R 5 and the other of the two is independently hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 1-4 Alkanoyl, C 1-4 Alkanoyloxy, N-(C 1-4 alkyl)amino, N,N-(C 1-4 Alkyl)2amino, C 1-4 Alkanoylamino, N-(C 1-4 alkyl)carbamoyl, N,N-(C 1-4 Alkyl)2carbamoyl, C 1-4 AlkylS(O) a (where a is 0 to 2), C 1-4 Alkoxycarbonyl, N-(C 1-4 alkyl)sulfamoyl and N,N-(C 1-4 alkyl)2sulfamoyl; 3 and R 6 , and R 4 and R 5 The other of these may optionally be one or more R 14 may be substituted on carbon by; R7 is carboxy, sulfo, sulfino, phosphono, -P(O)(OR a )(OR b ), P(O)(OH)(OR a ), -P(O)(OH)(R a ), or P(O)(OR a )(R b ), where R a and R b independently, C 1-6 alkyl; or R 7 is the (VIF) group of the formula: [ka] R 8 and R 9 are independently hydrogen, C 1-4 alkyl or saturated cyclic group, or R 8 and R 9 Together they form C 2-6 Forms an alkylene; where R 8 and R 9 , or R 8 and R 9 together, independently, and optionally R 15 and when said saturated cyclic group contains an —NH— moiety, the nitrogen may optionally be substituted on carbon by one or more substituents selected from R 20 May be substituted with; R 10 is hydrogen or C 1-4 alkyl; where R 10 Optionally, R 24 may be substituted on carbon by one or more substituents selected from: R 11 is hydrogen, C 1-4 alkyl, carbocyclyl, or heterocyclyl; where R 11 Optionally, R 16 and when said heterocyclyl contains an -NH- moiety, the nitrogen may optionally be substituted on the carbon by one or more substituents selected from R21 May be substituted with; R 12 is hydrogen or C 1-4 alkyl, carbocyclyl, or heterocyclyl; where R 12 Optionally, R 17 and when said heterocyclyl contains an -NH- moiety, the nitrogen may optionally be substituted on the carbon by one or more substituents selected from R 22 May be substituted with; R 13 is carboxy, sulfo, sulfino, phosphono, -P(O)(OR c )(OR d ), -P(O)(OH)(OR c ), -P(O)(OH)(R c ) or -P(O)(OR c )(R d ), where R c and R d independently, C 1-6 alkyl; m is 1 to 3; where R 8 and R 9 The values ​​of can be the same or different; n is 1 to 3; where R 11 The values ​​of can be the same or different; p is 1 to 3; where R 12 The values ​​of can be the same or different; R 14 and R 16 are independently halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 1-4 Alkanoyl, C 1-4 Alkanoyloxy, N-(C 1-4 alkyl)amino, N,N-(C 1-4 Alkyl)2amino, C 1-4 Alkanoylamino, N-(C 1-4alkyl)carbamoyl, N,N-(C 1-4 Alkyl)2carbamoyl, C 1-4 AlkylS(O) a (where a is 0 to 2), C 1-4 Alkoxycarbonyl, N-(C 1-4 alkyl)sulfamoyl and N,N-(C 1-4 alkyl)2sulfamoyl; 14 and R 16 independently, optionally one or more R 18 may be substituted on carbon by; R 15 and R 17 are independently halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 1-4 Alkanoyl, C 1-4 Alkanoyloxy, N-(C 1-4 alkyl)amino, N,N-(C 1-4 Alkyl)2amino, C 1-4 Alkanoylamino, N-(C 1-4 alkyl)carbamoyl, N,N-(C 1-4 Alkyl)2carbamoyl, C 1-4 AlkylS(O) a (where a is 0 to 2), C 1-4 Alkoxycarbonyl, N-(C 1-4 alkyl)sulfamoyl and N,N-(C 1-4 alkyl)2sulfamoyl, carbocyclyl, heterocyclyl, sulfo, sulfino, amidino, phosphono, -P(O)(OR e )(OR f ), -P(O)(OH)(OR e ), -P(O)(OH)(R e ), or -P(O)(OR e )(R f ), where R e and R f independently, C1-6 alkyl; where R 15 and R 17 independently and optionally, one or more R 19 when said heterocyclyl contains an -NH- moiety, the nitrogen may optionally be substituted on the carbon by one or more R 23 may be replaced by; R 18 , R 19 and R 25 is independently selected from halo, hydroxy, cyano, carbamoyl, ureido, amino, nitro, carboxy, carbamoyl, mercapto, sulfamoyl, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy, ethoxy, vinyl, allyl, ethynyl, methoxycarbonyl, formyl, acetyl, formamido, acetylamino, acetoxy, methylamino, dimethylamino, N-methylcarbamoyl, N,N-dimethylcarbamoyl, methylthio, methylsulfinyl, mesyl, N-methylsulfamoyl, and N,N-dimethylsulfamoyl; R 20 , R 21 , R 22 , R 23 and R 26 independently, C 1-4 Alkyl, C 1-4 Alkanoyl, C 1-4 Alkyl sulfonyl, sulfamoyl, N-(C 1-4 alkyl)sulfamoyl, N,N-(C 1-4 Alkyl)2sulfamoyl, C 1-4 Alkoxycarbonyl, carbamoyl, N-(C 1-4 alkyl)carbamoyl, N,N-(C 1-4 alkyl)2carbamoyl, benzyl, phenethyl, benzoyl, phenylsulfonyl and phenyl; R 24 is halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C1-4 Alkoxy, C 1-4 Alkanoyl, C 1-4 Alkanoyloxy, N-(C 1-4 alkyl)amino, N,N-(C 1-4 Alkyl)2amino, C 1-4 Alkanoylamino, N-(C 1-4 alkyl)carbamoyl, N,N-(C 1-4 Alkyl)2carbamoyl, C 1-4 AlkylS(O) a (where a is 0 to 2), C 1-4 Alkoxycarbonyl, N-(C 1-4 alkyl)sulfamoyl and N,N-(C 1-4 alkyl)2sulfamoyl, carbocyclyl, heterocyclyl; where R 24 independently, optionally one or more R 25 when said heterocyclyl contains an -NH- moiety, the nitrogen may optionally be substituted on the carbon by one or more R 26 may be replaced by; wherein saturated cyclic groups are fully or partially saturated monocyclic or bicyclic rings containing 3 to 12 atoms, of which 0 to 4 atoms are selected from nitrogen, sulfur or oxygen, and may be linked at carbon or nitrogen; wherein any heterocyclyl is a saturated, partially saturated or unsaturated monocyclic or bicyclic ring containing 3 to 12 atoms, at least one atom of which is selected from nitrogen, sulfur or oxygen, and may be carbon- or nitrogen-linked, in which a -CH2- group may optionally be replaced by -C(O)- or a ring sulfur atom may optionally be oxidized to form an S-oxide; wherein any carbocyclyl is a saturated, partially saturated or unsaturated monocyclic or bicyclic carbocyclic ring containing 3 to 12 atoms, in which the -CH2- group can optionally be replaced by -C(O)-.

[0211] In some embodiments, the compound of formula IV is 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-1'-phenyl-1'-[N'-(carboxymethyl)carbamoyl]methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine; 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N'-((S)-1-carboxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-1'-phenyl-1'-[N'-(carboxymethyl)carbamoyl]methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N'-((S)-1-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine; or a salt thereof.

[0212] In some embodiments, any compound described herein is covalently conjugated to a bile acid using any suitable method, hi some embodiments, a compound described herein is covalently conjugated to a cyclodextrin or a biodegradable polymer (e.g., a polysaccharide).

[0213] In certain embodiments, the compounds described herein are not systemically absorbed. Additionally, provided herein are compounds that inhibit bile salt recycling in the gastrointestinal tract of an individual. In some embodiments, the compounds described herein may not be transported from the intestinal lumen and / or may not interact with ASBT. In some embodiments, the compounds described herein have no or minimal effect on fat digestion and / or absorption. In certain embodiments, administration of a therapeutically effective amount of any compound described herein does not result in gastrointestinal distress or lactic acidosis in an individual. In certain embodiments, the compounds described herein are orally administered. In some embodiments, the ASBTI is released in the distal ileum. ASBTIs compatible with the methods described herein can be direct, allosteric, or partial inhibitors of the apical sodium-dependent bile acid transporter.

[0214] In certain embodiments, compounds that inhibit ASBT or any recuperative bile acid transporter are disclosed in European Patent Application Publication No. 1810689; U.S. Patent Nos. 6,458,851, 7,413,536, 7,514,421; U.S. Patent Application Publication Nos. 2002 / 0147184, 2003 / 0119809, 2003 / 0149010, 2004 / 0014806, 2004 / 0092500, 2004 / 0180861, 2004 / 0180860, 2005 / 0031651, 2006 / 0069080, 2007 / 008025, 2008 / 0092500, 2009 ... 6 / 0199797, 2006 / 0241121, 2007 / 0065428, 2007 / 0066644 , 2007 / 0161578, 2007 / 0197628, 2007 / 0203183, 2007 / 025 No. 4952, No. 2008 / 0070888, No. 2008 / 0070892, No. 2008 / 0070889, No. 20 08 / 0070984, 2008 / 0089858, 2008 / 0096921, 2008 / 0161400 , 2008 / 0167356, 2008 / 0194598, 2008 / 0255202, 2008 / 0261990; WO2002 / 50027, WO2005 / 046797, WO2006 / 017257, WO2006 / 10591 3, WO2006 / 105912, WO2006 / 116499, WO2006 / 117076, WO2006 / 121861, WO2006 / 122186, WO2006 / 124713, WO2007 / 050628, WO2007 / 101531, WO2 007 / 134862, WO2007 / 140934, WO2007 / 140894, WO2008 / 028590, WO2008 / 033431, WO2008 / 033464, WO2008 / 031501, WO2008 / 031500, WO2008 / 033465, WO2008 / 034534, WO2008 / 039829, WO2008 / 064788, WO2008 / 064789, WO2008 / 088836, WO2008 / 104306, WO2008 / 124505;Compounds described therein that inhibit restorative bile acid transport are incorporated herein by reference.

[0215] In certain embodiments, the compound that inhibits ASBT or any resilient bile acid transporter is selected from the group consisting of WO93 / 16055, WO94 / 18183, WO94 / 18184, WO96 / 05188, WO96 / 08484, WO96 / 16051, WO97 / 33882, WO98 / 38182, WO99 / 35135, WO98 / 40375, WO99 / 64409, WO99 / 64410, WO00 / 01687, WO00 / 47568, WO00 / 61568, DE19825804, WO00 / 38725, WO00 / 38726, WO00 / 3872 7 (including those compounds having a 2,3,4,5-tetrahydro-1-benzothiepine 1,1-dioxide structure), WO00 / 38728, WO01 / 66533, WO02 / 50051, European Patent Application Publication No. 0864582 (e.g., (3R,5R)-3-butyl-3-ethyl-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,4-benzo-thiazepin-8-yl(β-D-glucopyranosiduronic acid), WO94 / 24087, WO98 / 07749, WO98 / 56757, WO99 / 32478, WO99 / 351 35, WO00 / 20392, WO00 / 20393, WO00 / 20410, WO00 / 20437, WO01 / 34570, WO00 / 35889, WO01 / 68637, WO01 / 68096, WO02 / 08211, WO03 / 020710, WO03 / 022825, WO03 / 022830, WO03 / 0222861; JP 10-072371; U.S. Patent Nos. 5,910,494, 5,723,458, 5,817,652, 5,663,165, 5,998,400, 6,465,451, 5 ,994,391, 6,107,494, 6,387,924, 6,784,201, 6,875,877, 6,740,663, 6,852,753, 5,070,103, 6,114,322, 6,020,330, 7,179,792; European Patent Application Publication Nos. 251315, 417725, 489423, 549967, 573848, 624593, 624594, 624595, 869121, 1070703;The compounds disclosed in WO04 / 005247 and those disclosed as having IBAT activity in Drugs of the Future, 24, 425-430 (1999), Journal of Medicinal Chemistry, 48, 5837-5852, (2005) and Current Medicinal Chemistry, 13, 997-1016, (2006) (the compounds described therein inhibiting restorative bile acid transport are incorporated herein by reference);

[0216] In some embodiments, the compound that inhibits ASBT or any resilient bile acid transporter is a benzothiepine, a benzothiazepine (including 1,2-benzothiazepine; 1,4-benzothiazepine; 1,5-benzothiazepine; and / or 1,2,5-benzothiadiazepine). In some embodiments, the compound that inhibits ASBT or any resilient bile acid transporter includes S-8921 (European Patent Application Publication No. 597107, disclosed in WO 93 / 08155), 264W94 (GSK) disclosed in WO 96 / 05188; SC-435 (1-[4-[4-[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4

[0033] In some embodiments, the ASBTI includes, but is not limited to, N-(2-hydroxy-1,1-dioxide-1-benzothiepin-5-yl)phenoxy]butyl]4-aza-1-azoniabicyclo[2.2.2]octane methanesulfonate), SC-635 (Searle); 2164U90 (3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine 1,1-dioxide); BARI-1741 (Aventis SA), AZD 7508 (Astra Zeneca); barixibat (11-(D-gluconamido)-N-{2-[(1S,2R,3S)-3-hydroxy-3-phenyl-2-(2-pyridyl)-1-(2-pyridylamino)propyl]phenyl}undecaneamide), and the like, or combinations thereof. In some embodiments, the ASBTI is: [ka]

[0217] In certain embodiments, the compounds described herein contain one or more chiral centers. Accordingly, 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 possess the therapeutically useful properties described herein. Preparation of optically active forms can be achieved by any suitable method, including, but not limited to, resolution of racemates by recrystallization techniques, synthesis from optically active starting materials, chiral synthesis, or chromatographic separation using a chiral stationary phase. 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 contain one or more chiral centers. These compounds are prepared by any means, including enantioselective synthesis and / or separation of a mixture of enantiomers and / or diastereomers. Resolution of the compounds and their isomers can be achieved by any means, including, but not limited to, chemical processes, enzymatic processes, fractional crystallization, distillation, chromatography, etc.

[0218] In some embodiments, the ASBTI [ka] (maralixibat, LUM-001, SHP625, lopixibat chloride), or an alternative pharmaceutically acceptable salt thereof.

[0219] 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 pharmaceutically acceptable salt thereof.

[0220] In some embodiments, the ASBTI is [ka] (LUM-002; SHP626; SAR548304; vorixibat potassium), or an alternative pharmaceutically acceptable salt thereof.

[0221] 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)-α-[N-((S)-1-carboxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine), or a pharmaceutically acceptable salt thereof.

[0222] 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 pharmaceutically acceptable salt thereof.

[0223] 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 pharmaceutically acceptable salt thereof.

[0224] In some embodiments, the ASBTI used in the methods or compositions of the invention is maralixibat (SHP625), vorixibat (SHP626), or odevixibat (A4250), or a pharmaceutically acceptable salt thereof.

[0225] In some embodiments, the ASBTI used in the methods or compositions of the invention is maralixibat, or a pharmaceutically acceptable salt thereof.

[0226] In some embodiments, the ASBTI used in the methods or compositions of the invention is vorixibat, or a pharmaceutically acceptable salt thereof.

[0227] In some embodiments, the ASBTI used in a method or composition of the invention is odevixibat, or a pharmaceutically acceptable salt thereof.

[0228] In some embodiments, the ASBTI used in a method or composition of the invention is elobixibat, or a pharmaceutically acceptable salt thereof.

[0229] In some embodiments, the ASBTI used in the methods or compositions of the invention is GSK2330672, or a pharmaceutically acceptable salt thereof.

[0230] In some embodiments, the ASBTI can include a mixture of different ASBTIs. For example, the ASBTI can be a composition including maralixibat, vorixibat, odebixibat, GSK2330672, elobixibat, or various combinations thereof.

[0231] How to Treat Cholestasis Provided herein is a method for treating cholestasis in a subject with liver disease. The method comprises administering to a subject in need thereof an apical sodium-dependent bile acid transporter inhibitor (ASBTI). The ASBTI is maralixibat or vorixibat, or a pharmaceutically acceptable salt thereof. The ASBTI is administered in an amount of about 140 μg / kg / day to about 1400 μg / kg / day.

[0232] 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 cholestatic liver diseases, or various combinations thereof.

[0233] In certain embodiments, the cholestatic liver disease is 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, The biliary liver disease is a pediatric liver disease. In some embodiments, the biliary liver disease is a pediatric liver disease. In some embodiments, the subject has intrahepatic cholestasis of pregnancy (ICP).

[0234] 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.

[0235] 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 those mutations described 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.

[0236] In various embodiments, the subject has the condition that is related to, caused by, or partially caused by BSEP deficiency.In certain embodiments, the condition that is 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.

[0237] 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, premature infant, infant, toddler, preschooler, school-age child, pre-adolescent child, post-adolescent child, adolescent, or teenager under the age of 18. In some embodiments, the pediatric subject is a newborn, premature infant, infant, toddler, preschooler, or school-age child. In some embodiments, the pediatric subject is a newborn, premature infant, infant, toddler, or preschooler. In some embodiments, the pediatric subject is a newborn, premature infant, infant, or toddler. In some embodiments, the pediatric subject is a newborn, premature newborn, or 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 any pediatric cholestatic condition that results in subnormal growth, height, or weight.

[0238] In certain embodiments, the methods of the present invention involve non-systemic administration of a therapeutically effective amount of ASBTI. In certain embodiments, the methods involve 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 methods of the present invention result in a reduction in intraenterocyte bile acids or a reduction in damage to hepatocytes or intestinal structures caused by cholestasis or cholestatic liver disease.

[0239] In various embodiments, the methods of the present invention comprise delivering a therapeutically effective amount of any ASBTI described herein to the ileum or colon of an individual.

[0240] In various embodiments, the methods of the present invention involve reducing damage to hepatocytes or intestinal structures or cells from cholestasis or cholestatic liver disease, including administering a therapeutically effective amount of ASBTI. In certain embodiments, the methods of the present invention involve reducing intraenterocyte bile acids / salts by administering a therapeutically effective amount of ASBTI to an individual in need thereof.

[0241] In some embodiments, the methods of the present invention provide for 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.

[0242] In various embodiments, contacting an individual's distal ileum with an ASBTI (e.g., any ASBTI described herein) inhibits bile acid reuptake and increases bile acid / salt concentrations near the L-cells of the distal ileum and / or colon and / or rectum, thereby reducing enterocyte bile acids, reducing 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 a particular theory, reducing serum and / or liver bile acid levels ameliorates hypercholesterolemia and / or cholestatic disease.

[0243] Administration of the compounds described herein can be achieved by any suitable method, including, but not limited to, 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 manner or formulation suitable for treating newborns or infants. Any compound or composition described herein can be administered in an oral formulation (e.g., solid or liquid) to treat newborns or infants. Any compound or composition described herein can be administered before, with, or after food intake.

[0244] In certain embodiments, the compound or composition comprising the compound described herein is administered for preventive and / or therapeutic treatment.In therapeutic use, the composition is administered to the individual who has already suffered from disease or condition in an amount sufficient to cure or at least partially prevent the symptoms of disease or condition.In various cases, the amount that is effective for this use depends on the severity and course of disease or condition, previous treatment, individual health condition, weight and response to drugs, and the judgment of the treating physician.

[0245] In prophylactic 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 precise amount of compound administered will depend on the individual's health, weight, and the like. Furthermore, in some instances, when a compound or composition described herein is 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 and response to the drugs, and the judgment of the treating physician.

[0246] In certain embodiments of the methods of the present invention, if an individual's condition does not improve after administration of a selected dose of a compound or composition described herein, at the physician's discretion, the compound or composition described herein is optionally administered chronically, i.e., administered over an extended period of time, including for the duration of the individual's life, to ameliorate or otherwise control or limit the symptoms of the individual's disorder, disease, or condition.

[0247] In certain embodiments of the methods of the present invention, the effective amount of a given drug will vary depending on one or more of several factors, such as the specific compound, the disease or condition and its severity, the personality (e.g., weight) of the subject or host requiring treatment, and will be determined according to the specific circumstances surrounding the case, including, for example, the specific drug being administered, the route of administration, the condition being treated, and the subject or host being treated. In some embodiments, the administered dose will include a dose up to the maximum tolerated dose. In some embodiments, the administered dose will include a dose up to the maximum tolerated dose by a newborn or infant.

[0248] In various embodiments of the methods 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, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 5 days, 6 days, or once a week. In some embodiments, the total single dose of ASBTI is within the ranges described below.

[0249] In various embodiments of the methods of the present invention, if the patient's condition improves, at the physician's discretion, ASBTI is optionally continued; 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 from 2 days to 1 year, including, by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days. Dose 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.

[0250] Once improvement of the patient's condition occurs, a maintenance dose is administered as needed. Thereafter, the dosage and / or frequency of administration are reduced as a function of symptoms to a level at which the improved disease, disorder, or condition is maintained. In some embodiments, patients require long-term intermittent treatment upon any recurrence of symptoms.

[0251] In certain instances, there are numerous variables regarding any particular treatment regimen, and significant deviations from these recommendations are contemplated within the ranges set forth herein. The dosages set forth herein are optionally subject to variation depending upon many variables, including, but not limited to, the activity of the compound being 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.

[0252] The toxicity and therapeutic efficacy of such treatment regimens are evaluated by the LD 50 (50% lethal dose in the population) and ED 50The LD is optionally determined by pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, determination of the LD (therapeutically effective dose in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, and the LD 50 and ED 50 Therapeutic indices 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 to formulate a range of dosages for use in humans. In certain embodiments, the dosage of the compounds described herein is adjusted to achieve an ED with minimal toxicity. 50 The dosage optionally varies within this range depending upon the dosage form employed and the route of administration utilized.

[0253] In certain embodiments, the composition used or administered comprises an absorption inhibitor, a carrier, and one or more of a cholesterol absorption inhibitor, an enteroendocrine peptide, a peptidase inhibitor, a spreading agent, and a wetting agent.

[0254] In some embodiments of the methods 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 lining of the colon, ileum, rectum, or a combination 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 24 to 48 hours, while in other embodiments, the anorectal reaction lasts for a period of more than 48 hours.

[0255] Dosage In various embodiments, the ASBTI is maralixibat or vorixibat, or a pharmaceutically acceptable salt thereof.

[0256] In various embodiments, the efficacy and safety of administering ASBTI to patients is monitored by measuring serum levels 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 a combination 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 serum levels 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 a combination 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.

[0257] In some embodiments, 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, / kg, 200μg / kg, 240μg / kg, 280μg / kg, 300μg / kg, 250μg / kg, 280μg / kg, 300μg / kg, 400μg / kg, 500μg / kg, 560μg / kg, 600μg / kg, 700μg / kg, 800μg / kg, 900μg / kg, 1,000μg / kg, 1,100μg / kg, 1,200μg / kg, 1,300μg / kg, 1,400μg / kg, 1,500μg / kg, 1,600μg / kg, 1,700μg / kg, 1,800μg / kg, 1,900μg / kg, 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, 80μg / kg, 85μg / kg, 90μg / kg, 100μg / kg, 140μg / kg, 150μg / kg, 200μg / kg, 240μg / kg, 280 μg / kg, 300 μg / kg, 250 μg / kg, 280 μg / kg, 300 μg / kg, 400 μg / kg, 500 μg / kg, 560 μg / kg, 600 μg / kg, 700 μg / kg, 800 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 μg / kg, or 2,100 μg / kg. In various embodiments, ASBTI is administered at a dose of about or at least about 0.5 mg / day, 1 mg / day, 2 mg / day, 3 mg / day, 4 mg / day, 5 mg / day, 6 mg / day, 7 mg / day, 8 mg / day, 9 mg / day, 10 mg / day, 11 mg / day, 12 mg / day, 13 mg / day, 14 mg / day, 15 mg / day, 16 mg / day, 17 mg / day, 18 mg / day , 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 a dose of 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.

[0258] 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, It is administered at doses of 150 μg / kg / day, 200 μg / kg / day, 240 μg / kg / day, 280 μg / kg / day, 300 μg / kg / day, 250 μg / kg / day, 280 μg / kg / day, 300 μg / kg / day, 400 μg / kg / day, 500 μg / kg / day, 560 μg / kg / day, 600 μg / kg / day, 700 μg / kg / day, 800 μg / kg / day, 900 μg / kg / day, 1000 μg / kg / day, 1100 μg / kg / day, 1200 μg / kg / day, or 1300 μg / kg / day. In various embodiments, ASBTI is administered at a dose of 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, 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, 2000 μg / kg / day, 2500 μg / kg / day, 3000 μg / kg / day, 3500 μg / kg / day, 4000 μg / kg / day, 4500 μg / kg / day, 5000 μg / kg / day, 1000 μg / kg / day, 1400 μg / kg / day, 1500 μg / kg / day, 2000 μg / kg / day, 2500 μg / kg / day, 3000 μg / kg / day, 3500 μg / kg / day, 4000 μg / kg / day / kg / day, 240 μg / kg / day, 280 μg / kg / day, 300 μg / kg / day, 250 μg / kg / day, 280 μg / kg / day, 300 μg / kg / day, 400 μg / kg / day, 500 μg / kg / day, 560 μg / kg / day, 600 μg / kg / day, 700 μg / kg / day, 800 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, approx. 250~550μg / kg / day, approx. 560μg / kg / day ~ approx. 1400μg / kg / day, 700μg / kg / day ~ approx. 1400μg / kg / day, approx. 560μg / kg / day ~ approx. 120 0μg / 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 to about 1000μg / kg / day, about 200μg / kg / day to about 600μg / kg / day, about 300μg / kg / day to about 600μg / kg / day, about 400μg / kg / day to about 500μg / kg / day, about 400μg / kg / day to 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 9 The drug is administered at a dose of about 100 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 2,000 μg / kg / day.

[0259] In some embodiments, ASBTI is administered at a dose of about 30 μg / kg to about 1400 μg / kg per dose. In some embodiments, ASBTI is administered at a dose of about 0.5 μg / kg to about 2000 μg / kg per dose, about 0.5 μg / kg to about 1500 μg / kg per dose, about 100 μg / kg to about 700 μg / kg per dose, about 5 μg / kg to about 100 μg / kg per dose, about 10 μg / kg to about 500 μg / kg per dose, about 50 μg / kg to about 1400 μg / kg per dose, about 300 μg / kg to about 2000 μg / kg per dose, about 60 μg / kg to about 1200 μg / kg per dose, about 70 μg / kg to about 1000 μg / kg per dose, about 70 ...1500 μg / kg per dose, about 100 μg / kg to about 1500 μg / kg per dose, about 100 μg / kg to about 1500 μg / kg per dose, It is administered at a dose of μg / kg to about 700 μg / kg per dose, 80 μg / kg to about 1000 μg / kg per dose, 80 μg / kg to about 800 μg / kg per dose, 100 μg / kg to about 800 μg / kg per dose, 100 μg / kg to about 600 μg / kg per dose, 150 μg / kg to about 700 μg / kg per dose, 150 μg / kg to about 500 μg / kg per dose, 200 μg / kg to about 400 μg / kg per dose, 200 μg / kg to about 300 μg / kg per dose, or 300 μg / kg to about 400 μg / kg per dose.

[0260] 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.

[0261] 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 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 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.

[0262] 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-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, or 100-fold higher than the first dose level. In some embodiments, the second dose level is about 1.5x, 2x, 3x, 4x, 5x, 6x, 7x, 8x, 9x, 10x, 15x, 20x, 30x, 40x, 50x, 60x, 70x, 80x, 90x, 100x, or 150x higher than the first dose level.

[0263] In various embodiments, ASBTI is administered once daily (QD) at one of the doses or within one of the dose ranges above. In various embodiments, ASBTI is administered twice daily (BID) at one of the doses or within one of the dose ranges above. In various embodiments, ASBTI doses are administered daily, every other day, twice a week, or once a week.

[0264] In various embodiments, ASBTI is administered periodically for a period of about or at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 48, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, or 800 weeks. In various embodiments, ASBTI is administered for a period of about or less than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 48, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, or 1000 weeks. In various embodiments, 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, 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.

[0265] Relief of symptoms of cholestatic liver disease or changes in disease-related laboratory measurements In various embodiments of the above-described methods of the invention, administration of ASBTI results in a reduction in symptoms of cholestatic liver disease or a change in disease-related laboratory measurements (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 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks, 1 year, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 2 years, 2.5 years, 3 years, 3.5 years, 4 years, 4.5 years, 5 years, 5.5 years, 6 years, 6.5 years, 7 years, 8 years, 9 years, or 10 years. In various embodiments, the symptom reduction or change in disease-related laboratory measurements includes a decrease in sBA concentration, an increase in serum 7αC4 concentration, an increase in the 7αC4:sBA ratio, an increase in fBA excretion, a reduction in pruritus, a decrease in serum total cholesterol concentration, a decrease in serum LDL-C cholesterol concentration, a decrease in ALT level, an increase in quality of life scale score, an increase in fatigue quality of life scale score, a decrease in xanthomatosis score, a decrease in serum autotaxin concentration, an increase in growth, or a combination thereof.In various embodiments, the symptom reduction or change in disease-related laboratory measurements is determined relative to baseline levels.That is, the symptom reduction or change in disease-related laboratory measurements is determined relative to the change in symptom measurement or disease-related laboratory measurements 1) before changing the dose level of ASBTI administered to the patient, 2) before changing the dosing regimen followed by the patient, 3) before starting administration of ASBTI, or 4) before various other changes made to reduce symptoms or change disease-related laboratory measurements in the patient.In various embodiments, the symptom reduction or change in disease-related laboratory measurements is a statistically significant reduction.

[0266] In various embodiments, the reduction in symptoms of cholestatic liver disease or the change in a disease-related laboratory measurement can be measured as a gradual reduction in symptoms or a change in a disease-related laboratory measurement 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, or the like. , 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.

[0267] In some embodiments, the patient is a pediatric patient, and the reduction in symptoms or change in disease-related laboratory measurements 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 progressively during about or at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 48, 50, 60, 70, or 72 week period of administration of ASBTI.

[0268] 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.

[0269] In various embodiments, administration of ASBTI increases the ratio of 7αC4:sBA by about or at least about 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 75, 100, 150, 200, 300, 500, 750, 1,000, 2,000, 3,000, 4,000, 5,000, or 10,000 times or more relative to baseline.

[0270] 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-fold relative to baseline. In some embodiments, fBA excretion increases 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 relative to baseline. In various embodiments, administration of ASBTI results in a dose-dependent increase in fBA excretion, such that administration of higher doses of ASBTI results in correspondingly higher levels of fBA excretion. In various embodiments, ASBTI is administered at a dose sufficient to result in at least about a 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 20-, 30-, 40-, 50-, 60-, 70-, 80-, 90-, or 100-fold increase in bile acid secretion relative to baseline.

[0271] In various embodiments, administration of ASBTI results in a reduction 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.

[0272] 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 the ITCHRO (OBS) score, the ITCHRO score, the CSS score, or a combination thereof. In various embodiments, administration of ASBTI results in a reduction in the 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 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 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.

[0273] In some embodiments, patients with higher baseline ITCHRO (OBS) scores exhibit greater symptom relief or change in disease-related laboratory measurements than patients with lower baseline ITCHRO (OBS) scores. 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 greater symptom relief or change in disease-related laboratory measurements compared to baseline than smaller reductions in patients with lower baseline severity of pruritus scores. In various embodiments, patients with PSC and a baseline ITCHRO score of at least 4 exhibit greater symptom relief or change in disease-related laboratory measurements than patients with a baseline ITCHRO score of less than 4. In various embodiments, the method includes predicting that a patient will have greater symptom relief or change in disease-related laboratory measurements 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 smaller decrease is about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, or 60% of the larger decrease, or less.In various embodiments, the difference in symptom relief or change in disease-related laboratory measurements (i.e., the difference between a greater decrease and a lesser decrease) 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 greater than or equal to about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, or 23 weeks after the initial administration of ASBTI at the first dose or the second dose. , 22 weeks, 23 weeks, 24 weeks, 6 months, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks, 1 year, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 2 years, 2.5 years, 3 years, 3.5 years, 4 years, 4.5 years, 5 years, 5.5 years, 6 years, 6.5 years, 7 years, 8 years, 9 years, or 10 years later.

[0274] In various embodiments, the reduction in the severity of pruritus resulting from administration of ASBTI to a patient is positively correlated with a decrease in the concentration of sBA in the patient. In various embodiments, a greater decrease in the concentration of sBA in the patient is correlated with a corresponding greater reduction in the severity of pruritus.

[0275] In various embodiments, administration of ASBTI results in a decrease in serum LDL-C concentrations compared to baseline, hi some embodiments, serum LDL-C concentrations 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.

[0276] 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 level, 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 ASBTI results in a decrease in serum total cholesterol concentration, serum LDL-C level, 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.

[0277] In various embodiments, administering ASBTI causes serum autotaxin concentration to decrease.In some embodiments, administering ASBTI causes the autotaxin concentration to decrease by about or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% or 80% compared to baseline.

[0278] 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 the PedsQL score or the PedsQL score for fatigue of about or at least about 5%, 10%, 15%, 20%, 25%, 30%, 45%, or 50% relative to baseline.

[0279] In various embodiments, administration of ASBTI results in a reduction in xanthomas score compared to baseline. In some embodiments, the xanthomas score is reduced by about or at least about 2.5%, 5%, 10%, 15%, 20%, 35%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% compared to baseline.

[0280] In various embodiments, the 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, 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 Result in a reduction in symptoms or a change in disease-related laboratory measurements by 4 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.

[0281] In various embodiments, the serum bilirubin concentration is measured at about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 2 months, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 4 months, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks, 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 Pre-dose baseline levels or normal levels at or by 7 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.

[0282] In various embodiments, the serum ALT concentration 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, 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, 96 weeks 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52 weeks, or 1 year, or at or by the pre-administration baseline level or normal level. 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.

[0283] 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, or the like. , 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, are within the normal range or are at pre-dose baseline levels. In various embodiments, the 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 continued 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 does not result in a significant change from baseline in serum conjugated bilirubin concentrations for a period of 2 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks, or 1 year.

[0284] Dose adjustment In various embodiments, the method includes adjusting the dosage of ASBTI administered to the patient, wherein the adjustment 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 after adjusting (e.g., increasing) the dosage of ASBTI to a second dose. If the 7αC4:sBA ratio 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 dose of ASBTI is increased until the serum serotonin concentration is increased by at least about 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 75, 100, 150, 200, 300, 500, 750, 1,000, 2,000, 3,000, 4,000, 5,000, or 10,000-fold relative to baseline. In various embodiments, the dose of ASBTI is titrated to achieve and maintain a particular 7αC4:sBA ratio.

[0285] In various embodiments, modulation occurs when the 7αC4:sBA ratio initially increases 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 and then begins to decrease or decreases by 1, 1 If the dose of ASBTI is decreased by less than or equal to 0.25, 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, the dose of ASBTI may be increased from the first dose level to a second dose level higher than the first dose level. Dose levels are increased 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.

[0286] 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 higher than the first dose. The dose administered to the patient continues to be increased 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.

[0287] In various embodiments, the 7αC4:sBA ratio is measured approximately 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.

[0288] Pharmaceutical Composition In some embodiments, ASBTI is administered as a pharmaceutical composition (composition or pharmaceutical composition) comprising ASBTI. Any of the compositions described herein can be formulated for delivery to the ileum, rectum, and / or colon. In more specific embodiments, the composition is formulated for non-systemic or local 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 local delivery to the rectum and / or colon and is administered rectally. In other specific embodiments, the compositions are formulated for non-systemic or local delivery to the rectum and / or colon and are administered orally.

[0289] 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).

[0290] 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 formulation depends on the selected route of administration.Summary of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Edition (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 Edition (Lippincott Williams & Wilkins 1999), all of which are incorporated herein in their entirety for all purposes.

[0291] As used herein, a pharmaceutical composition refers to a mixture of a compound described herein with other chemical components, such as a carrier, stabilizer, diluent, dispersant, suspending agent, thickener, and / or excipient. In certain instances, the pharmaceutical composition facilitates administration of the compound to an individual or cell. In certain embodiments of practicing 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.

[0292] In certain embodiments, the pharmaceutical formulations described herein are administered to an individual by any method, 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.

[0293] In certain embodiments, the pharmaceutical compositions described herein contain one or more compounds described herein as active ingredients in the form of a free acid or free base, or in the form of a pharmaceutically 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, where solvated forms include any pharmaceutically acceptable solvent, such as water, ethanol, etc. Solvated forms of the compounds presented herein are also considered to be described herein.

[0294] "Carriers," in some embodiments, comprise pharmaceutically acceptable excipients and are selected based on compatibility with a compound 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, Pennsylvania 1975; Liberman, H.A. 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.

[0295] Furthermore, in certain embodiments, the pharmaceutical compositions described herein are formulated as dosage forms.Therefore, in some embodiments, the dosage forms provided herein are suitable for administration to individuals and comprise the compounds described herein.In certain embodiments, suitable dosage forms include, but are not limited to, aqueous oral dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, solid oral dosage forms, aerosols, controlled release (or sustained release) formulations, fast dissolving formulations, effervescent formulations, lyophilized formulations, tablets, powders, pills, dragees, capsules, delayed release formulations, extended release formulations, pulsed release formulations, multiparticulate formulations, and mixed immediate release and controlled release formulations.

[0296] In some embodiments, provided herein is a composition for alleviating symptoms of cholestasis or cholestatic liver disease in an individual, comprising an enteroendocrine peptide secretion enhancing agent, and optionally a pharmaceutically acceptable carrier.

[0297] 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 specific enteroendocrine peptide secretagogue (or at least one thereof) with which it is combined. In some embodiments, the composition comprises an enteroendocrine peptide secretagogue, an absorption inhibitor, and a carrier (e.g., an orally suitable carrier or a rectally suitable carrier, 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.

[0298] In other embodiments, the compositions described herein are orally administered for non-systemic delivery of ASBTI to the rectum and / or colon, including the sigmoid colon, transverse colon, and / or ascending colon. In certain embodiments, compositions formulated for oral administration are enterically coated or enterically formulated oral dosage forms, such as, by way of non-limiting example, tablets and / or capsules.

[0299] 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 inhibitor includes an agent or agents that inhibit the absorption of bile acids / salts.

[0300] 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-hexaneaminium chloride with (chloromethyl)oxirane, 2-propen-1-amine, and N-2-propenyl-1-decaneamine hydrochloride), cyclodextrins, chitosan, chitosan derivatives, bile acid-binding carbohydrates, bile acid-binding lipids, bile acid-binding proteins and proteinaceous substances, and bile acid-binding antibodies and albumins. 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.

[0301] In certain embodiments, the absorption inhibitor is cholestyramine. In certain embodiments, cholestyramine is combined with bile acids. The ion exchange resin cholestyramine is a styrene polymer containing quaternary ammonium groups cross-linked by divinylbenzene. In other embodiments, the absorption inhibitor is colestipol. In certain embodiments, colestipol is combined with bile acids. The ion exchange resin colestipol is a copolymer of diethylenetriamine and 1-chloro-2,3-epoxypropane.

[0302] In certain embodiments of the compositions and methods described herein, ASBTI is linked to an antiresorptive agent, while in other embodiments, ASBTI and the antiresorptive agent are separate molecular entities.

[0303] Cholesterol absorption inhibitors In certain embodiments, the compositions described herein optionally contain 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, plant sponin, plant sterols, 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.

[0304] 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.

[0305] Spreading agent / wetting agent In certain embodiments, the compositions described herein optionally contain a spreading agent. In some embodiments, a spreading agent is used to improve the spread of the composition in the colon and / or rectum. Suitable spreading agents include, but are not limited to, 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 ethers, Aethoxal™ B, 2-ethylhexyl palmitate, Cegesoft™ C24, and isopropyl fatty acid esters.

[0306] In some embodiments, the compositions described herein optionally include a wetting agent. In some embodiments, the wetting agent is utilized to improve the wetting of the composition in the colon and rectum. Suitable wetting agents include, but are not limited to, surfactants. In some embodiments, the surfactant may be, but is not limited to, polysorbate (e.g., 20 or 80), stearyl hetanoate, or a 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.

[0307] vitamin In some embodiments, the methods provided herein further comprise administering one or more vitamins.

[0308] 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, or menaquinone.

[0309] In some embodiments, the vitamin is a fat-soluble vitamin such as vitamins 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).

[0310] Bile Acid Sequestrants / 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 higher concentrations in the human colon or rectum compared to concentrations found in the small intestine. Examples of microflora-activating systems include dosage forms containing pectin, galactomannan, and / or Azohydrogel and / or glycoside conjugates (e.g., conjugates of D-galactosides, β-D-xylopyranosides, etc.) of active agents. Examples of gastrointestinal microflora enzymes include bacterial glycosidases such as D-galactosidase, β-D-glucosidase, α-L-arabinofuranosidase, β-D-xylopyranosidase, etc.

[0311] 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 the 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 the 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 the 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 the 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 bile acids 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, hi some embodiments, the labile bile acid sequestrant releases bile acids or is degraded after 1, 2, or 3 days of sequestration.

[0312] 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.

[0313] 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 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 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 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 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 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.

[0314] 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 comprising 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 a combination 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 entirety for all purposes. In some embodiments, the bile acid binder is colestipol or colesevelam.

[0315] Route of administration, dosage form, 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 local delivery of the composition to the rectum and / or colon (sigmoid colon, transverse colon, 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.

[0316] In certain embodiments, the compositions or methods described herein are non-systemic. In some embodiments, the compositions described herein do not systemically deliver ASBTI to the distal ileum, colon, and / or rectum (e.g., a significant portion of the enteroendocrine peptide secretagogue is not systemically absorbed). In some embodiments, the oral compositions described herein do not systemically deliver ASBTI to the distal ileum, colon, and / or rectum (e.g., a significant portion of the enteroendocrine peptide secretagogue is not systemically absorbed). In some embodiments, the rectal compositions described herein do not systemically deliver ASBTI to the distal ileum, colon, and / or rectum (e.g., a significant portion of the enteroendocrine peptide secretagogue is not systemically absorbed). In certain embodiments, the non-systemic compositions described herein systemically deliver less than 90% by weight (% w / w) of ASBTI. In certain embodiments, the non-systemic compositions described herein systemically deliver less than 80% w / w of ASBTI. In certain embodiments, the non-systemic compositions described herein systemically deliver less than 70% w / w of ASBTI. In certain embodiments, the non-systemic compositions described herein systemically deliver less than 60% w / w of ASBTI. In certain embodiments, the non-systemic compositions described herein systemically deliver less than 50% w / w of ASBTI. In certain embodiments, the non-systemic compositions described herein systemically deliver less than 40% w / w of ASBTI. In certain embodiments, the non-systemic compositions described herein systemically deliver less than 30% w / w of ASBTI. In certain embodiments, the non-systemic compositions described herein systemically deliver less than 25% w / w of ASBTI. In certain embodiments, the non-systemic compositions described herein systemically deliver less than 20% w / w of ASBTI. In certain embodiments, the non-systemic compositions described herein systemically deliver less than 15% w / w of ASBTI. In certain embodiments, the non-systemic compositions described herein systemically deliver less than 10% w / w of ASBTI. In certain embodiments, the non-systemic compositions described herein systemically deliver less than 5% w / w of ASBTI.In some embodiments, systemic absorption is determined by any suitable method, including total circulating amount, amount cleared after administration.

[0317] 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 dosing regimen of the compositions comprising ASBTI described herein is determined by taking into account various factors such as the patient's age, sex, and diet.

[0318] The concentration of ASBTI administered in the formulations described herein ranges from about 1 mM to about 1 mM. 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.

[0319] In certain embodiments, by targeting the distal gastrointestinal 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 secretagogue (e.g., compared to oral doses that do not target the distal gastrointestinal tract).

[0320] Rectal preparations The pharmaceutical compositions described herein for non-systemic delivery of the compounds described herein to the rectum and / or colon are formulated for rectal administration as rectal enemas, rectal foams, rectal gels, and rectal suppositories.The components of such formulations are described herein.As used herein, it should be understood that pharmaceutical compositions and compositions are or comprise the formulations described herein.In some embodiments, rectal formulations include rectal enemas, foams, gels, or suppositories.

[0321] In certain embodiments, the liquid carrier vehicle or co-solvent in the compositions and / or formulations described herein may include, by way of non-limiting example, purified water, propylene glycol, PEG200, PEG300, PEG400, PEG600, polyethylene glycol, ethanol, 1-propanol, 2-propanol, 1-propen-3-ol (allyl alcohol), propylene glycol, glycerol, 2-methyl-2-propanol, formamide, methylformamide, dimethylformamide, ethylformamide, diethylformamide, acetamide, methylacetamide, dimethylacetamide, ethylacetamide, diethylacetamide, 2-pyrrolidone, N-methyl-2-pyrrolidone, N-ethyl-2-pyrrolidone, tetramethylurea, 1,3-dimethyl-2-imidazolidinone, propylene carbonate, 1,2-butylene carbonate, 2,3-butylene carbonate, dimethyl sulfoxide, diethyl sulfoxide, hexamethylphosphoramide, pyruvic aldehyde dimethyl acetal, dimethyl isosorbide, and combinations thereof.

[0322] In some embodiments, stabilizers used in the compositions and / or formulations described herein include, but are not limited to, partial glycerides of polyoxyethylene saturated fatty acids.

[0323] In certain embodiments, surfactants / emulsifiers used in the compositions and / or formulations described herein include, by way of non-limiting example, mixtures of sorbitan esterified with polyoxyethylene fatty acids and cetostearyl alcohol, polyoxyethylene fatty acid ethers, polyoxyethylene fatty acid esters, fatty acids, sulfated fatty acids, phosphorylated fatty acids, sulfosuccinates, amphoteric surfactants, nonionic poloxamers, nonionic meroxapol, petroleum derivatives, fatty amines, polysiloxane derivatives, sorbitan fatty acid esters, laureth-4, PEG-2 dilaurate, stearic acid, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, cocoamphopropionate, poloxamer 188, meroxapol 258, triethanolamine, dimethicone, polysorbate 60, sorbitan monostearate, pharmaceutically acceptable salts thereof, and combinations thereof.

[0324] In some embodiments, non-ionic surfactants used in the compositions and / or formulations described herein include, by way of non-limiting example, phospholipids, alkyl poly(ethylene oxide), poloxamer (e.g., poloxamer 188), polysorbates, dioctyl sodium sulfosuccinate, Brij™-30 (Laureth-4), Brij™-58 (Ceteth-20) and Brij™-78 (Steareth-20), Brij™-721 (Steareth-21), Crillet-1 (Polysorbate 20), Crillet-2 (Polysorbate 40), Crillet-3 (Polysorbate 60), Crillet 45 (Polysorbate 80), Myrj-52 (PEG-40 stearate), Myrj-53 (PEG-50 stearate), Pluronic® F77 (Poloxamer 217), Pluronic® F87 (Poloxamer 237), Pluronic® F98 (Poloxamer 288), Pluronic® L62 (Poloxamer 182), Pluronic Pluronic® polymers include Pluronic® L64 (poloxamer 184), Pluronic® F68 (poloxamer 188), Pluronic® L81 (poloxamer 231), Pluronic® L92 (poloxamer 282), Pluronic® L101 (poloxamer 331), Pluronic® P103 (poloxamer 333), Pluracare™ F108 NF (poloxamer 338), and Pluracare™ F127 NF (poloxamer 407), and combinations thereof. Pluronic® polymers are commercially available from BASF, USA, and Germany.

[0325] In certain embodiments, anionic surfactants used in the compositions and / or formulations described herein include, by way of non-limiting example, sodium lauryl sulfate, sodium dodecyl sulfate (SDS), ammonium lauryl sulfate, alkyl sulfates, alkyl benzene sulfonates, and combinations thereof.

[0326] In some embodiments, cationic surfactants used in the compositions and / or formulations described herein include, by way of non-limiting example, benzalkonium chloride, benzethonium chloride, cetyltrimethylammonium bromide, hexadecyltrimethylammonium bromide, other alkyltrimethylammonium salts, cetylpyridinium chloride, polyethoxylated tallow, and combinations thereof.

[0327] In certain embodiments, thickeners used in the compositions and / or formulations described herein include, but are not limited to, natural polysaccharides, semi-synthetic polymers, synthetic polymers, and combinations thereof. Natural polysaccharides include, but are not limited to, acacia, agar, alginate, carrageenan, guar, gum arabic, tragacanth gum, pectin, dextran, gellan, and xanthan gum. Semi-synthetic polymers include, but are not limited to, cellulose esters, modified starch, modified cellulose, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose. Synthetic polymers include, but are not limited to, polyoxyalkylenes, polyvinyl alcohols, polyacrylamides, polyacrylates, carboxypolymethylene (carbomer), polyvinylpyrrolidone (povidone), polyvinyl acetate, polyethylene glycol, and poloxamers. Other thickening agents include, by way of non-limiting example, polyoxyethylene glycol isostearate, cetyl alcohol, polyglycol 300 isostearate, propylene glycol, collagen, gelatin, and fatty acids (e.g., lauric acid, myristic acid, palmitic acid, stearic acid, palmitoleic acid, linoleic acid, linolenic acid, oleic acid, etc.).

[0328] In some embodiments, chelating agents used in the compositions and / or formulations described herein include, by way of non-limiting example, ethylenediaminetetraacetic acid (EDTA) or its salts, phosphate salts, and combinations thereof.

[0329] In some embodiments, the concentration of the chelating agent(s) used in the rectal formulations described herein is a suitable concentration, for example, about 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.4%, or 0.5% (w / v).

[0330] In some embodiments, preservatives used in the compositions and / or formulations described herein include, by way of non-limiting example, parabens, ascorbyl palmitate, benzoic acid, butylated hydroxyanisole, butylated hydroxytoluene, chlorobutanol, ethylenediamine, ethylparaben, methylparaben, butylparaben, propylparaben, monothioglycerol, phenol, phenylethyl alcohol, propylparaben, sodium benzoate, sodium propionate, sodium formaldehyde sulfoxylate, sodium metabisulfite, sorbic acid, sulfur dioxide, maleic acid, propyl gallate, benzalkonium chloride, benzethonium chloride, benzyl alcohol, chlorhexidine acetate, chlorhexidine gluconate, sorbic acid, potassium sorbitol, chlorbutanol, phenoxyethanol, cetylpyridinium chloride, phenylmercuric nitrate, thimerosal, and combinations thereof.

[0331] In certain embodiments, antioxidants used in the compositions and / or formulations described herein include, by way of non-limiting example, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, propyl gallate, sodium ascorbate, sodium sulfite, sodium bisulfite, sodium formaldehyde sulfoxylate, potassium metabisulfite, sodium metabisulfite, oxygen, quinone, t-butylhydroquinone, erythorbic acid, olea eurpaea oil, pentasodium pentetate, pentetic acid, tocopheryl, tocopheryl acetate, and combinations thereof.

[0332] In some embodiments, the concentration of one or more antioxidants used in the rectal formulations described herein is sufficient to achieve the desired result, e.g., about 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.4%, or 0.5% (w / v).

[0333] Lubricants used in the compositions and / or formulations described herein include, by way of non-limiting example, natural or synthetic fats or oils (e.g., tris fatty acid glycerates, etc.). In some embodiments, lubricants include, by way of non-limiting example, glycerin (also known as glycerin, glycerol, 1,2,3-propanetriol, and trihydroxypropane), polyethylene glycol (PEG), polypropylene glycol, polyisobutene, polyethylene oxide, behenic acid, behenyl alcohol, sorbitol, mannitol, lactose, polydimethylsiloxane, and combinations thereof.

[0334] In certain embodiments, mucoadhesive and / or bioadhesive polymers are used in the compositions and / or formulations described herein as agents for inhibiting the absorption of enteroendocrine peptide secretagogues across the rectal or colonic mucosa. Non-limiting examples of bioadhesive or mucoadhesive polymers include hydroxypropyl cellulose, polyethylene oxide homopolymer, polyvinyl ether-maleic acid copolymer, methylcellulose, ethylcellulose, propylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, polycarbophil, polyvinylpyrrolidone, carbopol, polyurethane, polyethylene oxide-polypropylene oxide copolymer, sodium carboxymethylcellulose, polyethylene, polypropylene, lectin, xanthan gum, alginate, sodium alginate, polyacrylic acid, chitosan, hyaluronic acid and its ester derivatives, vinyl acetate homopolymer, calcium polycarbophil, gelatin, natural gum, karaya, tragacanth, algin, chitosan, starch, pectin, and combinations thereof.

[0335] In some embodiments, buffers / pH adjusters used in the compositions and / or formulations described herein include, but are not limited to, phosphoric acid, monobasic sodium or potassium phosphate, triethanolamine (TRIS), bicine, hepes, Trizma, glycine, histidine, arginine, lysine, asparagine, aspartic acid, glutamine, glutamic acid, carbonate, bicarbonate, potassium metaphosphate, potassium phosphate, monobasic sodium acetate, acetic acid, acetate, citric acid, anhydrous sodium citrate, sodium citrate dihydrate, and combinations thereof. In certain embodiments, an acid or base is added to adjust the pH. Suitable acids or bases include, but are not limited to, HCl, NaOH, and KOH.

[0336] In certain embodiments, the concentration of buffering agent(s) used in the rectal formulations described herein is sufficient to achieve or maintain a physiologically desirable pH, e.g., about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.8%, 0.9%, or 1.0% (w / w).

[0337] Tonicity adjusting agents used in the compositions and / or formulations described herein include, by way of non-limiting example, sodium chloride, potassium chloride, sodium phosphate, mannitol, sorbitol or glucose.

[0338] Oral administration for colonic delivery In certain aspects, compositions or formulations containing 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. In certain embodiments, such pills, tablets, or capsules contain the compositions described herein encapsulated or embedded in microspheres. In some embodiments, microspheres include, by way of non-limiting example, chitosan microcore 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 containing the active agent(s) described above, alone or in combination with one or more carriers, additives, etc. In alternative embodiments, tablets are prepared using a wet granulation or dry granulation process. In some embodiments, tablets are molded rather than compressed, starting with a moist or otherwise tractable material.

[0339] 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 cohesive properties to the tablet and ensure that it remains intact after compression. Suitable binder materials include, by way of non-limiting example, starch (including cornstarch 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 practical tablet 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 production; examples of 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 promote tablet disintegration, and examples include but are not limited to, starch, clay, cellulose, algin, gum, cross-linked polymers, 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. In certain embodiments, the surfactant is an anionic, cationic, amphoteric, or nonionic surfactant.

[0340] In some embodiments, ASBTI, or other compounds described herein, is administered orally with a carrier suitable for delivery to the distal gastrointestinal tract (e.g., the distal ileum, colon, and / or rectum).

[0341] In certain embodiments, the compositions described herein comprise ASBTI or other compounds described herein in association with a matrix (e.g., a matrix comprising 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 comprise a polymer that is pH-sensitive (e.g., an 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 contain 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 comprise 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, bacterially activated systems are suitable for targeted delivery to the distal portion of the ileum. Examples of microflora-activated systems include dosage forms containing pectin, galactomannan, and / or Azo hydrogels and / or glycoside conjugates (e.g., D-galactosides, β-D-xylopyranosides, etc.) of active agents. Examples of gut microflora enzymes include bacterial glycosidases such as D-galactosidase, β-D-glucosidase, α-L-arabinofuranosidase, β-D-xylopyranosidase, etc.

[0342] The pharmaceutical compositions described herein optionally comprise an additional therapeutic compound described herein and one or more pharmaceutically acceptable additives, such as a compatible carrier, binder, filler, suspending agent, flavoring agent, sweetener, disintegrant, dispersing agent, surfactant, lubricant, colorant, diluent, solubilizer, humectant, plasticizer, stabilizer, penetration 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 uncoated.

[0343] In a further embodiment, tablets or capsules containing ASBTI or other compounds described herein are film-coated for delivery to target sites in the gastrointestinal tract. Examples of enteric film coatings include, but are not limited to, hydroxypropylmethylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose, polyethylene glycol 3350, 4500, 8000, methylcellulose, pseudoethylcellulose, amylopectin, etc.

[0344] Pediatric Formulations and Compositions Provided herein, in certain embodiments, is a pediatric dosage 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).

[0345] 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, dragees, delayed-release formulations, extended-release formulations, pulsed-release formulations, multiparticulate formulations, and mixed immediate-release and controlled-release formulations. In some embodiments, provided herein are pharmaceutical compositions wherein 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.

[0346] In another aspect, provided herein is a pharmaceutical composition wherein at least one excipient is a flavoring or sweetening agent. In some embodiments, provided herein is a coating. In some embodiments, provided herein is a taste-masking technology selected from: coating drug particles with a taste-neutral polymer by spray drying, wet granulation, fluidized bed, and microencapsulation; coating a mixture of molten wax and other pharmaceutical adjuvants 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 a drug and one or more neutral-tasting compounds are melted and cooled or co-precipitated by solvent evaporation. In some embodiments, provided herein is a delayed-release or sustained-release formulation comprising drug particles or granules in a rate-controlling polymer or matrix.

[0347] Suitable sweeteners include sucrose, glucose, fructose, or high-intensity sweeteners, i.e., agents with a sweetening power greater than that of 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, and Magnasweet®. The total concentration of the sweetener, based on the reconstituted liquid composition, can range from substantially zero to about 300 mg / ml.

[0348] To enhance the palatability of the liquid composition upon reconstitution 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 flavor, or a combination thereof. The flavoring agent typically accounts for 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.

[0349] Flavoring agents herein are substances capable of enhancing the taste or aroma of the 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 agents and / or sweeteners 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, and coca-cola. Citrus, cyclamate, cylamate, dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger, glycyrrhetinic acid salt, licorice syrup, grapes, grapefruit, honey, isomalt, lemon, lime, lemon cream, monoammonium glycyrrhizinate (MagnaSweet®), maltol, mannitol, maple, marshmallow, menthol, mint cream, mixed berry, honey Ohesperidin 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, talc, ciritol, sucralose, sorbitol Flavoring agents may be used alone or in combinations of two or more. In some embodiments, the aqueous liquid dispersion contains 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.

[0350] In certain embodiments, the pediatric pharmaceutical compositions described herein contain one or more compounds described herein as active ingredients in the form of a free acid or free base, or in the form of a pharmaceutically 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, where solvated forms include any pharmaceutically acceptable solvent, such as water, ethanol, etc. Solvated forms of the compounds presented herein are also considered to be described herein.

[0351] The "carrier" of a pediatric pharmaceutical composition, in some embodiments, comprises a pharmaceutically acceptable excipient, selected based on compatibility with a compound 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, H.A. 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 herein by reference in their entirety for all purposes.

[0352] Furthermore, in certain embodiments, the pediatric pharmaceutical compositions described herein are formulated as dosage forms.Thus, in some embodiments, provided herein are dosage forms comprising the compounds described herein suitable for administration to individuals.In certain embodiments, suitable dosage forms include, but are not limited to, 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.

[0353] In certain aspects, pediatric compositions or formulations containing 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. In certain embodiments, such pills, tablets, or capsules contain the compositions described herein encapsulated or embedded in microspheres. In some embodiments, microspheres include, by way of non-limiting example, chitosan microcore HPMC capsules and cellulose acetate butyrate (CAB) microspheres. In certain embodiments, oral dosage forms are prepared using conventional methods known in the pharmaceutical arts. 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 containing an active agent, alone or in combination with one or more carriers, additives, etc. In alternative embodiments, tablets are prepared using a wet granulation or dry granulation process. In some embodiments, tablets are molded rather than compressed, starting with a moist or otherwise tractable material.

[0354] 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, flav...

Claims

1. A composition for use in treating a cholestatic liver disease selected from primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) in a subject in need thereof, comprising an apical sodium-dependent bile acid transporter inhibitor (ASBTI), wherein the ASBTI is: 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, wherein the ASBTI is administered in an amount of 20 mg / day to 200 mg / day.

2. A composition for treating or alleviating cholestatic pruritus in a subject with a cholestatic liver disease selected from primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), comprising an apical sodium-dependent bile acid transporter inhibitor (ASBTI), wherein the ASBTI is: 【Chemistry 2】 or a pharmaceutically acceptable salt thereof, wherein the ASBTI is administered in an amount of 20 mg / day to 200 mg / day.

3. A composition described in claim 1 or 2, wherein the ASBTI is borixib potassium.

4. The ASBTI, 【Transformation 3】 The composition according to claim 1 or 2,

5. A composition described in any one of claims 1 to 4, wherein the cholestatic liver disease is PBC.

6. A composition described in any one of claims 1 to 4, wherein the cholestatic liver disease is PSC.

7. A composition described in any one of claims 1 to 6, wherein the ASBTI is administered once daily (QD) or twice daily (BID).

8. A composition described in any one of claims 1 to 7, wherein the ASBTI is administered in an amount of 20 mg / day to 150 mg / day.

9. A composition described in any one of claims 1 to 7, wherein the ASBTI is administered twice daily (BID) in an amount of 20 mg to 100 mg.

10. A composition described in any one of claims 1 to 9, wherein the ASBTI is administered twice daily (BID) in an amount of 20 mg.

11. A composition described in any one of claims 1 to 10, administered before ingestion of food.

12. A composition described in any one of claims 1 to 11, which is administered orally.

13. A method described in any one of claims 1 to 12, wherein the subject is an adult aged 18 years or older.

14. A composition described in any one of claims 1 to 13, wherein the subject experiences pruritus before administration of the composition and shows a reduction in the severity of the pruritus after administration of the composition compared to the severity of the pruritus before administration of the composition.

15. The composition described in claim 14, wherein the reduction in the severity of pruritus is measured as a reduction of at least 1.0 in the Itch Reported Outcome in Adults (ITCHRO) score.

16. A composition described in any one of claims 1 to 15, wherein the subject exhibits at least about a 20% decrease in serum bile acid (sBA) concentration after administration of the composition compared to the sBA concentration before administration of the composition.

17. The composition of claim 16, wherein the subject exhibits at least about a 20% reduction in serum bile acid (sBA) concentrations by 18 weeks.

18. A composition described in any one of claims 1 to 17, wherein the subject shows an increase in serum 7αC4 concentration of at least about 30% after administration of the composition compared to the serum 7αC4 concentration before administration of the composition.

19. The composition described in claim 18, wherein the subject exhibits at least a 100% increase in serum 7αC4 concentration relative to baseline after administration of the composition.

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