Genotype and dose dependent response to ASBTI in patients suffering from bile salt export pump deficiency

Abstract

The present application relates to genotype and dose dependent responses to ASBTI in patients suffering from bile salt export pump deficiency. Provided herein are methods for treating or ameliorating cholestatic liver disease in a subject in need thereof. The methods comprise administering to the subject an apical sodium dependent bile acid transport inhibitor (ASBTI). The method includes determining a genotype of the subject, and predicting a response of the subject to administration of the ASBTI based on the genotype. The method further comprises determining, adjusting, or modulating a dose of the ASBTI administered to the subject based on the genotype or based on a measurement of a clinically related disease parameter.

Description

[0001] This application is a divisional application of the invention patent application filed on February 12, 2020, with application number 202080028415.3 and invention title "Genotype and dose-dependent response of patients with bile salt output pump deficiency to ASBTI". Cross-references to related applications

[0002] This application claims the benefit of U.S. Provisional Application No. 62 / 504,523, filed February 12, 2019; U.S. Provisional Application No. 62 / 863,904, filed June 20, 2019; U.S. Provisional Application No. 62 / 908,431, filed September 30, 2019; and U.S. Provisional Application No. 62 / 932,015, filed November 7, 2019, filed under 35 USC §119(e), which are incorporated herein by reference in their entirety for all purposes. Technical Field

[0003] This invention generally relates to methods for treating or improving cholestatic liver disease. In particular, the invention relates to methods for adjusting the dosage of a apical sodium-dependent bile acid transport inhibitor (ASBTI) administered to a subject, and methods for using the subject's genotype to predict the response to ASBTI administration at a specific dose level. Background Technology

[0004] Hypercholesterolemia and cholestatic liver disease are liver diseases associated with impaired bile secretion (i.e., cholestasis), related to and often secondary to the intracellular accumulation of bile acids / salts in hepatocytes. Hypercholesterolemia is characterized by elevated serum concentrations of bile acids or bile salts. Cholestasis can be classified into two main categories clinicopathologically: obstructive (usually extrahepatic) cholestasis and non-obstructive or intrahepatic cholestasis. Non-obstructive intrahepatic cholestasis can be further divided into two main subgroups: primary intrahepatic cholestasis caused by constitutive bile secretion defects and secondary intrahepatic cholestasis caused by hepatocyte damage. Primary intrahepatic cholestasis includes diseases such as benign recurrent intrahepatic cholestasis (primarily the adult type with similar clinical symptoms) and progressive familial intrahepatic cholestasis (PFIC) types 1, 2, and 3 (which are diseases affecting children).

[0005] Neonatal respiratory distress syndrome and pneumonia are often 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 low-dose ursodeoxycholic acid administration. Effective and safe medications are needed for hypercholesterolemia and cholestatic liver disease. Summary of the Invention

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

[0007] In one aspect, the invention provides a method for treating or improving cholestatic liver disease in a subject who requires it, wherein the subject has bile salt export pump (BSEP) deficiency, and the method comprises administering a apical sodium-dependent bile acid transport inhibitor (ASBTI) to the subject. In some embodiments, the ASBTI is... (maralixibat) (volixibat) (odevixibat) (elobixibat) (GSK2330672), or a pharmaceutically acceptable salt thereof. In some embodiments, ASBTI is macibazide or a pharmaceutically acceptable salt thereof. In some embodiments, ASBTI is vocibazide or a pharmaceutically acceptable salt thereof. In various embodiments, ASBTI is ozevibazide or a pharmaceutically acceptable salt thereof. In some embodiments, ASBTI is erobixibizide or a pharmaceutically acceptable salt thereof. In some embodiments, ASBTI is GSK2330672 or a pharmaceutically acceptable salt thereof.

[0008] In various embodiments, cholestatic liver disease is progressive familial intrahepatic cholestasis type 2 (PFIC type 2), benign recurrent intrahepatic cholestasis (BRIC), or intrahepatic cholestasis of pregnancy (ICP), or biliary atresia. In some embodiments, the subject has residual BSEP function. In various embodiments, BSEP deficiency results in impaired or reduced bile flow or cholestasis.

[0009] In some embodiments, the subject's ABCB11 The gene contains non-truncated mutations. In various embodiments, ABCB11 The gene contains one or more of E297G, D482G, substitutional missense mutations, or combinations thereof. In some embodiments, ABCB11 The gene contains an E297G or D482G mutation, or both. In various embodiments, ABCB11 The gene contains a missense mutation, rather than an E297G or D482G mutation.

[0010] In some embodiments, the method further includes determining the subject's genotype. In some embodiments, determining the genotype includes identification and characterization. ABCB11 Mutations in genes. In some embodiments, the subject's... ABCB11The gene was characterized as containing only non-truncated mutations.

[0011] In various embodiments, the method includes determining the ratio (7αC4:sBA) of serum 7α-hydroxy-4-cholesten-2-one (7αC4) to serum bile acid (sBA) concentration before administering ASBTI at a first dose level (baseline ratio), and further determining the 7αC4:sBA ratio after ASBTI administration, wherein ASBTI administration results in a 7αC4:sBA ratio that is approximately two-fold or higher than the baseline 7αC4:sBA ratio. In some embodiments, if the 7αC4:sBA ratio begins to decrease or decreases to less than two-fold or higher than baseline, a second dose level of ASBTI is administered to the subject. The second dose level is higher than the first dose level.

[0012] In various embodiments, the method includes determining the ratio of serum 7αC4 concentration to sBA concentration (7αC4:sBA) before administering ASBTI at a first dose level (baseline ratio), and further determining the 7αC4:sBA ratio after administering ASBTI, wherein if administering ASBTI fails to result in a 7αC4:sBA ratio that is approximately 2 times higher than the baseline 7αC4:sBA ratio, a second dose level of ASBTI is administered to the subject, wherein the second dose level is higher than the first dose level.

[0013] In various embodiments, the method further includes adjusting the dose of ASBTI, the adjustment comprising determining the serum 7αC4 concentration to sBA concentration ratio (7αC4:sBA) before administering ASBTI at a first dose level (baseline ratio), and further determining the 7αC4:sBA ratio after administering ASBTI, wherein if administering ASBTI fails to result in a 7αC4:sBA ratio that is approximately 2 times higher than the baseline 7αC4:sBA ratio, then ASBTI is administered at a second dose level that does indeed result in a 7αC4:sBA ratio that is approximately 2 times higher than the baseline ratio. In various embodiments, the second dose is at least approximately two times and less than approximately five times the first dose.

[0014] In various embodiments, the method further includes adjusting the dose of ASBTI, the adjustment comprising determining the ratio of serum 7αC4 concentration to sBA concentration (7αC4:sBA) before administering ASBTI at a first dose level (baseline ratio), and further determining the 7αC4:sBA ratio after administering ASBTI, wherein if the treating physician believes that the ratio can be increased beyond the current level by a higher dose level of ASBTI, ASBTI is administered to the subject at a second dose level that results in a 7αC4:sBA ratio higher than the baseline ratio.

[0015] In some embodiments, the subjects are pediatric subjects under the age of 18. In some embodiments, administration of ASBTI results in improved growth relative to baseline in the subjects. In various embodiments, the improved growth in the subjects is measured as an increase in height z-score.

[0016] In some embodiments, ASBTI is administered at a daily dose of about 140 µg / kg to about 1400 µg / kg. In some embodiments, ASBTI is administered once daily. In various embodiments, ASBTI is administered twice daily. In various embodiments, ASBTI is administered at a daily dose of about 5 mg / day to about 100 mg / day. In some embodiments, ASBTI is administered regularly for at least one year. In some embodiments, ASBTI is administered regularly for at least four years.

[0017] In various embodiments, administration of ASBTI resulted in a reduction of symptoms of cholestatic liver disease or a change in disease-related laboratory measurements, sustained for at least one year. In various embodiments, the reduction of symptoms or the change in disease-related laboratory measurements included a decrease in sBA concentration, an increase in serum 7αC4 concentration, an increase in the serum 7αC4 to sBA concentration ratio (7αC4:sBA), a reduction in pruritus, an increase in a quality of life inventory score, an increase in a fatigue-related quality of life inventory score, or a combination thereof. In some embodiments, the reduction of symptoms or the change in disease-related laboratory measurements was determined relative to baseline levels. In various embodiments, the subject was a pediatric subject under 18 years of age, and the reduction of symptoms or the change in disease-related laboratory measurements included an increase in growth.

[0018] In some embodiments, administration of ASBTI results in an increase in serum 7αC4 concentration. In various embodiments, serum 7αC4 concentration increases by about 1.5 to about 40 times relative to baseline. In some embodiments, administration of ASBTI results in an increase in the ratio of serum 7αC4 concentration to sBA concentration (7αC4:sBA). In some embodiments, 7αC4:sBA increases by about 2 to about 5,000 times relative to baseline.

[0019] In various embodiments, administration of ASBTI resulted in an increase of at least 100% in fecal bile acids (fBA) relative to baseline. In some embodiments, administration of ASBTI resulted in a decrease of at least about 70% in sBA concentration relative to baseline.

[0020] In various embodiments, administration of ASBTI leads to a reduction in the severity of pruritus. In some embodiments, the reduction in pruritus severity is measured as a decrease of at least 1.0 in the Observer-Reported Itching Outcome (ITCHRO(OBS)) score. In some embodiments, administration of ASBTI results in an ITCHRO(OBS) score ≤1. In various embodiments, administration of ASBTI leads to an increase in the quality of life inventory score.

[0021] In some embodiments, the quality of life inventory score is a health-related quality of life (HRQoL) score. In some embodiments, the quality of life inventory score is a pediatric quality of life inventory (PedsQL) score, and the PedsQL score increases by at least 10% relative to baseline.

[0022] In various embodiments, approximately 4 months after the first administration of ASBTI, serum bilirubin concentrations were at baseline levels before administration. In various embodiments, approximately 4 months after the first administration of ASBTI, serum alanine aminotransferase (ALT) concentrations were at baseline levels before administration. In some embodiments, approximately 4 months after the first administration of ASBTI, serum aspartate aminotransferase (AST) concentrations and serum bilirubin concentrations were within the normal range. In some embodiments, administration of ASBTI resulted in a decrease in serum ALT concentration of at least approximately 10% relative to baseline.

[0023] In various embodiments, the subjects had biliary atresia or intrahepatic cholestasis of pregnancy.

[0024] In one aspect, the present invention provides a method for predicting the response of a subject to treatment for cholestatic liver disease. The treatment comprises administering ASBTI to a subject requiring such treatment. The method comprises determining the subject's genotype and predicting the subject's response to treatment based on the genotype.

[0025] In various embodiments, ASBTI is (Mashibat) (Voshibat) (Ovichbart) (Erobishbart) (GSK2330672), or a pharmaceutically acceptable salt thereof. In some embodiments, ASBTI is macibazide or an alternative pharmaceutically acceptable salt thereof. In some embodiments, ASBTI is vocibazide or a pharmaceutically acceptable salt thereof. In various embodiments, ASBTI is ozevibazide or a pharmaceutically acceptable salt thereof. In some embodiments, ASBTI is erobixibizide or a pharmaceutically acceptable salt thereof. In various embodiments, ASBTI is GSK2330672 or a pharmaceutically acceptable salt thereof.

[0026] In various embodiments, the method includes determining the genotype, comprising determining... ABCB11 The sequence of a gene. In some embodiments, the method includes identification and characterization. ABCB11 Gene mutations. In various embodiments, the method further includes predicting if... ABCB11 If a gene contains a truncated mutation, the subject will not respond to ASBTI administration. In some embodiments, the method includes predicting if... ABCB11 If a gene contains a mutation that results in the complete loss of BSEP activity, the subject will not respond to ASBTI administration. In some embodiments, the method includes predicting if... ABCB11 The gene contains mutations that lead to residual BSEP activity and ABCB11 If the gene does not contain a mutation that results in the absence of BSEP activity, the subject will respond to administration of ASBTI. In some embodiments, ABCB11 The gene contains one or more of E297G, D482G, a substitutional missense mutation, or some combination thereof. In various embodiments, the method includes administering ASBTI to the subject if a response to ASBTI administration is predicted.

[0027] In some embodiments, the subject has biliary atresia or intrahepatic cholestasis of pregnancy.

[0028] In one aspect, the present invention provides a method for treating or improving cholestatic liver disease in a subject who requires it. The subject suffers from BSEP deficiency. The method includes determining the subject's genotype, using the subject's genotype to predict whether the subject will respond to treatment with ASBTI, and administering ASBTI to the subject if the predicted response to ASBTI administration is found.

[0029] In various embodiments, determining the genotype includes determining... ABCB11 The sequence of a gene. In some embodiments, the method includes identification and characterization. ABCB11 Gene mutations. In various embodiments, the method includes predicting if... ABCB11 If a gene contains a truncated mutation, the subject will not respond to ASBTI administration. In some embodiments, the method includes predicting if... ABCB11 If a gene contains a mutation that results in the complete loss of BSEP activity, the subject will not respond to ASBTI administration. In some embodiments, the method includes predicting if... ABCB11 The gene contains mutations that lead to residual BSEP activity and ABCB11If the gene does not contain mutations that result in the absence of BSEP activity, the subject will respond to ASBTI administration. In various embodiments, ABCB11 The gene contains one or more of the following: E297G, D482G, a substitution missense mutation, or a combination thereof.

[0030] In various embodiments, the method includes determining the ratio of serum 7αC4 concentration to serum bile acid (sBA) concentration (7αC4:sBA) before administering ASBTI at a first dose (baseline ratio), and further determining the 7αC4:sBA ratio after administering ASBTI. In some embodiments, the method includes administering a second dose of ASBTI, wherein the second dose is greater than the first dose if the 7αC4:sBA ratio does not remain above approximately >2 times the baseline ratio after administering the first dose of ASBTI.

[0031] In some embodiments, the method includes administering a second dose of ASBTI, wherein if the 7αC4:sBA ratio initially increases by at least >2 times from baseline and then begins to decrease back to the baseline ratio, the second dose is greater than the first dose. In some embodiments, the second dose is at least about twice and less than about five times the first dose.

[0032] In some embodiments, the subjects are pediatric subjects under the age of 18. In various embodiments, administration of ASBTI resulted in improved growth in the subjects. In various embodiments, the improved growth in the subjects was measured as an increase in height z-score.

[0033] In some embodiments, ASBTI is administered at a daily dose of about 140 µg / kg to about 1400 µg / kg. In various embodiments, ASBTI is administered once daily. In some embodiments, ASBTI is administered twice daily. In some embodiments, ASBTI is administered at a dose of about 5 mg / day to about 100 mg / day. In various embodiments, ASBTI is administered regularly for at least one year. In some embodiments, ASBTI is administered regularly for at least four years.

[0034] In various embodiments, administration of ASBTI resulted in a reduction of symptoms of cholestatic liver disease or a change in disease-related laboratory measurements, sustained for at least one year. In various embodiments, the reduction of symptoms or the change in disease-related laboratory measurements included a decrease in sBA concentration, an increase in serum 7αC4 concentration, an increase in the serum 7αC4 to sBA concentration ratio (7αC4:sBA), a reduction in pruritus, an increase in a quality of life inventory score, an increase in a fatigue-related quality of life inventory score, or a combination thereof. In some embodiments, the reduction of symptoms or the change in disease-related laboratory measurements was determined relative to baseline levels. In various embodiments, the subject was a pediatric subject under 18 years of age, and the reduction of symptoms or the change in disease-related laboratory measurements included an increase in growth.

[0035] In some embodiments, administration of ASBTI resulted in an increase in serum 7αC4 concentration. In various embodiments, serum 7αC4 concentration increased by about 1.5 to about 40 times relative to baseline. In some embodiments, serum 7αC4 concentration increased by at least 100% relative to baseline.

[0036] In some embodiments, administration of ASBTI results in an increase in the serum 7αC4 to sBA concentration ratio (7αC4:sBA). In some embodiments, the 7αC4:sBA ratio increases by approximately 2-fold to approximately 5,000-fold relative to baseline.

[0037] In various embodiments, administration of ASBTI resulted in an increase of at least 100% in fBA relative to baseline. In some embodiments, administration of ASBTI resulted in a decrease of at least about 70% in sBA concentration relative to baseline.

[0038] In some embodiments, administration of ASBTI results in a reduction in the severity of pruritus. In various embodiments, the reduction in pruritus severity is measured as a decrease in the observer-reported pruritus outcome (ITCHRO(OBS)) score relative to baseline of at least 1.0. In some embodiments, administration of ASBTI results in an ITCHRO(OBS) score ≤1.

[0039] In various embodiments, administration of ASBTI resulted in an increase in the quality of life inventory score. In some embodiments, the quality of life inventory score is a health-related quality of life (HRQoL) score. In various embodiments, the quality of life inventory score is a pediatric quality of life inventory (PedsQL) score. In some embodiments, the PedsQL score increased by at least 10% relative to baseline.

[0040] In some embodiments, serum bilirubin concentrations are at baseline levels approximately 4 months after the first administration of ASBTI. In various embodiments, serum ALT concentrations are at baseline levels approximately 4 months after the first administration of ASBTI. In various embodiments, serum ALT, serum AST, and serum bilirubin concentrations are within the normal range approximately 4 months after the first administration of ASBTI. In some embodiments, administration of ASBTI results in a decrease in serum ALT concentration of at least approximately 10% relative to baseline.

[0041] In various embodiments, the subject had biliary atresia or intrahepatic cholestasis of pregnancy. In some embodiments, the subject had PFIC 2.

[0042] These and other aspects of the invention will become apparent to those skilled in the art after reading the following detailed description of the invention, including the appended claims. Attached Figure Description

[0043] Figure 1 A schematic diagram outlining the physiological effects of macibatide administration on patients is provided. CYP7A1, cholesterol 7α-hydroxylase; FGF, fibroblast growth factor; FXR, farnesoid X receptor.

[0044] Figure 2 A schematic diagram is shown, providing an overview of the dosing regimen used in the INDIGO Phase 2 open-label clinical study of the safety and efficacy of macibar in children with PFIC (the INDIGO Clinical Study). The clinical study investigated long-term exposure to macibar.

[0045] Figures 3A-3F Each study provided quantitative summaries of response metrics measured in six participants in the INDIGO clinical trial. The six participants were 3-year-old girls ( Figure 3A ), 10-year-old boy ( Figure 3B ), the younger sister of a 6-year-old girl and a 10-year-old boy ( Figure 3C ), 4-year-old girl ( Figure 3D ), 3-year-old boy ( Figure 3E ) and 1-year-old girl ( Figure 3F ). Figures 3A-3F Three scatter plots were provided for each study week, showing sBA levels (concentrations), pruritus severity scores, and Pediatric Quality of Life Inventory (PEDSQL) scores. Pruritus severity scores were measured using the Clinical Scratch Scale (CSS) and the Itch Reporting Outcomes (ITCHRO) score. Figures 3A-3F Each also provided a summary of observed changes in ALT (alanine aminotransferase) and AST (aspartate aminotransferase) levels, bilirubin levels, and C4 levels for each responder.

[0046] Figure 4 A scatter plot was created showing the change in height Z-scores from baseline over time in responders and non-responders in the INDIGO clinical study. The decrease in mean height Z-score at week 60 was attributed to one patient who was not measured at that time point.

[0047] Figure 5A and 5B A scatter plot was provided, showing the changes in serum bile acid (sBA) concentrations over time for patients participating in the INDIGO clinical study. Figure 5A A bile salt output pump (BSEP) with a non-truncated configuration was plotted. ABCB11 Changes in sBA concentration over time in patients with gene coding mutations. Figure 5B The changes in sBA concentration over time in patients with truncated BSEP mutations were plotted. Figures 5A-5B This indicates that the sBA response varies depending on the BSEP mutation status. A solid black circle indicates termination. A solid white circle indicates the start of a BID (280 μg / kg BID). Figure 5A and 5B In the middle, the lines corresponding to no responders are marked with an asterisk.

[0048] Figure 6 A scatter plot is provided that plots the weekly mean scores of observer-reported pruritus (ITCHRO(OBS)) in patients who participated in the INDIGO clinical study and had non-truncated BSEP mutations. Figure 6 This indicates that the ITCHRO (OBS) response lasted for many years, and >50% (10 / 19) of patients showed a ≥1.0 pt decrease in their ITCHRO (OBS) score. A solid black circle indicates termination. A solid white circle indicates the start of a BID (280 μg / kg BID). The ITCHRO (OBS) score range is 0 to 4. Figure 6 In the middle, the lines corresponding to no responders are marked with an asterisk.

[0049] Figure 7 A scatter plot is provided, which plots the change over time in the mean serum concentration of 7α-hydroxy-4-cholesten-3-one (7αC4 or C4) in patients who participated in the INDIGO clinical trial and had a non-truncated BSEP mutation. Figure 7 This indicates that non-truncated BSEP mutant responders showed a significant increase in 7αC4 concentration. A solid black circle indicates termination. A solid white circle indicates the start of BID dosing (280 μg / kg BID). ITCHRO (OBS) measurements ranged from 0 to 4. Figure 7 In the middle, the lines corresponding to no responders are marked with an asterisk.

[0050] Figure 8 A scatter plot is provided showing the change over time in the ratio of 7αC4 to sBA concentration (7αC4:sBA) in patients participating in the INDIGO clinical trial with non-truncated BSEP mutations. Figure 8 This indicates that non-truncated BSEP mutant responders had a significantly different 7αC4:sBA ratio compared to non-responders. Both non-truncated BSEP mutant responders showed an increase in the 7αC4:sBA ratio after dose escalation. A solid black circle indicates termination. A solid white circle indicates the start of BID dosing (280 μg / kg BID). ITCHRO (OBS) measurements ranged from 0 to 4. Figure 8 In the middle, the lines corresponding to no responders are marked with an asterisk.

[0051] Figure 9 A bar graph is provided showing the mean change in fecal bile acid (fBA) excretion from baseline to days 6 and 7 in a phase 1, blinded, placebo-controlled, dose-range clinical study (NCT02475317) among specified doses of macibatide, vocibatide, and placebo. BID, twice daily; QD, once daily; SE, standard error.

[0052] Figure 10 A bar graph is provided showing the mean change in serum 7αC4 concentration from baseline to day 7 among specified doses of macibatide, vocibatide, and placebo. BID, twice daily; fBA, fecal bile acids; QD, once daily; SE, standard error.

[0053] Figure 11 A bar chart is provided showing the mean weekly total ITCHRO score in the overall population, including participants with any itching at baseline, 14 weeks, single-arm, open-label, phase 2a, Masibart proof-of-concept study (CAMEO clinical study), and participants with an ITCHRO daily score ≥4 at baseline.

[0054] Figure 12 Bar graphs showing sBA concentrations (left) and 7αC4 concentrations (right) in the overall population participating in the CAMEO clinical study and in participants with an ITCHRO daily score ≥4 at baseline.

[0055] Figure 13 The bar chart shows serum autotaxin concentration (left) and serum low-density lipoprotein cholesterol (LDL-C) concentration (right) in the overall population participating in the CAMEO clinical study and in participants with an ITCHRO daily score ≥4 at baseline.

[0056] Figure 14Bar graphs showing percentage changes from baseline to week 14 or early termination are presented for efficacy measures, including ITCHRO scores (daily scores 1–10), sBA concentrations, and serum autotaxin concentrations of 6 participants in the CAMEO clinical study with an ITCHRO daily score ≥4 at baseline.

[0057] Figure 15 A diagram summarizing the clinical study design of a double-blind, randomized, placebo-controlled discontinuation study is provided, in which the long-term open-label treatment period is macibatide 400 μg / kg QD (ICONIC clinical study).

[0058] Figure 16 A chart is provided that summarizes the distribution of participants in the ICONIC clinical study.

[0059] Figure 17A and 17B This indicates that sBA levels were significantly improved relative to baseline and placebo in participants in the ICONIC clinical study. Figure 17A A graph showing the mean change in sBA concentration from baseline across all participants up to week 48 is shown. Figure 17B A bar graph is shown, which illustrates the mean change in sBA among sBA responders from week 8 to week 22 during the randomization period.

[0060] Figure 18 The graph shows the mean sBA concentrations of participants in the ICONIC clinical study during the core study period (first 48 weeks) and during the extension period (time after 48 weeks). MRX = Macibart; PLA = placebo.

[0061] Figure 19 A bar chart is provided showing the mean change in sBA levels from baseline (BL) observed in the ICONIC clinical study.

[0062] Figure 20A and 20B This study demonstrates the improvement in ITCHRO (Obs) scores maintained during randomization and discontinuation in participants of the ICONIC clinical study in the case of macibat. Figure 20A The average change in participants' ITCHRO (OBS) scores from baseline over time is shown. Figure 20B The ITCHRO (OBS) score graph of participants during the placebo-controlled drug withdrawal period is shown.

[0063] Figure 21A and 21B This indicates an improvement in the Clinic Scratch Scale (CSS) score from baseline throughout the ICONIC clinical study. Figure 21AThe proportion of total patients with indicated CSS scores at baseline, week 18, and week 48 is shown. Figure 21B The proportion of total patients with indicated CSS scores who received macibatide or placebo during the discontinuation period at week 22 (placebo-controlled) is shown.

[0064] Figure 22 The changes in CSS scores from baseline (BL) of participants in the ICONIC clinical study at weeks 48 and 191 are shown.

[0065] Figures 23A-23D The graphs show the changes in the weekly mean ITCHRO (OBS) score of participants in the ICONIC clinical study over time during the core study period and the extension period. Figure 23A A scatter plot showing the average ITCHRO (OBS) score over time is provided. Figure 23B This shows that the reduction in itching was maintained over a long period. Each line represents the individual patient's ITCHRO (OBS) score. Figure 23C and 23D As shown, the reduction in itching was maintained by macibatide, rather than by switching to placebo-free periods (represented by the boxed areas in the figure). Each row represents an individual patient's ITCHRO (OBS) score. MRX = macibatide; PLA = placebo. N = number of participants measured at the specified time point.

[0066] Figure 24 The changes in ITCHRO (OBS) scores from baseline (BL) of participants in the ICONIC clinical study at weeks 48 and 193 are shown.

[0067] Figure 25 A bar chart is provided showing the proportion of study days with an ITCHRO (OBS) score ≤1 for all subjects (%) in the ICONIC clinical trial, both during placebo administration and during macibatim administration.

[0068] Figure 26 The graph shows the change in HRQoL scores over time for patients participating in the ICONIC clinical study. The HRQoL score was measured using the PEDSQL score.

[0069] Figure 27 A bar chart is provided showing the change from baseline (BL) in participants' PEDSQL Fatigue Scale scores (0-100 scale) at weeks 48 and 191 in the ICONIC clinical study. n = number of participants represented at the specified time point.

[0070] Figure 28The graph shows the changes in the clinician xanthomas scale scores of patients participating in the ICONIC clinical study over time.

[0071] Figure 29 A bar chart is provided showing the changes in the Clinician Xanthomas Scale score from baseline (BL) in participants at weeks 48 and 191 in the ICONIC clinical study.

[0072] Figure 30 A scatter plot is provided showing the changes over time in serum concentrations of liver function markers, including GGT (gamma-glutamyl transferase), in participants of the ICONIC clinical study.

[0073] Figure 31 The graph shows the percentage change in sBA from baseline in participants of the ICONIC clinical study at week 48, relative to the change in the average weekly morning ITCHRO (OBS) score from baseline.

[0074] Figures 32A-32H A grid diagram of each participant in the ICONIC clinical study up to week 48 is shown (identified by the subject number above each diagram). Figures 32A-32H The plot shows a dot plot of sBA concentration (blue; left axis; µmol / L) and the change of the average weekly ITCHRO (OBS) score (red; right axis) over time (bottom axis) for each participant in the ICONIC clinical study. Figure 32A and 32D A grid diagram of patients in the MRX-MRX-MRX study group is shown, which includes only those patients who received macibatim before, during, and after the placebo discontinuation period in the ICONIC clinical study. Figure 32E and 32H A grid diagram of patients in the MRX-Placebo-MRX study group is shown, which includes only those patients who received macibatide before the placebo-controlled drug discontinuation period, received placebo during that period, and received macibatide again afterward. Patient 090004 was not assessed after baseline, so baseline data points are not visible in the graph.

[0075] Figure 33 This is a scatter plot showing the mean change in height Z-score from baseline over time for all participants in the ICONIC clinical study. The number of patients (N) measured at each data point is shown below the x-axis. BL = baseline.

[0076] Figure 34A scatter plot shows the mean change in height Z-score from baseline over time for participants in the ICONIC clinical study who consented to a long-term extension and remained as participants for approximately four years (n=15). The number of patients (N) measured at each data point is shown below the x-axis. BL = baseline.

[0077] Figure 35 A scatter plot showing the mean change in weight Z-score from baseline over time for all participants in the ICONIC clinical study (n=31). The number of patients (N) measured at each data point is shown below the x-axis. BL = baseline.

[0078] Figure 36 A scatter plot shows the mean change in height Z-score from baseline over time for participants in the ICONIC clinical study who agreed to a long-term extension and remained as participants for approximately four years (n=15). The number of patients (N) measured at each data point is shown below the x-axis. BL = baseline. Detailed Implementation

[0079] This document discloses detailed embodiments of the invention; however, it should be understood that the disclosed embodiments are merely examples of the invention that can be implemented in various forms. Furthermore, each example given in conjunction with the various embodiments of the invention is intended to be illustrative and not restrictive. Therefore, the specific structural and functional details disclosed herein should not be construed as restrictive, but merely as a representative basis for teaching those skilled in the art to use the invention in various ways.

[0080] Bile acids / salts play a crucial role in activating digestive enzymes and dissolving fats and fat-soluble vitamins, and are associated with liver, biliary tract, and intestinal diseases. Bile acids are synthesized in the liver via a multi-step, multi-organelle pathway. A hydroxyl group is added to a specific site on the steroid structure, the double bond of the cholesterol B ring is reduced, and the hydrocarbon chain is shortened by three carbon atoms, forming a carboxyl group at the chain end. The most common bile acids are cholic acid and chenodeoxycholic acid (“major bile acids”). Before leaving hepatocytes and forming bile, bile acids are conjugated with glycine (to produce glycocholic acid or glycochenodeoxycholic acid) or with taurine (to produce taurocholic acid or taurochenodeoxycholic acid). The conjugated bile acids are called bile salts, and their amphiphilic nature makes them more effective detergents than bile acids. Bile salts, not bile acids, are present in bile.

[0081] Bile salts are secreted by hepatocytes into tubules to form bile. These tubules flow into the left and right hepatic ducts, and the bile flows into the gallbladder. Bile is released from the gallbladder and travels into the duodenum, where it aids in the metabolism and degradation of fats. Bile salts are reabsorbed in the terminal ileum and transported back to the liver via the portal vein. Bile salts typically undergo multiple enterohepatic circulation cycles before being excreted in feces. A small percentage of bile salts are reabsorbed in the proximal intestine via passive or carrier-mediated transport processes. Most bile salts are reabsorbed in the terminal ileum by apical sodium-dependent bile acid transporters (called apical sodium-dependent bile acid transporters (ASBTs)). A truncated form of the ASBT participates in the carrier transport of bile acids / salts into the portal circulation on the basolateral surface of intestinal epithelial cells. The completion of enterohepatic circulation occurs via transport processes on the basolateral surface of hepatocytes, primarily mediated by sodium-dependent bile acid transporters. Intestinal bile acid transport plays a crucial role in the enterohepatic circulation of bile salts. Recent molecular analyses of this process have made significant progress in understanding the biology, physiology, and pathophysiology of intestinal bile acid transport.

[0082] Within the intestinal lumen, bile acid concentrations vary, with most reuptake occurring in the distal intestine. This article describes compositions and methods that control bile acid concentrations in the intestinal lumen, thereby controlling hepatocellular damage caused by bile acid accumulation in the liver.

[0083] Classification of cholestasis and cholestatic liver disease As used herein, “cholestasis” refers to a disease or symptom involving impaired bile formation and / or bile flow. As used herein, “cholestatic liver disease” refers to liver disease associated with cholestasis. Cholestatic liver disease is often accompanied by jaundice, fatigue, and pruritus. Biomarkers of cholestatic liver disease include elevated serum bile acid concentrations, elevated serum alkaline phosphatase (AP), elevated gamma-glutamyl transferase (GGT), elevated conjugated hyperbilirubinemia, and elevated serum cholesterol.

[0084] Cholestatic liver disease can be divided into two main categories in clinicopathology: obstructive (often extrahepatic) cholestasis and non-obstructive or intrahepatic cholestasis. In the former, cholestasis occurs when bile flow is mechanically blocked, such as through gallstones or tumors, or in extrahepatic biliary atresia.

[0085] The latter group, with non-obstructive intrahepatic cholestasis, was further divided into two main subgroups. In the first subgroup, cholestasis resulted when processes of bile secretion and modification, or the synthesis of bile components, were secondary captured in hepatocellular injury to such an extent that nonspecific impairment of many functions, including those that promote bile formation, could be expected. In the second subgroup, the presumed cause of hepatocellular injury could not be determined. Cholestasis in these patients appeared to result from constitutive impairment of one of the steps in bile secretion or modification, or the synthesis of bile components. This type of cholestasis was considered primary.

[0086] Therefore, this document provides methods and compositions for stimulating epithelial proliferation and / or regeneration of the intestinal lining and / or enhancing adaptive processes in individuals with hypercholesterolemia and / or cholestatic liver disease. In some such embodiments, the methods comprise increasing the concentration of bile acids and / or GLP-2 in the intestinal lumen.

[0087] Elevated levels of bile acids, as well as elevated levels of AP (alkaline phosphatase), LAP (leukocyte alkaline phosphatase), γGT (gamma-glutamyl transferase), and 5'-nucleotidase, are biochemical markers of cholestasis and cholestatic liver disease. Therefore, this document provides 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, LAP, γGT, and / or 5'-nucleotidase. In some such embodiments, the methods comprise increasing the concentration of bile acids in the intestinal lumen. This document further provides methods and compositions for alleviating hypercholesterolemia and elevated levels of AP, LAP, γGT, and 5'-nucleotidase, comprising reducing total serum bile acid load by excreting bile acids in feces.

[0088] Itching is frequently associated with hypercholesterolemia and cholestatic liver disease. It has been suggested that itching is caused by bile salts acting on peripheral pain afferent nerves. The severity of itching varies from person to person (i.e., some individuals are more sensitive to elevated levels of bile acids / salts).

[0089] It has been shown that the administration of agents that reduce serum bile acid concentrations can alleviate pruritus in some individuals. Therefore, this document provides methods and compositions for stimulating epithelial proliferation and / or regeneration of the intestinal lining and / or enhancing adaptive processes in the intestine in individuals suffering from pruritus. In some such embodiments, the methods comprise increasing the concentration of bile acids in the intestinal lumen. This document further provides methods and compositions for treating pruritus comprising reducing the total serum bile acid load by excreting bile acids in feces.

[0090] Another symptom of hypercholesterolemia and cholestatic liver disease is elevated serum conjugated bilirubin concentrations. Elevated serum conjugated bilirubin concentrations lead to jaundice and melena. The magnitude of the elevation is not diagnostically significant, as a relationship between serum conjugated bilirubin levels and the severity of hypercholesterolemia and cholestatic liver disease has not been established. Conjugated bilirubin concentrations rarely exceed 30 mg / dL. Therefore, this document provides 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 conjugated bilirubin concentrations. In some such embodiments, the method comprises increasing the concentration of bile acids in the intestinal lumen. This document further provides methods and compositions for treating elevated serum conjugated bilirubin concentrations, comprising reducing the total serum bile acid load by excreting bile acids in the feces.

[0091] Increased serum concentrations of unconjugated bilirubin are also considered diagnostic indicators of hypercholesterolemia and cholestatic liver disease. A portion of serum bilirubin is covalently bound to albumin (δ-bilirubin or cholinesterin). In patients with cholestatic jaundice, this portion may constitute a large proportion of total bilirubin. The presence of high levels of δ-bilirubin indicates chronic cholestasis. δ-bilirubin in umbilical cord blood or neonatal blood indicates prenatal cholestasis / choleretic liver disease. Therefore, this article provides methods and compositions for stimulating epithelial proliferation and / or regeneration of the intestinal lining and / or enhancing adaptive processes in individuals with elevated serum concentrations of unconjugated or δ-bilirubin. In some such embodiments, the method comprises increasing the concentration of bile acids in the intestinal lumen. This article further provides methods and compositions for treating elevated serum concentrations of both unconjugated and δ-bilirubin, comprising reducing the total serum bile acid load by excreting bile acids in feces.

[0092] Cholestasis and cholestatic liver disease can lead to hypercholesterolemia. During metabolic cholestasis, hepatocytes retain bile salts. Bile salts reflux from hepatocytes into the serum, resulting in an increased concentration of bile salts in the peripheral circulation. Furthermore, the uptake efficiency of bile salts entering the liver from the portal vein is low, leading to bile salt spillage into the peripheral circulation. Therefore, this document provides 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 methods comprise increasing the concentration of bile acids in the intestinal lumen. This document further provides methods and compositions for treating hypercholesterolemia comprising reducing the total serum bile acid load by excreting bile acids in feces.

[0093] Hyperlipidemia is characteristic of some, but not all, cholestatic diseases. Serum cholesterol is elevated in cholestasis due to a reduction in circulating bile salts that contribute to cholesterol metabolism and degradation. Cholesterol retention is associated with increased membrane cholesterol content and decreased membrane fluidity and function. Furthermore, since bile salts are metabolites of cholesterol, reduced 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. Therefore, this document provides 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 methods comprise increasing the concentration of bile acids in the intestinal lumen. This document further provides methods and compositions for treating hyperlipidemia comprising reducing the total serum bile acid load by excreting bile acids in feces.

[0094] In individuals with hypercholesterolemia and cholestatic liver disease, xanthomas form due to the deposition of excessive circulating cholesterol into the dermis. Xanthoma formation is more characteristic of obstructive cholestasis than hepatocellular cholestasis. Flat xanthomas first appear around the eyes, then in the creases of the palms and soles, and subsequently on the neck. Nodular xanthomas are associated with chronic and long-term cholestasis. Therefore, this article provides 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 xanthoma. In some such embodiments, the methods comprise increasing the concentration of bile acids in the intestinal lumen. This article further provides methods and compositions for treating xanthoma, comprising reducing the total serum bile acid load by excreting bile acids in feces.

[0095] In children with chronic cholestasis, one of the main consequences of hypercholesterolemia and cholestatic liver disease is developmental arrest. Developmental arrest results from reduced delivery of bile salts into the intestine (leading to inefficient fat digestion and absorption) and reduced vitamin absorption (vitamins E, D, K, and A are all poorly absorbed in cholestasis). Furthermore, delivery of fat into the colon can lead to colonic secretions and diarrhea. Treatment for developmental arrest includes dietary replacements 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 has no effect on fat absorption. Therefore, this article provides 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 developmental arrest (e.g., children). In some such embodiments, the methods comprise increasing the concentration of bile acids in the intestinal lumen. This article further provides methods and compositions for treating developmental arrest comprising reducing the total serum bile acid load by excreting bile acids in feces.

[0096] Primary biliary cirrhosis (PBC) Primary biliary cirrhosis (PBC) is an autoimmune liver disease characterized by the destruction of bile ducts. Damage to the bile ducts leads to the accumulation of bile in the liver (i.e., cholestasis). The retention of bile in the liver damages liver tissue and can lead to scarring, fibrosis, and cirrhosis. PBC typically occurs in adulthood (e.g., 40 years of age and older). Individuals with PBC often present with fatigue, itching, and / or jaundice. PBC is diagnosed if an individual has elevated AP levels for at least 6 months, elevated γGT levels, the presence of antimitochondrial antibodies (AMA) in serum (>1:40), and florid ductlesion. Serum ALT and AST, as well as conjugated bilirubin, may also be elevated, but these are not considered diagnostic. Cholestasis associated with PBC has been treated or improved by administration of ursodeoxycholic acid (UDCA or ursodeoxycholic acid). Corticosteroids (e.g., prednisone and budesonide) and immunosuppressants (e.g., azathioprine, cyclosporine A, methotrexate, chlorambucil, and mycophenolate mofetil) have been used to treat cholestasis associated with PBC. Sulindac, bezafibrate, tamoxifen, and lamivudine have also been shown to treat or improve cholestasis associated with PBC.

[0097] Progressive familial intrahepatic cholestasis (PFIC) PFIC is a rare, inherited disorder that causes progressive liver disease, often leading to liver failure. In individuals with PFIC, hepatocytes have a reduced ability to secrete bile. The resulting bile accumulates in the affected individual, causing liver disease. Signs and symptoms of PFIC typically begin in infancy. Patients experience severe itching, jaundice, failure to grow at the expected rate (developmental arrest), and progressive loss of liver function (liver failure). It is estimated that in the United States and Europe, one in every 50,000 to 100,000 births is affected by the disease. Six genetic types of PFIC have been identified, all sharing the common characteristic of impaired bile flow and progressive liver disease.

[0098] PFIC 1 PFIC 1 (also known as Byler's disease or FIC1 deficiency) is associated with mutations in the ATP8B1 gene (also known as FIC1). This gene (encoding a P-type ATPase) is located on human chromosome 18 and is also mutated in mild phenotype, benign recurrent type 1 intrahepatic cholestasis (BRIO), and Greenland familial cholestasis. The FIC1 protein is located on the tubular membrane of hepatocytes, but intrahepatically it is primarily expressed in bile duct cells. The P-type ATPase appears to be an aminophospholipid transporter responsible for maintaining the enrichment of phosphatidylserine and phosphatidylethanolamine on the inner lobule, compared to the outer lobule. The asymmetric distribution of lipids in the membrane bilayer protects against high bile salt concentrations in the tubular lumen. Abnormal protein function can indirectly interfere with bile acid secretion. Abnormal bile acid / salt secretion leads to bile acid overload in hepatocytes.

[0099] PFIC 1 typically occurs in infants (e.g., aged 6–18 months). Infants may present with signs such as itching, jaundice, abdominal distension, diarrhea, malnutrition, and short stature. Biochemically, patients with PFIC 1 have elevated serum transaminases, elevated bilirubin, elevated serum bile acid levels, and low levels of gamma-GT. Individuals may also have liver fibrosis. Patients with PFIC 1 typically do not have bile duct hyperplasia. Most patients with PFIC 1 will develop end-stage liver disease before the age of 10. No drug treatment has been shown to be beneficial for long-term treatment of PFIC 1. To alleviate extrahepatic symptoms (e.g., malnutrition and developmental arrest), medium-chain triglycerides and fat-soluble vitamins are often administered to children. Ursodeoxycholic acid has not been shown to be effective in patients with PFIC 1.

[0100] PFIC 2 PFIC 2 (also known as Byler syndrome or BSEP deficiency) and ABCB11 It is related to mutations in the gene (also known as BSEP). ABCB11 The gene encodes the ATP-dependent tubular bile salt export pump (BSEP) in the human liver and is located on human chromosome 2. The BSEP protein, expressed at the tubular membrane of hepatocytes, is the primary exporter of primary bile acids / salts resistant to extreme concentration gradients. Mutations in this protein result in reduced bile salt secretion as described in affected patients, leading to decreased bile flow and bile salt accumulation within hepatocytes, accompanied by persistent and severe hepatocellular damage.

[0101] PFIC 2 typically occurs in infants (e.g., aged 6–18 months). Infants may present with signs of itching. Biochemically, patients with PFIC 2 have elevated serum transaminases, elevated bilirubin, elevated serum bile acid levels, and low levels of γGT. Individuals may also develop portal vein inflammation and giant cell hepatitis. Furthermore, individuals frequently develop hepatocellular carcinoma. No drug treatment has been shown to be beneficial for long-term treatment of PFIC 2. To alleviate extrahepatic symptoms (e.g., malnutrition and developmental arrest), children are often given medium-chain triglycerides and fat-soluble vitamins. The PFIC 2 patient population accounts for approximately 60% of the PFIC population.

[0102] PFIC 3 PFIC 3 (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) is caused by the P-glycoprotein (P-gp), a phospholipid transporter involved in the excretion of bile phospholipids (phosphatidylcholine) from the tubular membranes of hepatocytes. PFIC 3 is caused by bile toxicity, where detergent bile salts are not inactivated by phospholipids, leading to damage to the bile ducts and bile duct epithelium.

[0103] PFIC 3 also occurs in early childhood. Compared to PFIC 1 and PFIC 2, individuals have elevated γGT levels. Individuals also suffer from portal vein inflammation, fibrosis, cirrhosis, and extensive bile duct hyperplasia. Individuals may also develop intrahepatic cholelithiasis. Ursodeoxycholic acid has been effectively used to treat or improve PFIC 3.

[0104] Benign recurrent intrahepatic cholestasis (BRIC) BRIC 1 BRIC1 is caused by a genetic defect in the FIC1 protein in the tubular membrane of hepatocytes. BRIC1 is normally associated with normal serum cholesterol and gamma-glutamyl transferase levels, but is associated with elevated serum bile salts. Residual FIC1 expression and function are associated with BRIC1. Despite recurrent episodes of cholestasis or cholestatic liver disease, most patients do not progress to chronic liver disease. During an episode, patients experience severe jaundice and may also have pruritus, steatorrhea, and weight loss. Some patients also have kidney stones, pancreatitis, and diabetes.

[0105] BRIC 2 BRIC 2 by ABCB11 Mutations in hepatocytes can cause defects in BSEP expression and / or function in the tubular membranes of hepatocytes.

[0106] BRIC 3 BRIC 3 is associated with deficiencies in the expression and / or function of MDR3 in the tubular membranes of hepatocytes. Patients with MDR3 deficiency typically exhibit elevated serum gamma-glutamyl transferase levels in the presence of normal or slightly elevated bile acid levels.

[0107] Durbin-Johnson syndrome (DJS) DJS is characterized by conjugated hyperbilirubinemia due to a genetic dysfunction of MRP2. Liver function is preserved in affected patients. Several different mutations are associated with this condition, resulting in the complete absence of immunohistochemically detectable MRP2 or impaired protein maturation and sorting in affected patients.

[0108] Acquired cholestatic diseases Primary biliary cirrhosis (PBC) Prostatic biliary cholangitis (PBC) is a chronic inflammatory liver disorder that progresses slowly in most affected patients until end-stage liver failure. In PBC, the inflammatory process primarily affects the small bile ducts.

[0109] Primary sclerosing cholangitis (PSC) In most affected patients, PSC is a chronic inflammatory liver disorder that slowly progresses to end-stage liver failure. In PSC inflammation, fibrosis and obstruction of large and medium-sized intrahepatic and extrahepatic ducts are predominant.

[0110] The defining characteristic of PSC is progressive cholestasis. Cholestasis often leads to severe itching, which significantly impairs quality of life.

[0111] Intrahepatic cholestasis of pregnancy (ICP) ICP is characterized by transient cholestasis or cholestatic liver disease in pregnant women, typically occurring in late pregnancy when circulating estrogen levels are high. ICP is associated with varying degrees of pruritus and biochemical cholestasis or cholestatic liver disease, and constitutes a risk factor for preterm birth and intrauterine fetal death. A genetic predisposition has been suspected based on strong regional clustering, a higher prevalence among female family members of patients with ICP, and the susceptibility of ICP patients to developing intrahepatic cholestasis or cholestatic liver disease under other hormonal challenges such as oral contraceptives. Heterogeneous status of MDR3 gene defects may represent a genetic predisposition.

[0112] gallstones Gallstone disease is one of the most common and expensive digestive system disorders, with a prevalence of up to 17% in white women. Cholesterol-containing gallstones are the main form of gallstones, therefore, supersaturation of bile with cholesterol is a prerequisite for gallstone formation. ABCB4 mutations may be involved in the pathogenesis of cholesterol gallstone disease.

[0113] Drug-induced cholestasis Drug inhibition of BSEP function is a crucial mechanism underlying drug-induced cholestasis, leading to bile salt accumulation in the liver and subsequent hepatocellular damage. Several drugs are associated with BSEP inhibition. Most of these drugs, such as rifampin, cyclosporine, glibenclamide, or troglitazone, competitively and directly inhibit ATP-dependent taurocholate transport in a cis manner, while estrogen and progesterone metabolites indirectly and trans-inhibit BSEP after secretion into the bile ducts via Mrp2. Alternatively, drug-mediated MRP2 stimulation can promote cholestasis or cholestatic liver disease by altering bile composition.

[0114] Total parenteral nutrition-related cholestasis TPNAC is one of the most severe clinical scenarios characterized by rapid onset and high correlation with early death in cholestatic liver disease or cholestatic liver disease. Typically, it occurs in preterm infants who have undergone bowel resection, whose growth is dependent on TPN and who frequently develop cholestatic liver disease or cholestatic liver disease, which usually progresses rapidly to fibrosis, cirrhosis, and portal hypertension within the first 6 months of life. The severity of cholestasis or cholestatic liver disease and survival chances in these infants are related to the frequency of sepsis episodes, possibly due to recurrent bacterial translocation on their intestinal mucosa. Although cholestatic effects from intravenously administered preparations are present in these infants, sepsis mediators are likely the most significant factor contributing to altered liver function.

[0115] Alagille syndrome (ALGS) Alagille syndrome is a genetic disorder that affects the liver and other organs. ALGS is also known as syndrome of intrahepatic bile duct anemia or hepatic artery dysplasia. ALGS is a rare genetic disorder in which bile ducts are abnormally narrowed, malformed, and reduced in number, leading to the accumulation of bile in the liver and ultimately resulting in progressive liver disease. ALGS is an autosomal dominant disorder caused by mutations in JAG1 (>90% of cases) or NOTCH2. It is estimated that the incidence of ALGS is 1 in 30,000 or 50,000 deliveries in the United States and Europe. In patients with ALGS, multiple organ systems can be affected by the mutation, including the liver, heart, kidneys, and central nervous system. The accumulation of bile acids can impair the liver's ability to properly remove waste from the bloodstream and lead to progressive liver disease, ultimately requiring a liver transplant in 15% to 47% of patients. Signs and symptoms of liver damage in ALGS may include jaundice, itching, xanthoma, and slowed growth. The itching experienced by patients with ALGS is the most severe of any chronic liver disease, and it is present in most affected children by the third year of age.

[0116] ALGS typically appears in infancy (e.g., 6–18 months) to early childhood (e.g., 3–5 years) and may stabilize after age 10. Symptoms may include chronic progressive cholestasis, bile duct openings, jaundice, pruritus, xanthoma, congenital heart problems, intrahepatic bile duct agenesis, linear growth retardation, hormone resistance, retrocorneal embryonic ring, Axonfeld anomaly, retinitis pigmentosa, pupillary abnormalities, heart murmurs, atrial septal defect, ventricular septal defect, patent ductus arteriosus, and tetralogy of Fallot. Patients diagnosed with Alagille syndrome have been treated with ursodeoxycholic acid, hydroxyzine, cholestyramine, rifampin, and phenobarbital. Due to reduced absorption of fat-soluble vitamins, patients with Alagille syndrome are further given high-dose multivitamins.

[0117] Biliary atresia Biliary atresia is a life-threatening condition in infants in which the bile ducts, either inside or outside the liver, lack normal openings. In biliary atresia, bile is trapped, accumulates, and damages the liver. This 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. There are two types of biliary atresia: fetal and perinatal. Fetal biliary atresia occurs while the infant is in utero. Perinatal biliary atresia is more common and does not become apparent until 2 to 4 weeks after birth.

[0118] Post-Kasai biliary atresia Biliary atresia is treated with a procedure called the Kasai procedure or liver transplant. The Kasai procedure is usually the first-line treatment for biliary atresia. During a Kasai procedure, a pediatric surgeon removes the infant's damaged bile ducts and creates an intestinal loop to replace them. While the Kasai procedure can restore bile flow and correct many problems caused by biliary atresia, it does not cure the condition. If the Kasai procedure is unsuccessful, the infant usually needs a liver transplant within 1 to 2 years. Even if the surgery is successful, most infants with biliary atresia will slowly develop cirrhosis years later and will require a liver transplant in adulthood. Possible complications after the Kasai procedure include ascites, bacterial cholangitis, portal hypertension, and pruritus.

[0119] Biliary atresia after liver transplantation If the atresia is complete, liver transplantation is the only option. Although liver transplantation is generally successful in treating biliary atresia, it can have complications such as organ rejection. Furthermore, a donor liver may not be available. Additionally, in some patients, liver transplantation may not be successful in curing biliary atresia.

[0120] xanthoma Xanthoma is a skin condition associated with cholestatic liver disease, in which certain fats accumulate beneath the surface of the skin. Cholestasis leads to several disorders of lipid metabolism, resulting in the formation of abnormal lipid particles in the blood called lipoprotein X. Lipoprotein X is formed from bile lipids flowing back into the bloodstream from the liver and does not bind to LDL receptors like normal LDL to deliver cholesterol to cells throughout the body. Lipoprotein X increases cholesterol production in the liver by five times and prevents the normal clearance of lipoprotein particles from the blood via the liver.

[0121] 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 pertains.

[0122] As used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural references unless the context clearly indicates otherwise. Thus, for example, reference to “method” includes one or more methods, and / or steps of the type described herein, and / or methods that will become apparent to those skilled in the art upon reading this disclosure.

[0123] As used herein, the term “baseline” or “pre-administration baseline” refers to information collected at the start of a study or an initial known value used for comparison with later data. A baseline is an initial measurement of a measurable condition at an early time point and is used for comparison over time to understand changes in the measurable condition. For example, serum bile acid concentrations in patients before (baseline) and after drug administration. A baseline is an observation or value representing a normal or initial level of a measurable quality, used for comparison with values ​​representing a response to an intervention or environmental stimulus. A baseline is a time “zero”, prior to when participants in a study receive the experimental drug or intervention or a negative control. For example, “baseline” can in some contexts refer to 1) the state of a measurable quantity just before the start of a clinical study, or 2) the state of a measurable quantity just before the dose level or composition administered to a patient is changed from a first dose level or composition to a second dose level or composition.

[0124] The terms “level” and “concentration” are used interchangeably as used herein. For example, “high serum level of bilirubin” can be expressed as “high serum concentration of bilirubin”.

[0125] As used herein, the terms "normalization" or "normal range" refer to age-specific values ​​(i.e., normalized values) within a range corresponding to healthy individuals. For example, the phrase "serum bilirubin concentration normalized over three weeks" means that the serum bilirubin concentration falls within a range known in the art to correspond to the concentration in a healthy individual over three weeks (i.e., within a normal range and not, for example, elevated). In various embodiments, the normalized serum bilirubin concentration is from about 0.1 mg / dL to about 1.2 mg / dL. In various embodiments, the normalized serum bile acid concentration is from about 0 µmol / L to about 25 µmol / L.

[0126] As used herein, the terms “ITCHRO(OBS)” and “ITCHRO” (or alternatively, “ITCHRO(Pt)”) are used interchangeably with the following qualifiers: 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 at least 18 years of age. Therefore, when referring to the ITCHRO(OBS) scale for adult patients, the ITCHRO scale is the designated scale. Similarly, whenever referring to the ITCHRO scale for pediatric patients, the ITCHRO(OBS) scale is generally the designated scale (allowing some older children to report their own scores as ITCHRO scores). The ITCHRO(OBS) scale ranges from 0 to 4, and the ITCHRO scale ranges from 0 to 10.

[0127] As used herein, the term "bile acid" includes steroidal acids (and / or their carboxylic acid anions) and their salts found in the bile of animals (e.g., humans), including but not limited to cholic acid, cholates, deoxycholic acid, deoxycholates, porcine deoxycholic acid, porcine deoxycholate, glycocholic acid, glycocholates, taurocholic acid, taurocholates, chenodeoxycholic acid, ursodeoxycholic acid, ursodeoxycholic acid, tauroursodeoxycholic acid, glycoursodeoxycholic acid, 7-B-methylcholic acid, methyllithocholic acid, chenodeoxycholates, lithocholic acid, lithochlates, etc. Taurocholic acid and / or taurocholates are referred to herein as TCA. Any reference to bile acids as used herein includes reference to bile acid, one and only one bile acid, one or more bile acids, or at least one bile acid. Therefore, unless otherwise stated, the terms “bile acid,” “bile salt,” and “bile acid / salt” are used interchangeably herein. Any reference to bile acids as used herein includes a reference to bile acids or their salts. Furthermore, pharmaceutically acceptable bile esters are optionally used as “bile acids” as used herein, such as bile acids / salts conjugated with amino acids (e.g., glycine or taurine). Other bile esters include, for example, substituted or unsubstituted alkyl esters, substituted or unsubstituted heteroalkyl esters, substituted or unsubstituted aryl esters, substituted or unsubstituted heteroaryl esters, etc. For example, the term “bile acid” includes bile acids conjugated with glycine or taurine: glycinecholate and taurinecholate (and their salts), respectively. Any reference to bile acids as used herein includes a reference to the same compounds, whether naturally occurring or synthetically prepared. Furthermore, it should be understood that any singular reference to a component (bile acid or other) used herein includes a reference to one and only one, one or more, or at least one such component. Similarly, unless otherwise stated, any plural reference to a component used herein includes a reference to one and only one, one or more, or at least one such component.

[0128] The terms “subject,” “patient,” “participant,” or “individual” are used interchangeably herein and refer to both mammals and non-mammals, such as those suffering from the disorders described herein. Examples of mammals include, but are not limited to, any member of the mammal class: humans, non-human primates such as chimpanzees and other ape and monkey species; farm animals such as cattle, horses, sheep, goats, and pigs; livestock 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, etc. In one embodiment of the methods and compositions provided herein, the mammal is a human.

[0129] As used herein, the term “about” includes any value within 10% of the stated value.

[0130] As used herein, the term "composition" includes both compositions and compositions administered as described herein. Furthermore, in some embodiments, the compositions of the present invention are or comprise "formulations," oral dosage forms, or rectal dosage forms as described herein.

[0131] As used herein, the terms “treat,” “treating,” or “treatment,” and other grammatical equivalents, include reducing, suppressing, or alleviating symptoms; reducing or suppressing the severity of symptoms of a disease or condition; decreasing the incidence of symptoms of a disease or condition; reducing or suppressing the recurrence of symptoms of a disease or condition; delaying the onset of symptoms of a disease or condition; delaying the recurrence of symptoms of a disease or condition; reducing or improving symptoms of a disease or condition; improving the root cause of symptoms; suppressing a disease or condition, such as preventing its development; alleviating a disease or condition; causing the remission of a disease or condition; alleviating symptoms caused by a disease or condition; or stopping the symptoms of a disease or condition. The terms further include achieving a therapeutic benefit. A therapeutic benefit refers to the eradication or improvement of the underlying disorder being treated, and / or the eradication or improvement of one or more physiological symptoms associated with the underlying disorder, resulting in an improvement observed in the patient.

[0132] As used herein, the term "effective amount" or "therapeutic effective amount" refers to a sufficient amount of at least one pharmaceutical agent (e.g., a therapeutically active agent) to be administered, which achieves the desired outcome in a subject or individual, such as, to a certain extent, relief of one or more symptoms of a disease or condition to be treated. In some cases, the outcome is a reduction and / or relief of the signs, symptoms, or cause of the disease, or any other desired alteration of the biological system. In some cases, an "effective amount" for therapeutic use is the amount required for a composition comprising a pharmaceutical agent as described herein to provide a clinically significant reduction in a disease. The appropriate "effective" amount in any individual case is determined using any suitable technique, such as dose escalation studies. In some embodiments, a "therapeutic effective amount" or "effective amount" of an ASBTI refers to an amount of ASBTI sufficient to treat cholestasis or cholestatic liver disease in a subject or individual.

[0133] As used herein, the terms “administer,” “administering,” “administration,” etc., refer to methods that can be used to deliver a pharmaceutical agent or composition to the desired site of biological action. These methods include, but are not limited to, oral, duodenal, parenteral (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular, or infusion), local, and rectal administration. Administration techniques optionally used with the pharmaceutical agents and methods described herein can be found in sources such as Goodman and Gilman, *The Pharmacological Basis of Therapeutics*, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, PA (all incorporated herein by reference in their entirety for all purposes). In some embodiments, the pharmaceutical agents and compositions described herein are administered orally.

[0134] The term "ASBT inhibitor" refers to a compound that inhibits apical sodium-dependent bile transport or any reversible bile salt transport. The terms apical sodium-dependent bile transporter (ASBT) and ileal bile acid transporter (IBAT) are used interchangeably.

[0135] The phrase “pharmaceutical acceptable” as used in conjunction with the compositions of the present invention means the molecular entity and other components of such compositions that are physiologically tolerable and generally do not produce adverse effects when administered to mammals (e.g., humans). Preferably, as used herein, the term “pharmaceutical acceptable” means approved by a federal or state regulatory agency or listed in the United States Pharmacopeia or other recognized pharmacopoeia for use in mammals, and more particularly humans.

[0136] In various embodiments, as a non-limiting example, pharmaceutically acceptable salts described herein include nitrates, chlorides, bromides, phosphates, sulfates, acetates, hexafluorophosphates, citrates, gluconates, benzoates, propionates, butyrates, subsalicylates, maleates, laurates, malates, fumarates, succinates, tartrates, stilbene sulfonates, pyruvates, p-toluenesulfonates, mesylates, etc. Furthermore, as a non-limiting example, pharmaceutically acceptable salts include alkaline earth metal salts (e.g., calcium or magnesium), alkali metal salts (e.g., sodium-dependent or potassium-dependent), ammonium salts, etc.

[0137] bile acids Bile contains water, electrolytes, and a large number of organic molecules, including bile acids, cholesterol, phospholipids, and bilirubin. Bile is secreted by the liver and stored in the gallbladder, and when the gallbladder contracts, it is released into the intestines through the bile ducts due to the ingestion of a fatty meal. Bile acids / salts are essential for the digestion and absorption of fats and fat-soluble vitamins in the small intestine. Adults produce 400 to 800 mL of bile daily. Bile secretion can be considered to occur in two phases. Initially, hepatocytes secrete bile into tubules, which flow into the bile ducts, and this hepatic bile contains a large amount of bile acids, cholesterol, and other organic molecules. Then, as the bile flows through the bile ducts, it is modified by the addition of a watery, bicarbonate-rich secretion from the ductal epithelial cells. Bile is concentrated during its storage in the gallbladder, typically by a factor of 5.

[0138] During fasting, bile flow is at its lowest, and most of it is diverted to the gallbladder for concentration. When chyme from a meal enters the small intestine, acids and partially digested fats and proteins stimulate the secretion of cholecystokinin and secretin, both important for bile secretion and flow. Cholecystokinin (cholecysto = gallbladder, kinin = movement) is a hormone that stimulates contractions of the gallbladder and common bile duct, thereby delivering bile into the intestines. The strongest stimulus for the release of cholecystokinin is the presence of fat in the duodenum. Secretin is a hormone secreted in response to acids in the duodenum, and it mimics bile duct cells to secrete bicarbonate and water, thereby increasing the volume of bile and its flow into the intestines.

[0139] Bile acids / salts are derivatives of cholesterol. Cholesterol (ingested as part of a diet or synthesized in the liver) is converted into bile acids / salts in liver cells. Examples of these bile acids / salts include cholic acid and chenodeoxycholic acid, which are then conjugated with amino acids such as glycine or taurine to produce conjugated forms that are actively secreted into the tubules. The most abundant bile salts in the human body are cholates and deoxycholates, and they are typically conjugated with glycine or taurine to form glycocholates or taurocholates, respectively.

[0140] Free cholesterol is practically insoluble in aqueous solution; however, it becomes soluble in bile due to the presence of bile acids / salts and lipids. The liver synthesizes most of the bile acids / salts, accounting for the majority of cholesterol breakdown in the body. In humans, approximately 500 mg of cholesterol is converted into bile acids / salts and eliminated in bile daily. Therefore, secretion into bile is the primary route for cholesterol removal. A significant amount of bile acids / salts are secreted into the intestines daily, but only a relatively small amount is lost from the body. This is because approximately 95% of the bile acids / salts delivered to the duodenum are reabsorbed back into the bloodstream in the ileum—a process known as enterohepatic recirculation.

[0141] Venous blood flows directly from the ileum into the portal vein, thus passing through the hepatic sinusoids. Hepatocytes extract bile acids / salts very efficiently from the sinusoidal blood, with very little escaping from a healthy liver into the systemic circulation. The bile acids / salts are then transported across the hepatocytes to be re-secreted into the tubules. The net effect of this enterohepatic recirculation is that each bile salt molecule is reused approximately 20 times, typically 2 or 3 times during a single digestive phase. 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 metabolism. In contrast, steroid hormone biosynthesis consumes only about 50 mg of cholesterol per day. An additional 400 mg of bile salts are needed daily and secreted into the intestines, and this is achieved through bile salt recycling. Most of the bile salts secreted into the upper region of the small intestine are absorbed along with dietary lipids that they emulsify in the lower part of the small intestine. They are separated from the dietary lipids and returned to the liver for reuse. Therefore, recirculation can secrete 20-30 g of bile salts into the small intestine every day.

[0142] Bile acids / salts are amphiphilic, with the cholesterol-derived portion containing both a hydrophobic (lipophilic) and a polar (hydrophilic) moiety, while amino acid conjugates are typically both polar and hydrophilic. This amphiphilic property enables bile acids / salts to perform two important functions: emulsification of lipid aggregates and solubilization and transport of lipids in aqueous environments. Bile acids / salts act as detergents for dietary fat particles, causing fat globules to break down or become emulsified. Emulsification is important because it significantly increases the surface area of ​​fats available for digestion by lipases, which cannot penetrate the interior of lipid droplets. Furthermore, bile acids / salts are lipid carriers, capable of dissolving many lipids by forming micelles, and are crucial for the transport and absorption of fat-soluble vitamins.

[0143] As used herein, the terms “non-systemic” or “minimally absorbed” refer to low systemic bioavailability and / or absorption of the administered compound. In some embodiments, a non-systemic compound is a compound that is substantially not absorbed systemically. In some embodiments, the ASBTI compositions described herein deliver ASBTI to the distal ileum, colon, and / or rectum and are not systemic (e.g., a significant portion of the ASBTI is not absorbed systemically). In some embodiments, systemic absorption of a non-systemic compound is <0.1%, <0.3%, <0.5%, <0.6%, <0.7%, <0.8%, <0.9%, <1%, <1.5%, <2%, <3%, or <5% (wt% or mol%) of the administered dose. In some embodiments, systemic absorption of a non-systemic compound is <10% of the administered dose. In some embodiments, systemic absorption of a non-systemic compound is <15% of the administered dose. In some embodiments, systemic absorption of a non-systemic compound is <25% of the administered dose. In alternative approaches, non-systemic ASBTIs are compounds with lower systemic bioavailability relative to systemic ASBTIs (e.g., compounds 100A, 100C). In some embodiments, the bioavailability of the non-systemic ASBTIs described herein is <30%, <40%, <50%, <60%, or <70% of the bioavailability of systemic ASBTIs (e.g., compounds 100A, 100C).

[0144] In another alternative method, the composition described herein is formulated to deliver <10% of the ASBTI dose systemically. In some embodiments, the composition described herein is formulated to deliver <20% of the ASBTI dose systemically. In some embodiments, the composition described herein is formulated to deliver <30% of the ASBTI dose systemically. In some embodiments, the composition described herein is formulated to deliver <40% of the ASBTI dose systemically. In some embodiments, the composition described herein is formulated to deliver <50% of the ASBTI dose systemically. In some embodiments, the composition described herein is formulated to deliver <60% of the ASBTI dose systemically. In some embodiments, the composition described herein is formulated to deliver <70% of the ASBTI dose systemically. In some embodiments, systemic absorption is determined in any suitable manner, including total circulating volume, post-administration clearance, etc.

[0145] The terms "optionally substituted" or "substituted" refer to the mentioned group that is substituted by one or more additional groups. In some embodiments, the one or more additional groups are independently selected from amides, esters, alkyl groups, cycloalkyl groups, heteroalkyl groups, aryl groups, heteroaryl groups, heteroalicyclic groups, hydroxyl groups, alkoxy groups, aryloxy groups, alkylthio groups, arylthio groups, alkyl sulfoxide groups, aryl sulfoxide groups, esters, alkyl sulfones, aryl sulfones, cyano groups, halogen groups, alkanoyl groups, alkanoyl oxo groups, isocyanates, thiocyanates, isothiocyanates, nitro groups, haloalkyl groups, haloalkoxy groups, fluoroalkyl groups, amino groups, alkylamino groups, dialkylamino groups, and amide groups.

[0146] “Alkyl” refers to an aliphatic hydrocarbon group. References to alkyl include “saturated alkyl” and / or “unsaturated alkyl”. Alkyl groups, whether saturated or unsaturated, include branched, straight-chain, or cyclic groups. By way of example only, alkyl includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, and hexyl. In some embodiments, alkyl includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, vinyl, propenyl, butenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. “Lower alkyl” is a C1-C6 alkyl. “Heteroalkyl” is an alkyl group in which any carbon atom is replaced by a heteroatom (e.g., a CH2 group to an NH or O group) attached to an appropriate number of hydrogen atoms.

[0147] The term "alkylene" refers to a divalent alkyl radical. Any of the aforementioned monovalent alkyl groups can become alkylene groups by extracting a second hydrogen atom from an alkyl group. In one aspect, the olefin is C1-C. 10 Alkylenes. In another aspect, alkylenes are C1-C6 alkylenes. Typical alkylenes include, but are not limited to, -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2-, etc.

[0148] "Alkoxy" refers to an (alkyl) O- group, where the alkyl group is as defined herein.

[0149] The term "alkylamine" refers to –N (alkyl) x H y The groups, wherein the alkyl group is as defined herein, and x and y are selected from the group consisting of x=1, y=1 and x=2, y=0. When x=2, the alkyl group, together with the nitrogen to which it is attached, optionally forms a cyclic ring system.

[0150] "Amide" is a chemical moiety having the formula -C(O)NHR or -NHC(O)R, where R is selected from alkyl, cycloalkyl, aryl, heteroaryl (through cyclic carbon bonding), and... miscellaneous Alicyclic (through cyclic carbon bonding).

[0151] The term "ester" refers to the chemical part with the formula –C(=O)OR, where R is selected from alkyl, cycloalkyl, aryl, heteroaryl, and... miscellaneous A group composed of alicyclic compounds.

[0152] As used herein, the term "aryl" refers to an aromatic ring in which each atom forming the ring is a carbon atom. Aryl rings described herein include rings having five, six, seven, eight, nine, or more than nine carbon atoms. The aryl group may optionally be substituted. Examples of aryl groups include, but are not limited to, phenyl and naphthyl.

[0153] The term "aromatic" refers to a planar ring having a delocalized π-electron system containing 4n+2π electrons, where n is an integer. Aromatic rings can be formed of five, six, seven, eight, nine, ten, or more than ten atoms. Aromatic compounds are optionally substituted. The term "aromatic" includes carbocyclic aryl ("aryl," e.g., phenyl) and heterocyclic aryl (or "heteroaryl" or "heteroaromatic") (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings sharing adjacent carbon atom pairs) groups.

[0154] The term "cycloalkyl" refers to a monocyclic or polycyclic non-aromatic radical, wherein each atom forming the ring (i.e., the skeleton atom) is a carbon atom. In various embodiments, the cycloalkyl group is saturated or partially unsaturated. In some embodiments, the cycloalkyl group is fused with an aromatic ring. A cycloalkyl group comprises a group having 3 to 10 ring atoms. Illustrative examples of cycloalkyl groups include, but are not limited to, the following: etc. Monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0155] The term "heterocyclic" refers to a heterocyclic aromatic and heteroalicyclic group containing 1 to 4 heterocyclic atoms, each selected from O, S, and N. In some cases, each 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, but aromatic heterocyclic groups must have at least 5 atoms in their ring system. Heterocyclic groups include benzo[a]-fused ring systems. An example of a 3-membered heterocyclic group is aziridinyl (derived from aziridinium). 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 pyridinyl. An example of a 10-membered heterocyclic group is quinolinyl. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholinyl, thiomorpholinyl, thioxanyl, piperazine, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, and oxaziridinyl. Oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridyl, 2-pyrroleyl, 3-pyrroleyl, indolyl, 2H-pyranyl, 4H-pyranyl, dioxacyclohexyl, 1,3-dioxapentyl, pyrazolinyl, dithiolanyl, dithiolanyl, dihydropyranyl, dihydrothiophenyl, dihydrofuranyl, pyrazolinyl, imidazolinyl, imidazolinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, 3H-indolyl, and quinolinyl. Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furanyl, thiophene, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrroleyl, quinolinyl, isoquinolinyl, indoleyl, benzimidazolyl, benzofuranyl, cenolinyl, indazole, and indoleazine. base Phthaloazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazinyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzooxazolyl, quinazolinyl, quinoxolinyl, naphridinyl, and furanpyridinyl.

[0156] The term "heteroaryl," or alternatively "heteroaromatic," refers to an aryl group comprising one or more heterocyclic atoms selected from nitrogen, oxygen, and sulfur. NThe term "heteroaromatic" or "heteroaryl" refers to an aromatic group in which at least one skeletal atom of the ring is a nitrogen atom. In some embodiments, the heteroaryl group is monocyclic or polycyclic. Illustrative examples of heteroaryl groups include the following portions: wait.

[0157] A "heteroalicyclic" group or "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 free radical is an aryl or heteroaryl group. Illustrative examples of heterocyclic groups (also referred to as non-aromatic heterocycles) include: The term heterocyclic aliphatic also includes all cyclic forms of carbohydrates, including but not limited to monosaccharides, disaccharides, and oligosaccharides.

[0158] The term "halo" or alternatively "halogen" refers to fluorinated, chlorinated, brominated, and iodinated compounds.

[0159] The terms "haloalkyl" and "haloalkoxy" include alkyl and alkoxy structures substituted with one or more halogens. In the examples, where more than one halogen is included in the group, the halogens are either the same or they are different. The terms "fluoroalkyl" and "fluoroalkoxy" respectively include haloalkyl and haloalkoxy, wherein the halogen is fluorine.

[0160] The term "heteroalkyl" includes optionally substituted alkyl, alkenyl, and alkynyl radicals having one or more skeletal chain atoms selected from atoms other than carbon, such as oxygen, nitrogen, sulfur, phosphorus, silicon, or combinations thereof. In some embodiments, the heteroatom is located at any internal 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)2-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.

[0161] "Cyano" refers to the -CN group.

[0162] The "isocyanate" group refers to the -NCO group.

[0163] The "thiocyanate" group refers to the -CNS group.

[0164] The "isothiocyanate" group refers to the -NCS group.

[0165] "Alkoyloxy" refers to the RC(=O)O- group.

[0166] "Alkyl group" refers to the RC (=O)- group.

[0167] As used in this article, the term "regulation" refers to having some effect on (e.g., increasing, enhancing, or maintaining a certain level).

[0168] The terms "optionally substituted" or "substituted" mean that the mentioned group can be substituted by one or more additional groups, which are individually and independently selected from C1-C6 alkyl, C3-C8 cycloalkyl, aryl, heteroaryl, C2-C6 heteroalicyclic, hydroxyl, C1-C6 alkoxy, aryloxy, arylalkoxy, arylalkoxy, arylalkyloxy, C1-C6 alkylthio, arylthio, C1-C6 alkyl sulfoxide, aryl sulfoxide, C1-C6 alkyl sulfone, aryl sulfone, cyano, halogenated, C2-C8 acyl, C2-C8 acyloxy, nitro, C1-C6 haloalkyl, C1-C6 fluoroalkyl, and amino, including C1-C6 alkylamino and their protected derivatives. As an example, the optional substituent may be L... s R s , where each L s Independently selected from bonds, -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 s The groups are independently selected from H, (C1-C4 alkyl), (C3-C8 cycloalkyl), heteroaryl, aryl, and C1-C6 heteroalkyl. Optionally substituted non-aromatic groups may be substituted with one or more oxo (=O) groups. Protecting groups that can form protected derivatives of the above-described substituents are known to those skilled in the art and can be found in the aforementioned references such as Greene and Wuts. In some embodiments, the alkyl groups described herein are optionally substituted with O atoms attached to two adjacent carbon atoms (i.e., forming epoxides).

[0169] ASBT inhibitors In various embodiments of the method of the present invention, an ASBT inhibitor is administered to the subject. ASBT inhibitors (ASBTIs) reduce or inhibit the recirculation of bile acids in the distal gastrointestinal tract (GI) (including the distal ileum, colon, and / or rectum). Inhibition of apical sodium-dependent bile acid transport disrupts the enterohepatic circulation of bile acids and results in the excretion of more bile acids in the feces; see [link to previous section]. Figure 1 This leads to a decrease in systemic bile acid levels, thereby mitigating bile acid-mediated liver damage and related effects and complications. In some embodiments, ASBTIs are systemically absorbed. In some embodiments, ASBTIs are not systemically absorbed. In some embodiments, the ASBTIs described herein are modified or substituted (e.g., with -LK groups) to be non-systemic. In some embodiments, any ASBT inhibitor is modified or substituted with one or more charged groups (e.g., K) and optionally one or more linkers (e.g., L), wherein L and K are as defined herein.

[0170] In some embodiments, the ASBTI suitable for the methods described herein is a compound of formula I: Formula I in: R 1 It is a straight-chain C1-6 alkyl group; R 2 It is a straight-chain C1-6 alkyl group; R 3 Is it hydrogen or a group OR 11 , where R 11 It is hydrogen, and the C is optionally substituted. 1-6 Alkyl or C 1-6 Alkyl carbonyl; R 4 It is a pyridyl or optionally substituted phenyl or –L z -K z ; where z is 1, 2 or 3; each L is independently a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted alkoxy, a substituted or unsubstituted aminoalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl or a substituted or unsubstituted heterocycloalkyl; each K is the part that prevents systemic absorption; R 5 R 6 R 7 and R 8 They may be the same or different, and each is selected from hydrogen, halogen, cyano, R 5 - Acetylene, OR 15 Optional substitution of 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 Selected from ; 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 Independently selected from hydrogen and optionally substituted C 1-6 Alkyl; or R 6 and R 7 Link to form groups Where R 12 and R 13 As defined above, and m is 1 or 2; and R 9 and R 10 They may be the same or different, and each is selected from hydrogen or C. 1-6 Alkyl groups; and Its salts, solvates, and physiological functional derivatives.

[0171] In some embodiments of the method, the compound of formula I is such a compound in R 1 It is a straight chain C 1-6 alkyl; R 2 It is a straight chain C 1-6 alkyl; R 3 Is it hydrogen or a group OR 11 , where R 11 It is hydrogen, and the C is optionally substituted. 1-6 Alkyl or C 1-6 Alkyl carbonyl; R 4 It is an optionally substituted phenyl group; R 5 R 6 and R 8 C, independently selected from hydrogen and optionally substituted with fluorine 1-4 Alkyl, C 1-4 Alkyl, halogen, or hydroxyl; R 7 Selected from halogen, cyano, R 15 - Acetylene, OR 15 Optional substitution of 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 To R 15 As defined above; The condition is R 5 To R 8 At least two of them are not hydrogen; and Its salts, solvates, and physiological functional derivatives.

[0172] In some embodiments of the methods described herein, the compound of Formula I is a compound that... in R 1 It is a straight chain C 1-6 alkyl; R 2 It is a straight chain C 1-6 alkyl; R 3 Is it hydrogen or a group OR 11 , where R 11 It is hydrogen, and the C is optionally substituted. 1-6 Alkyl or C 1-6 Alkyl carbonyl; R 4 It is an unsubstituted phenyl group; R 5 It is hydrogen or halogen; R 6 and R 8 C, independently selected from hydrogen and optionally substituted with fluorine 1-4 Alkyl, C 1-4 Alkyl, halogen, or hydroxyl; R 7 Selected from 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 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 Independently selected from hydrogen and optionally substituted C 1-6 alkyl; R 9 and R 10 They may be the same or different, and each is selected from hydrogen or C. 1-6 Alkyl groups; and Its salts, solvates, and physiological functional derivatives.

[0173] In some embodiments of the method, the compound of formula I is such a compound in R 1 It is methyl, ethyl, or n-propyl; R 2 It is methyl, ethyl, n-propyl, n-butyl, or n-pentyl; R 3 Is it hydrogen or a group OR 11 , where R 11 It is hydrogen, and the C is optionally substituted. 1-6 Alkyl or C 1-6 Alkyl carbonyl; R 4 It is an unsubstituted phenyl group; R 5 It is hydrogen; R 6 and R 8 C, independently selected from hydrogen and optionally substituted with fluorine 1-4 Alkyl, C 1-4 Alkyl, halogen, or hydroxyl; R 7 Selected from 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 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 Independently selected from hydrogen and optionally substituted C 1-6 alkyl; R 9 and R 10 They may be the same or different, and each is selected from hydrogen or C. 1-6 Alkyl groups; and their salts, solvates and physiologically functional derivatives.

[0174] In some embodiments of the method, the compound of formula I is such a compound in R 1 It is methyl, ethyl, or n-propyl; R 2 It is methyl, ethyl, n-propyl, n-butyl, or n-pentyl; R 3 Is it hydrogen or a group OR 11 , where R 11 It is hydrogen, and the C is optionally substituted. 1-6 Alkyl or C 1-6 Alkyl carbonyl; R 4 It is an unsubstituted phenyl group; R 5 It is hydrogen; R 6 It is C 1-4 Alkyl, halogen, or hydroxyl; R 7 Is it OR 15 , where R 15 It is hydrogen or an optional substituted C 1-6 alkyl; R 8 It is hydrogen or halogen; R 9 and R 10 They may be the same or different, and each is selected from hydrogen or C. 1-6 Alkyl groups; and their salts, solvates and physiologically functional derivatives.

[0175] 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-benzothiazepine-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-benzothiazepine 1,1-dioxide; -Tetrahydro-7,8-dimethoxy-5-phenyl-1,4,-benzothiazolinone-4-ol 1,1-dioxide; (3R,5R)-7-bromo-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazolinone-4-ol 1,1-dioxide; (3R,5R)-7-bromo-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazolinone-4-ol 1,1-dioxide; (3R,5R)-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazolinone-7,8-diol 1,1-dioxide; (3R,5R)-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazolinone-7,8-diol 1,1-dioxide; (3R,5R)-3-butyl-3-ethyl-2 3,4,5-Tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazolin-7-ol 1,1-dioxide; (3R,5R)-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-1,4-benzothiazolin-8-ol 1,1-dioxide; (±)-trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazolin-8-ol 1,1-dioxide; (±)-trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazolin-8-ol 1,1-dioxide; (±)-trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazolin-8-ol 1,1-dioxide; (±)-trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5- Phenyl-1,4-benzothiazolinone-4,8-diol; (±)-trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazolinone-8-thiol 1,1-dioxide; (±)-trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazolinone-8-sulfonic acid 1,1-dioxide; (±)-trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8,9-dimethoxy-5-phenyl-1,4-benzothiazolinone-1,1-dioxide; (3R,5R)-3-butyl-7,8-diethoxy-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazolinone-1,1-dioxide;(±)-trans-3-butyl-8-ethoxy-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazolinone 1,1-dioxide; (±)-trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-isopropoxy-5-phenyl-1,4-benzothiazolinone 1,1-dioxide hydrochloride; (±)-trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazolinone-8-carboxaldehyde-1,1-dioxide; 3,3-diethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,4-benzothiazolinone 1,1-dioxide; 3,3-diethyl-2,3 4,5-Tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazolinone 1,1-dioxide; 3,3-diethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazolinone-4,8-diol 1,1-dioxide; (RS)-3,3-diethyl-2,3,4,5-tetrahydro-4-hydroxy-7,8-dimethoxy-5-phenyl-1,4-benzothiazolinone 1,1-dioxide; (±)-trans-3-butyl-8-ethoxy-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazolinone-4-ol-1-dioxide; (±)-trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8- Isopropoxy-5-phenyl-1,4-benzothiozazo-4-ol 1,1-dioxide; (±)-trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8,9-trimethoxy-5-phenyl-1,4-benzothiozazo-4-ol 1,1-dioxide; (3R,5R)-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiozazo-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-benzothiozazo-4,1-dioxide; 3,3-diethyl-2,3,4,5- Tetrahydro-5-phenyl-1,4-benzothiazolin-8-ol 1,1-dioxide; 3,3-diethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-1,4-benzothiazolin-8-ol 1,1-dioxide; 3,3-dibutyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazolin-8-ol 1,1-dioxide; (±)-trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-1,1-dioxo-5-phenyl-1,4-benzothiazolin-8-yl hydrogen sulfate; or 3,3-diethyl-2,3,4,5-tetrahydro-1,1-dioxo-5-phenyl-1,4-benzothiazolin-8-yl hydrogen sulfate.

[0176] In some embodiments, the compound of formula I is , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0177] In some embodiments of the method, the compound of formula I is .

[0178] In some embodiments, the compounds of Formula I do not have the structure shown below: Where m represents an integer of 1 or 2, and they can be different from each other in R. 3 and R 4 Each represents an alkyl group having 1 to 5 carbon atoms.

[0179] In some embodiments, the ASBTI suitable for the methods described herein is a compound of formula II. Formula II in: q is an integer from 1 to 4; n is an integer from 0 to 2; R 1 and R 2 Independently selected from the group consisting of: H, alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, aralkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl. The alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, aralkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl groups are optionally substituted by one or more substituents selected from the group consisting of: OR 9 NR 9 R 10 N + R 9 R 10 R w A - SR 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, halogens, oxidants and CONR 9 R 10 , The alkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl, (polyalkyl)aryl, and cycloalkyl groups optionally have one or more groups marked with O, NR. 9 N + R 9 R 10 A - S, SO, SO2, S + R 9 A - P + R 9 R 10 A - Or phenyl-substituted carbon, Where R 9 R 10 and R w Independently selected from the group consisting of: H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocyclic, ammoniumalkyl, aralkyl, and alkylammoniumalkyl; or R 1 and R 2 Together with the carbon they are attached to, they form C3-C 10 cycloalkyl; R 3 and R 4 Independently selected from the following groups: H, alkyl, alkenyl, alkynyl, acyloxy, aryl, heterocyclic, OR 9NR 9 R 10 SR 9 S(O)R 9 SO2R 9 and SO3R 9 , where R 9 and R 10 As defined above; or R 3 and R 4 Together they are =O, =NOR 11 =S, =NNR 11 R 12 =NR 9 or =CR 11 R 12 , Where R 11 and R 12 Independently selected from the group consisting of: H, alkyl, alkenyl, alkynyl, aryl, aralkyl, alkenylalkyl, alkynylalkyl, heterocyclic, carboxylalkyl, carbamoyloxyalkyl, cycloalkyl, cyanoalkyl, OR 9 NR 9 R 10 SR 9 S(O)R 9 SO2R 9 SO3R 9 CO2R 9 CN, halogens, oxidants and CONR 9 R 10 , where R 9 and R 10 As defined above, the condition is R. 3 and R 4 None of them can be OH, NH2, or SH, or R 11 and R 12 Together with the nitrogen or carbon atoms they are attached to, they form rings; R 5 and R 6 Independently selected from the following groups: H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclic, quaternary heterocyclic, quaternary aryl, OR 9 SR 9 S(O)R 9 SO2R 9 SO3R 9 and –L z -K z ; Where z is 1, 2, or 3; each L is independently a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted alkoxy, a substituted or unsubstituted aminoalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted heterocycloalkyl; each K is a portion that prevents systemic absorption; The alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclic, quaternary heterocyclic, and quaternary aryl groups may be substituted by one or more substituents independently selected from the group consisting of: alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocyclic, aralkyl, quaternary heterocyclic, quaternary aryl, halogen, oxo, R 15 OR 13 OR 13 R 14 NR 13 R 14 SR 13 S(O)R 13 SO2R 13 SO3R 13 NR 13 OR 14 NR 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 - , in: A - M is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation, wherein the alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocyclic groups may be further substituted by one or more substituents selected from the group consisting of: OR7 NR 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, heterocyclic, aralkyl, quaternary heterocyclic, quaternary aryl, P(O)R 7 R 8 P + R 7 R 8 R 9 A - and P(O)(OR) 7 OR 8 ,and The alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocyclic groups may optionally have one or more O, NR groups. 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 a phenylene-substituted carbon, and R 13 R 14 and R 15 Independently selected from the group consisting of: hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, aryl, aralkyl, cycloalkyl, heterocyclic, heteroaryl, quaternary heterocyclic, quaternary aryl, quaternary arylalkyl, and -GTVW. The alkyl, alkenyl, alkynyl, aralkyl, heterocyclic, and polyalkyl groups optionally have one or more O, NR groups. 9 N + R 9 R 10 A - S, SO, SO2, S + R 9 A - PR, P + R9 R 10 A - P(O)R 9 , phenylene, carbohydrates, C2-C7 polyols, amino acids, peptides or polypeptides substituted carbons, and 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 aralkyl, substituted or unsubstituted alkenylalkyl, alkynylalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted carboxylalkyl, substituted or unsubstituted carbamoyloxyalkyl, or substituted or unsubstituted cycloalkyl. W is a quaternary heterocyclic ring, quaternary aryl group, or quaternary arylalkyl group. + 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 Optionally substituted with one or more groups selected from the group consisting of: sulfoalkyl, quaternary heterocyclic, quaternary aryl, OR 9 NR 9 R 10 N + R 9 R 11 R 12 A - SR 9 S(O)R 9 SO2R 9 SO3R 9 Oxygenation, CO2R 9 CN, halogen, CONR 9 R 10 SO2OM, SO2NR 9 R 10 PO(OR) 16 OR 17 P + R 9 R10 R 11 A - S + R 9 R 10 A - and C(O)OM, Where R 16 and R 17 Independently selected from the constituent R 9 and substituents of M; or R 14 and R 15 Together with the nitrogen atoms they are attached to, they form a ring; and Selected from the group consisting of: alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocyclic, ammonium alkyl, alkylammonium alkyl, and aralkyl; and R 7 and R 8 Independently selected from groups composed of hydrogen and alkyl groups; and One or more R x Independently selected from the following groups: H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl, aralkyl, halogen, haloalkyl, cycloalkyl, heterocyclic, heteroaryl, polyether, quaternary heterocyclic, quaternary heteroaryl, OR 13 NR 13 R 14 SR 13 S(O)R 13 S(O)2R 13 SO3R 13 S + R 13 R 14 A - NR 13 OR 14 NR 13 NR 14 R 15 NO2, CO2R 13 CN, OM, SO2OM, SO2NR 13 R 14 NR 14 C(O)R 13 C(O)NR 13 R 14 NR 14 C(O)R 13 C(O)OM, COR 13 OR 18 S(O) n NR 18 NR 13 R 18 NR 18R 14 N + R 9 R 11 R 12 A - P + R 9 R 11 R 12 A - amino acids, peptides, polypeptides, and carbohydrates Alkyl, alkenyl, alkynyl, cycloalkyl, aryl, polyalkyl, heterocyclic, acyloxy, aralkyl, haloalkyl, polyether, quaternary heterocyclic, and quaternary aryl can be further ORed. 9 NR 9 R 10 N + R 9 R 11 R 12 A - SR 9 S(O)R 9 SO2R 9 SO3R 9 Oxygenation, 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 C(O)M substitution, and Where R 18 Selected from the following groups: acyl, arylalkoxycarbonyl, aralkyl, heterocyclic, heteroaryl, alkyl. The acyl, arylalkoxycarbonyl, aralkyl, heterocyclic, heteroaryl, alkyl, quaternary heterocyclic, and quaternary heteroaryl groups are optionally substituted by one or more substituents selected from the group consisting of: OR 9 NR 9 R 10 N + R 9 R 11 R 12 A - SR 9 S(O)R 9 SO2R9 SO3R 9 Oxygenation, CO3R 9 CN, halogen, CONR 9 R 10 SO3R 9 SO2OM, SO2NR 9 R 10 PO(OR) 16 OR 17 and C(O)OM, Among them, in R x In this process, one or more carbon atoms are optionally replaced by 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 acids, peptides, polypeptides, carbohydrates, polyethers or polyalkyl substitutes, In the polyalkyl, phenylene, amino acid, peptide, polypeptide, and carbohydrate, one or more carbons are optionally marked with O or 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 replace; The quaternary heterocycle and quaternary aryl group are optionally substituted by one or more groups selected from the group consisting of: alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocyclic, aralkyl, halogen, oxo, OR 13 NR 13 R 14 SR 13 S(O)R 13 SO2R 13 SO3R 13 NR 13 OR 14 NR 13 NR 14R 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 - , The condition is R 5 and R 6 Neither can be hydrogen or SH; The condition is when R 5 Or R 6 When it is a phenyl group, R 1 Or R 2 Only one of them is H; The condition is when q=1 and R x When it is styrene, aniline, or aniline carbonyl, R 5 Or R 6 Only one of them is an alkyl group; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0180] In some embodiments of the method, the compound of formula II is such a compound in q is an integer from 1 to 4; n is 2; R 1 and R 2 Independently selected from the following groups: H, alkyl, alkoxy, dialkylamino, and alkylthio. The alkyl, alkoxy, dialkylamino, and alkylthio groups are optionally substituted by one or more substituents selected from the group consisting of: OR 9 NR 9 R 10 SR 9 SO2R 9 CO2R 9CN, halogens, oxidants and CONR 9 R 10 ; Each R 9 and R 10 Each is independently selected from the following groups: H, alkyl, cycloalkyl, aryl, acyl, heterocyclic, and aralkyl; R 3 and R 4 Independently selected from the following groups: H, alkyl, acyloxy, OR 9 NR 9 R 10 SR 9 and SO2R 9 , where R 9 and R 10 As defined above; R 11 and R 12 Independently selected from the group consisting of: H, alkyl, alkenyl, alkynyl, aryl, aralkyl, alkenylalkyl, alkynylalkyl, heterocyclic, carboxylalkyl, carbamoyloxyalkyl, cycloalkyl, cyanoalkyl, OR 9 NR 9 R 10 SR 9 S(O)R 9 SO2R 9 SO3R 9 CO2R 9 CN, halogens, oxidants and CONR 9 R 10 , where R 9 and R 10 As defined above, the condition is R. 3 and R 4 None of them can be OH, NH2, or SH, or R 11 and R 12 Together with the nitrogen or carbon atoms they are attached to, they form rings; R 5 and R 6 Independently selected from the following groups: H, alkyl, aryl, cycloalkyl, heterocyclic, and –L z -K z ; Where z is 1 or 2; each L is independently a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted heterocycloalkyl; each K is the part that prevents systemic absorption; The alkyl, aryl, cycloalkyl, and heterocyclic groups may be substituted by one or more substituents independently selected from the following group: alkyl, aryl, haloalkyl, cycloalkyl, heterocyclic, aralkyl, quaternary heterocyclic, quaternary aryl, halogen, oxo, OR 13 OR 13 R 14 NR 13 R 14 SR 13 SO2R 13 NR 13 NR 14 R 15 NO2, CO2R 13 CN, OM and CR 13 , in: A - M is a pharmaceutically acceptable anion, and M is a pharmaceutically acceptable cation; R 13 R 14 and R 15 Independently selected from the group consisting of: hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, aryl, aralkyl, cycloalkyl, heterocyclic, heteroaryl, quaternary heterocyclic, quaternary aryl and quaternary arylalkyl, wherein R 13 R 14 and R 15 Optionally substituted with one or more groups selected from the group consisting of: quaternary heterocycles, quaternary aryl groups, OR 9 NR 9 R 10 N + R 9 R 11 R 12 A - SR 9 S(O)R 9 SO2R 9 SO3R 9 Oxygenation, CO2R 9 CN, halogens and CONR 9 R 10 ;or R 14 and R 15 Together with the nitrogen atoms they are attached to, they form a ring; and Selected from the group consisting of: alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocyclic, ammonium alkyl, alkylammonium alkyl, and aralkyl; and R 7 and R 8 Independently selected from groups composed of hydrogen and alkyl groups; and One or more Rx Independently selected from the following groups: H, alkyl, acyloxy, aryl, aralkyl, halogen, haloalkyl, cycloalkyl, heterocyclic, heteroaryl, OR 13 NR 13 R 14 SR 13 S(O)2R 13 NR 13 NR 14 R 15 NO2, CO2R 13 CN, SO2NR 13 R 14 NR 14 C(O)R 13 C(O)NR 13 R 14 NR 14 C(O)R 13 and COR 13 ; The condition is R 5 and R 6 Neither of them can be hydrogen; The condition is when R 5 Or R 6 When it is a phenyl group, R 1 Or R 2 Only one of them is H; The condition is when q=1 and R x When it is styrene, aniline or aniline carbonyl, R 5 Or R 6 Only one of them is an alkyl group; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0181] In some embodiments, the compound of formula II is a compound in which... q is 1; n is 2; R x It is N(CH3)2; R 7 and R 8 H stands alone; R 1 and R 2 It is an alkyl group; R 3 It is H, and R 4 It is OH; R 5 It is hydrogen, and R 6 Choose from the following groups: alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclic, quaternary heterocyclic, quaternary aryl, OR 9 SR 9 S(O)R9 SO2R 9 SO3R 9 and –L z -K z ; Where z is 1, 2, or 3; each L is independently a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted alkoxy, a substituted or unsubstituted aminoalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted heterocycloalkyl; each K is a portion that prevents systemic absorption; The alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclic, quaternary heterocyclic, and quaternary aryl groups may be substituted by one or more substituents independently selected from the group consisting of: alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocyclic, aralkyl, quaternary heterocyclic, quaternary aryl, halogen, oxo, R 15 OR 13 OR 13 R 14 NR 13 R 14 SR 13 S(O)R 13 SO2R 13 SO3R 13 NR 13 OR 14 NR 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 - , Where A -M is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation, wherein the alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocyclic groups may be further substituted by one or more substituents selected from the group consisting of: OR 7 NR 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, heterocyclic, aralkyl, quaternary heterocyclic, quaternary aryl, P(O)R 7 R 8 P + R 7 R 8 R 9 A - and P(O)(OR) 7 OR 8 ,and The alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocyclic groups may optionally have one or more O, NR groups. 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 a phenylene-substituted carbon, and R 13 R 14 and R 15 Independently selected from the group consisting of: hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, aryl, aralkyl, cycloalkyl, heterocyclic, heteroaryl, quaternary heterocyclic, quaternary aryl, quaternary arylalkyl, and -GTVW. The alkyl, alkenyl, alkynyl, aralkyl, heterocyclic, and polyalkyl groups optionally have one or more O, NR groups. 9 N + R 9 R 10 A- S, SO, SO2, S + R 9 A - PR, P + R 9 R 10 A - P(O)R 9 , phenylene, carbohydrates, C2-C7 polyols, amino acids, peptides or polypeptides substituted carbons, and 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 aralkyl, substituted or unsubstituted alkenylalkyl, alkynylalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted carboxylalkyl, substituted or unsubstituted carbamoyloxyalkyl, or substituted or unsubstituted cycloalkyl. W is a quaternary heterocyclic ring, quaternary aryl group, or quaternary arylalkyl group. + 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 Independently selected from the group consisting of: H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocyclic, ammonium alkyl, aralkyl, and alkylammonium alkyl; R 11 and R 12 Independently selected from the group consisting of: H, alkyl, alkenyl, alkynyl, aryl, aralkyl, alkenylalkyl, alkynylalkyl, heterocyclic, carboxylalkyl, carbamoyloxyalkyl, cycloalkyl, cyanoalkyl, OR 9 NR 9 R 10 SR 9 S(O)R 9 SO2R 9 SO3R 9 CO2R 9 CN, halogens, oxidants and CONR 9R 10 , where R 9 and R 10 As defined above, the condition is R. 3 and R 4 None of them can be OH, NH2, or SH, or R 11 and R 12 Together with the nitrogen or carbon atoms they are attached to, they form rings; R 13 R 14 and R 15 Optionally substituted with one or more groups selected from the group consisting of: sulfoalkyl, quaternary heterocyclic, quaternary aryl, OR 9 NR 9 R 10 N + R 9 R 11 R 12 A - SR 9 S(O)R 9 SO2R 9 SO3R 9 Oxygenation, 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 Independently selected from the constituent R 9 and substituents of M; or R 14 and R 15 Together with the nitrogen atoms to which they are attached, they form cyclic rings; and are selected from the group consisting of: alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocyclic, ammonium alkyl, alkylammonium alkyl, and aralkyl; Or a pharmaceutically acceptable salt, solvate, or prodrug.

[0182] In some embodiments, the compound of formula II is a compound in which... q is 1; n is 2; R x It is N(CH3)2; R 7 and R 8 H stands alone; R 1 and R 2 It is independently a C1-C4 alkyl group; R 3 It is H, and R 4 It is OH; R 5 It is H, and R 6 It is substituted by one or more substituents, said substituents being independently selected from the group consisting of: alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocyclic, aralkyl, quaternary heterocyclic, quaternary aryl, halogen, oxo, R 15 OR 13 OR 13 R 14 NR 13 R 14 SR 13 S(O)R 13 SO2R 13 SO3R 13 NR 13 OR 14 NR 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 - , Where A -M is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation, wherein the alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocyclic groups may be further substituted by one or more substituents selected from the group consisting of: OR 7 NR 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, heterocyclic, aralkyl, quaternary heterocyclic, quaternary aryl, P(O)R 7 R 8 P + R 7 R 8 R 9 A - and P(O)(OR) 7 OR 8 ,and The alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocyclic groups may optionally have one or more O, NR groups. 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 a phenylene-substituted carbon, and R 13 R 14 and R 15 Independently selected from the group consisting of: hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, aryl, aralkyl, cycloalkyl, heterocyclic, heteroaryl, quaternary heterocyclic, quaternary aryl, quaternary arylalkyl, and -GTVW. The alkyl, alkenyl, alkynyl, aralkyl, heterocyclic, and polyalkyl groups optionally have one or more O, NR groups. 9 N + R 9 R 10 A- S, SO, SO2, S + R 9 A - PR, P + R 9 R 10 A - P(O)R 9 , phenylene, carbohydrates, C2-C7 polyols, amino acids, peptides or polypeptides substituted carbons, and 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 aralkyl, substituted or unsubstituted alkenylalkyl, alkynylalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted carboxylalkyl, substituted or unsubstituted carbamoyloxyalkyl, or substituted or unsubstituted cycloalkyl. W is a quaternary heterocyclic ring, quaternary aryl group, or quaternary arylalkyl group. + 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 Independently selected from the group consisting of: H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocyclic, ammonium alkyl, aralkyl, and alkylammonium alkyl; R 11 and R 12 Independently selected from the group consisting of: H, alkyl, alkenyl, alkynyl, aryl, aralkyl, alkenylalkyl, alkynylalkyl, heterocyclic, carboxylalkyl, carbamoyloxyalkyl, cycloalkyl, cyanoalkyl, OR 9 NR 9 R 10 SR 9 S(O)R 9 SO2R 9 SO3R 9 CO2R 9 CN, halogens, oxidants and CONR 9R 10 , where R 9 and R 10 As defined above, the condition is R. 3 and R 4 None of them can be OH, NH2, or SH, or R 11 and R 12 Together with the nitrogen or carbon atoms they are attached to, they form rings; R 13 R 14 and R 15 Optionally substituted with one or more groups selected from the group consisting of: sulfoalkyl, quaternary heterocyclic, quaternary aryl, OR 9 NR 9 R 10 N + R 9 R 11 R 12 A - SR 9 S(O)R 9 SO2R 9 SO3R 9 Oxygenation, 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 Independently selected from the constituent R 9 and substituents of M; or R 14 and R 15 Together with the nitrogen atoms to which they are attached, they form cyclic rings; and are selected from the group consisting of: alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocyclic, ammonium alkyl, alkylammonium alkyl, and aralkyl; Or a pharmaceutically acceptable salt, solvate, or prodrug.

[0183] In some embodiments of the method, the compound of formula II is such a compound in R 5 and R 6 Independently selected from the following groups: H, aryl, heterocyclic, quaternary heterocyclic, and quaternary aryl. The aryl, heteroaryl, quaternary heterocyclic, and quaternary heteroaryl groups are optionally substituted by one or more groups selected from the group consisting of: alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocyclic, aralkyl, halogen, oxo, OR 13 OR 13 R 14 NR 13 R 14 SR 13 S(O)R 13 SO2R 13 SO3R 13 NR 13 OR 14 NR 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 .

[0184] In some embodiments of the method, the compound of formula II is such a compound in R 5 Or R 6 It is –Ar-(R y ) t t is an integer from 0 to 5; Ar is selected from the group consisting of: phenyl, thiophene, pyridinyl, piperazinyl, piperinyl, pyrroleyl, naphthyl, furanyl, anthraceneyl, quinolinyl, isoquinolinyl, quinoxalinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrimidinyl, thiazolyl, triazolyl, isothiazolyl, indolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, and benzoisothiazolyl; and One or more R y Independently selected from the following groups: alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocyclic, aralkyl, halogen, oxo, OR 13 OR 13 R 14 NR 13 R 14 SR 13 S(O)R 13 SO2R 13 SO3R 13 NR 13 OR 14 NR 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 ; The alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocyclic groups may be further substituted by one or more substituents selected from the group consisting of: OR 13 NR 13 R 14 SR 13 S(O)R13 SO2R 13 SO3R 13 NR 13 OR 14 NR 13 NR 14 R 15 NO2, CO2R 13 CN, oxo, CONR 7 R 8 N + R 7 R 8 R 9 A - Alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclic, aralkyl, quaternary heterocyclic, quaternary aryl, 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 heterocyclic groups may optionally have one or more O, NR groups. 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 carbon substituted with phenylene.

[0185] In some embodiments of the method, the compound of formula II is a compound in which... R 5 Or R 6 yes In some embodiments of the method, the compound of formula II is a compound in which n is 1 or 2. In some embodiments of the method, the compound of formula II is a compound in which R... 1 and R 2 Independently, it is H or C 1-7 Alkyl compounds. In some embodiments of the method, the compounds of formula II are those in which each C 1-7The alkyl group is independently an ethyl, n-propyl, n-butyl, or isobutyl compound. In some embodiments of the method, the compound of formula II is wherein R... 3 and R 4 Independently, it is hydrogen or OR 9 The compound. In some embodiments of the method, the compound of formula II is wherein R is... 9 It is a compound of H.

[0186] In some embodiments of the method, the compound of formula II is one or more of R. x A compound located at the 7-, 8-, or 9-position of the benzo[a] ring of formula II. In some embodiments of the method, the compound of formula II is wherein R... x A compound located at the 7-position of the benzo[a] ring of formula II. In some embodiments of the method, the compound of formula II is one or more of the R[a] rings. x Selected independently from OR 13 and NR 13 R 14 Compounds.

[0187] In some embodiments of the method, the compound of formula II is such a compound in: q is 1 or 2; n is 2; R 1 and R 2 Each is an alkyl group; R 3 It is a hydroxyl group; R 4 and R 6 It is hydrogen; R 5 It has the following formula in t is an integer from 0 to 5; One or more R Y Is it OR 13 OR 13 R 14 ; R 13 and R 14 Independently selected from the group consisting of: hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, aryl, aralkyl, cycloalkyl, heterocyclic, heteroaryl, quaternary heterocyclic, quaternary aryl and quaternary arylalkyl; The alkyl, alkenyl, alkynyl, aralkyl, heterocyclic, and polyalkyl groups optionally have one or more O, NR groups. 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 Carbons substituted by phenylene, carbohydrates, amino acids, peptides, or polypeptides; R 13 and R 14 Optionally substituted with one or more groups independently selected from the group consisting of: sulfoalkyl, quaternary heterocyclic, quaternary aryl, OR 9 NR 9 R 10 N + R 9 R 11 R 12 A - SR 9 S(O)R 9 SO2R 9 SO3R 9 Oxygenation, 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 A - M is a pharmaceutically acceptable anion, and M is a pharmaceutically acceptable cation. R 9 and R 10 Independently selected from the group consisting of: H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocyclic, ammonium alkyl, aralkyl, and alkylammonium alkyl; R 11 and R 12 Independently selected from the group consisting of: H, alkyl, alkenyl, alkynyl, aryl, aralkyl, alkenylalkyl, alkynylalkyl, heterocyclic, carboxylalkyl, carbamoyloxyalkyl, cycloalkyl, cyanoalkyl, OR 9 NR9 R 10 SR 9 S(O)R 9 SO2R 9 SO3R 9 CO2R 9 CN, halogens, oxidants and CONR 9 R 10 , where R 9 and R 10 As defined above, the condition is R. 3 and R 4 None of them can be OH, NH2, or SH; or R 11 and R 12 Together with the nitrogen or carbon atoms they are attached to, they form cyclic rings; and R 16 and R 17 Independently selected from the constituent R 9 and substituents of M; R 7 and R 8 It is hydrogen; and One or more R x Independently selected from the following groups: alkoxy, alkylamino, and dialkylamino, and –WR 31 Where W is O or NH, and R 31 Selected from ; Or a pharmaceutically acceptable salt, solvate, or prodrug.

[0188] In some embodiments, the compound of formula II is , (Mashibat) , , , , or wait.

[0189] In some embodiments of the method, the compound of formula II is .

[0190] In some embodiments, the ASBTI suitable for the methods described herein is a non-systematic analog of compound 100C. Some compounds provided herein are modified or substituted to include charged groups as analogs of compound 100C. In specific embodiments, the compound 100C analog is modified or substituted with a charged group, said charged group being an ammonium group (e.g., a cyclic or acyclic ammonium group). In some embodiments, the ammonium group is an aprotic ammonium group containing quaternary nitrogen.

[0191] In some embodiments, the compound of formula II is .

[0192] 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-dioxo-1-benzothiophene-5-yl]phenyl]amino]-5-oxopentyl]amino]-1-deoxy-D-glucitol or SA HMR1741 (also known as BARI-1741).

[0193] In some embodiments, the compound of formula II is (volixibat potassium).

[0194] 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]thiazo-5-yl)-phenyl]-ureido}-3,5-dihydroxy-tetrahydro-pyran-2-yl sulfate ethanol, hydrate, or SAR548304B (also known as SAR-548304).

[0195] In some embodiments, the ASBTI suitable for the methods described herein is a compound of formula III: Formula III in: Each R 1 R 2 Independently, it is H, hydroxyl, alkyl, alkoxy, -C(=X)YR 8 -YC(=X)R 8Substituted 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 they are attached to, they form optionally R 8 Replacement of 3-8 membered rings; Each R 3 R 4 Independently, it is H, hydroxyl, 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 It is H, hydroxyl, 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 Independently, it is H, hydroxyl, 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 Together they form bonds; Each X is independently NH, S, or O; Each Y is independently NH, S, or O; R 8It is a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted alkyl-aryl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted alkyl-cycloalkyl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted alkyl-heteroaryl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted alkyl-heterocycloalkyl, or –LK; L is A n ,in Each A is an independent 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; wherein each m is independently 0-2; n is 0-7; K is the part that prevents absorption throughout the body; The condition is R 1 R 2 R 3 Or R 4 At least one of them is –LK; Or a pharmaceutically acceptable prodrug.

[0196] In some embodiments of the compounds of formula III, R 1 and R 3 Yes – LK. In some embodiments, R 1 R 2 and R 3 Yes – LK.

[0197] In some embodiments, R 1 R 2 R 3 R 4 R 5 R 6 and R 7 At least one of them is H. In some embodiments, R 5 R 6 R 7 It is H, and R 1 R 2 R 3 and R 4 It is alkyl, aryl, alkyl-aryl, or heteroalkyl. In some embodiments, R 1 and R 2 It is H. In some embodiments, R 1 R 2 R 5 R 6 and R 7It is H. In some embodiments, R 6 and R 7 Together they form bonds. In some embodiments, R 5 R 6 and R 7 It is H, alkyl, or O-alkyl.

[0198] In some embodiments, R 1 and R 3 Yes – LK. In some embodiments, R 1 R 2 and R 3 Yes – LK. In some embodiments, R 3 and R 4 Yes – LK. In some embodiments, R 1 and R 2 Together with the nitrogen atoms they are attached to, they form 3-8 membered rings, and these rings are replaced by –LK. In some embodiments, R 1 Or R 2 Or R 3 Or R 4 It is an aryl group optionally replaced by –LK. In some embodiments, R 1 Or R 2 Or R 3 Or R 4 It is an alkyl group optionally substituted with –LK. In some embodiments, R 1 Or R 2 Or R 3 Or R 4 It is an alkyl-aryl group optionally substituted with -LK. In some embodiments, R 1 Or R 2 Or R 3 Or R 4 It is a heteroalkyl group that is optionally substituted with -LK.

[0199] In some embodiments, L is a C1-C7 alkyl. In some embodiments, L is a heteroalkyl. In some embodiments, L is a C1-C7 alkyl-aryl. In some embodiments, L is a C1-C7 alkyl-aryl-C1-C7 alkyl.

[0200] In some embodiments, K is an aprotic charged group. In some specific 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.

[0201] In some embodiments, each K is a cyclic aprotic ammonium group with the following structure: In some embodiments, K is an acyclic aprotic ammonium group with the following structure: Where p, q, R 9 R 10 Z is defined as above. In some embodiments, p is 1. In other embodiments, p is 2. In still other embodiments, p is 3. In some embodiments, q is 0. In other embodiments, q is 1. In some other embodiments, q is 2.

[0202] The compound further comprises 1, 2, 3, or 4 anionic counterions selected from 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- ;where R 11 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 a K group and a counter ion. In other embodiments, the compound of Formula III has a K group, and two molecules of the compound of Formula III have a counter ion. In still other embodiments, the compound of Formula III has two K groups and two counter ions. In some other embodiments, the compound of Formula III has a K group comprising two ammonium groups and two counter ions.

[0203] This article also describes compounds having formula IIIA: Formula IIIA in: Each R 1 R 2Independently, it is H, substituted or unsubstituted alkyl, or –LK; or R 1 and R 2 Together with the nitrogen they are attached to, they form optionally R 8 Replacement of 3-8 membered rings; And R 3 R 4 R 8 L and K are defined as above.

[0204] In some embodiments of compounds of formula IIIA, L is A. n Each A is a substituted or unsubstituted alkyl group, or a substituted or unsubstituted heteroalkyl group, and n is 0-7. In certain specific embodiments of compounds of formula IIIA, R 1 It is H. In some embodiments of Formula IIIA, R 1 and R 2 Together with the nitrogen to which they are attached, they form 3-8 membered rings, which are optionally substituted with –LK.

[0205] This article also describes compounds having formula IIIB: Formula IIIB in: Each R 3 R 4 Independently, it is H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkyl-aryl, or –LK; And R 1 R 2 L and K are defined as above.

[0206] In some embodiments of formula IIIB, R 3 It is H. In some embodiments, R 3 and R 4 Each is –LK. In some embodiments, R 3 It is H, and R 4 It is a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted alkyl-aryl containing one or two –LK groups.

[0207] In some embodiments, the ASBTI suitable for the methods described herein is a compound of formula IIIC. Formula IIIC in: Each R 1 R 2 Independently, it is H, hydroxyl, 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 they are attached to, they form optionally R 8 Replacement of 3-8 membered rings; Each R 3 R 4 Independently, it is H, hydroxyl, 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 It is H, hydroxyl, 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 Independently, it is H, hydroxyl, 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 Together they form bonds; Each X is independently NH, S, or O; Each Y is independently NH, S, or O; R 8It is a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted alkyl-aryl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted alkyl-cycloalkyl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted alkyl-heteroaryl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted alkyl-heterocycloalkyl, or –LK; L is A n ,in Each A is an independent 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; wherein each m is independently 0-2; n is 0-7; K is the part that prevents absorption throughout the body; Or its pharmaceutically acceptable salt.

[0208] In some specific embodiments of Formula I, II, or III, K is selected from... In some embodiments, the ASBTI suitable for the methods described herein is a compound of formula IV: IV in R 1 It is a straight chain C 1-6 alkyl; R 2 It is a straight chain C 1-6 alkyl; R 3 Is it hydrogen or a group OR 11 , where R 11 It is hydrogen, and the C is optionally substituted. 1-6 Alkyl or C 1-6 Alkyl carbonyl; R 4 It is a pyridyl or optionally substituted phenyl group; R 5 R 6 and R 8 Same or different, and each selected from: Hydrogen, halogen, cyano, R 15 - Acetylene, OR 15 Optional substitution of 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 ,in p is an integer between 1 and 4. n is an integer between 0 and 3, and R 12 R 13 R 14 and R 15 Independently selected from hydrogen and optionally substituted C 1-6 alkyl; R 7 It is a group of the following formula The hydroxyl group can be acetyl, benzyl, or –(C1–C6)-alkyl-R. 17 replace, The alkyl group can be replaced by one or more hydroxyl groups; R 16 It is ––COOH, ––CH2––OH, ––CH2––O-acetyl, ––COOMe, or ––COOEt; R 17 It is H, ––OH, ––NH2, ––COOH or COOR 18 ; R 18 It is (C1–C4)-alkyl or ––NH––(C1–C4)-alkyl; X is ––NH–– or ––O––; and R 9 and R 10 They may be the same or different, and each is hydrogen or C1-C6 alkyl; and their salts.

[0209] In some embodiments, the compound of formula IV has the structure of formula IVA or formula IVB: Formula IVA Formula IVB In some embodiments, the compound of formula IV has the structure of formula IVC: IVC.

[0210] In some embodiments of Formula IV, X is O, and R 7 Selected from In some embodiments, the compound of formula IV is: .

[0211] In some embodiments, the ASBTI suitable for the methods described herein is a compound of formula V: V in: R v Selected from hydrogen or C 1-6 alkyl; R 1 and R 2 One of them is selected from hydrogen or C. 1-6 Alkyl group, and another one selected from C4. 1-6 alkyl; R x and R y Independently selected from hydrogen, hydroxyl, 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 Alkyl S(O) a where a is between 0 and 2; R z Selected from halogen, nitro, cyano, hydroxyl, amino, carboxyl, carbamoyl, mercapto, aminosulfonyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkyl group, C 1-6Alkyloxy group, N-(C 1-6 Alkyl)amino, N,N-(C) 1-6 alkyl)2amino, C 1-6 Alkylamino, N-(C 1-6 alkyl)carbamoyl, N,N-(C 1-6 alkyl)2-carbamoyl, C 1-6 Alkyl S(O) a (where a is 0 to 2), C 1-6 alkoxycarbonyl, N-(C 1-6 -alkyl)aminosulfonyl and N,N-(C 1-6 alkyl)2-aminosulfonyl; n is 0-5; R 4 and R 5 One of them is the group of formula (VA): VA R 3 and R 6 and R 4 and R 5 The other group is independently selected from hydrogen, halogen, nitro, cyano, hydroxyl, amino, carboxyl, carbamoyl, mercapto, aminosulfonyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkyl group, C 1-6 Alkyloxy group, N-(C 1-6 Alkyl)amino, N,N-(C) 1-6 alkyl)2amino, C 1-6 Alkylamino, N-(C 1-6 alkyl)carbamoyl, N,N-(C 1-6 alkyl)2-carbamoyl, C 1-6 Alkyl S(O) a (where a is 0 to 2), C 1-6 alkoxycarbonyl, N-(C 1-6 alkyl)aminosulfonyl and N,N-(C 1-6 alkyl)2-aminosulfonyl, Where R 3 and R 6 and R 4 and R 5 The other one can optionally be on carbon by one or more R 17 replace; X is —O—, —N(R) a —、—S(O) b —or—CH(R) a—; Where R a Is it hydrogen or C? 1-6 Alkyl group, and b is 0-2; Ring A is aryl or heteroaryl; The ring A is optionally bounded on the carbon by one or more elements selected from R. 18 Substituents of the substituents; R 7 It is hydrogen, C 1-6 Alkyl, carbocyclic, or heterocyclic groups; Where R 7 Optionally, carbon is coated with one or more R-type carbon atoms. 19 The nitrogen may be replaced by a substituent; and if the heterocyclic group contains an -NH- group, the nitrogen may optionally be selected from R. 20 Substitution of groups; R 8 Is it hydrogen or C? 1-6 alkyl; R 9 Is it hydrogen or C? 1-6 alkyl; R 10 It is hydrogen, halogen, nitro, cyano, hydroxyl, amino, carbamoyl, mercapto, aminosulfonyl, hydroxyaminocarbonyl, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 Alkoxy, C 1-10 Alkyl group, C 1-10 Alkyloxy group, N-(C 1-10 Alkyl)amino, N,N-(C) 1-10 alkyl)2amino, N,N,N-(C 1-10 alkyl)3-amino, C 1-10 Alkylamino, N-(C 1-10 alkyl)carbamoyl, N,N-(C 1-10 alkyl)2-carbamoyl, C 1-10 Alkyl S(O) a (where a is 0 to 2), N—(C 1-10 alkyl)aminosulfonyl, N,N-(C 1-10 alkyl)2-aminosulfonyl, N-(C 1-10 alkyl)aminosulfonylamino, N,N-(C 1-10 alkyl)2-aminosulfonylamino, C 1-10 alkoxycarbonylamino, carbocyclic, carbocyclic C 1-10 Alkyl, heterocyclic, heterocyclic C 1-10 Alkyl, carbocyclo-(C 1-10 Alkylene) p -R 21 —(C1-10 Alkylene) q -or heterocyclic group-(C 1-10 Alkylene) r -R 22 —(C 1-10 Alkylene) s -; where R 10 Carbon is optionally marked with one or more atoms selected from R 23 The nitrogen may be replaced by a substituent; and if the heterocyclic group contains an -NH- group, the nitrogen may optionally be selected from R. 24 Substitution of the group; or R 10 It is a group of formula (VB): VB in: R 11 Is it hydrogen or C? 1-6 -alkyl; R 12 and R 13 Independently selected from hydrogen, halogen, carbamoyl, aminosulfonyl, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 Alkyl group, N-(C 1-10 alkyl)carbamoyl, N,N-(C 1-10 alkyl)2-carbamoyl, C 1-10 Alkyl S(O) a (where a is 0 to 2), N—(C 1-10 alkyl)aminosulfonyl, N,N-(C 1-10 alkyl)2-aminosulfonyl, N-(C 1-10 alkyl)aminosulfonylamino, N,N-(C 1-10 alkyl)2-aminosulfonylamino, carbocyclic or heterocyclic; wherein R 12 and R 13 It can be independently and optionally coated on carbon with one or more elements selected from R. 25 The nitrogen may be replaced by a substituent; and if the heterocyclic group contains an -NH- group, the nitrogen may optionally be selected from R. 26 Substitution of groups; R 14 Selected from hydrogen, halogen, carbamoyl, aminosulfonyl, hydroxyaminocarbonyl, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 Alkyl group, N-(C 1-10 alkyl)carbamoyl, N,N-(C 1-10 alkyl)2-aminosulfonyl, C 1-10 Alkyl S(O)a (where a is 0 to 2), N—(C 1-10 alkyl)aminosulfonyl, N,N-(C 1-10 alkyl)2-aminosulfonyl, N-(C 1-10 alkyl)aminosulfonylamino, N,N-(C 1-10 alkyl)2-aminosulfonylamino, carbocyclic, carbocyclic C 1-10 Alkyl, heterocyclic, heterocyclic C 1-10 Alkyl, carbocyclo-(C 1-10 Alkylene) p -R 27 —(C 1-10 Alkylene) q -or heterocyclic group-(C 1-10 Alkylene) r -R 28 —(C 1-10 Alkylene) s -; where R 14 Optionally, one or more atoms selected from R can be deposited on carbon. 29 The nitrogen may be replaced by a substituent; and if the heterocyclic group contains an -NH- group, the nitrogen may optionally be selected from R. 30 Substitution of the group; or R 14 It is a group of formula (VC): VC R 15 Is it hydrogen or C? 1-6 Alkyl; and R 16 Is it hydrogen or C? 1-6 Alkyl; wherein R 16 Optionally, one or more atoms selected from R can be deposited on carbon. 31 Substitution of groups; Or R 15 and R 16 Together with the nitrogen to which they are attached, they form a heterocyclic group; wherein the heterocyclic group may optionally be bonded to one or more R atoms on the carbon. 37 Substitution; and wherein if the heterocyclic group contains an -NH- group, the nitrogen may optionally be selected from R 38 Substitution of groups; m is 1–3; where R 7 The values ​​can be the same or different; R 17 R 18 R 19 R 23 R 25 R 29 R 31 and R 37Independently selected from halogen, nitro, cyano, hydroxyl, amino, carbamoyl, mercapto, aminosulfonyl, hydroxyaminocarbonyl, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 Alkoxy, C 1-10 Alkyl group, C 1-10 Alkyloxy group, N-(C 1-10 Alkyl)amino, N,N-(C) 1-10 alkyl)2amino, N,N,N-(C 1-10 alkyl)3-amino, C 1-10 Alkylamino, N-(C 1-10 alkyl)carbamoyl, N,N-(C 1-10 alkyl)2-carbamoyl, C 1-10 Alkyl S(O) a (where a is 0 to 2), N—(C 1-10 alkyl)aminosulfonyl, N,N-(C 1-10 alkyl)2-aminosulfonyl, N-(C 1-10 alkyl)aminosulfonylamino, N,N-(C 1-10 alkyl)2-aminosulfonylamino, C 1-10 alkoxycarbonylamino, carbocyclic, carbocyclic C 1-10 Alkyl, heterocyclic, heterocyclic C 1-10 Alkyl, carbocyclo-(C 1-10 Alkylene) p -R 32 —(C 1-10 Alkylene) q -or heterocyclic group-(C 1-10 Alkylene) r -R 33 —(C 1-10 Alkylene) s -; where R 17 R 18 R 19 R 23 R 25 R 29 R 31 and R 37 One or more R atoms can be independently and arbitrarily applied to carbon. 34 Substitution; and wherein if the heterocyclic group contains an -NH- group, the nitrogen may optionally be selected from R 35 Substitution of groups; R 21 R 22 R 27 R 28 R 32 Or R 33Independently selected from —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 —; where R 36 Selected from hydrogen or C 1-6 Alkyl group, and x is 0-2; p, q, r, and s are independently selected from 0 to 2; R 34 Selected from halogen, hydroxyl, cyano, carbamoyl, urea, amino, nitro, carbamoyl, mercapto, aminosulfonyl, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy, ethoxy, vinyl, allyl, ethynyl, formyl, acetyl, formamido, acetamido, acetoxy, methylamino, dimethylamino, N-methylcarbamoyl, N,N-dimethylcarbamoyl, methylthio, methylsulfonyl, mesylate, N-methylaminosulfonyl, N,N-dimethylaminosulfonyl, N-methylaminosulfonylamino and N,N-dimethylaminosulfonylamino; R 20 R 24 R 26 R 30 R 35 and R 38 Selected independently from C 1-6 Alkyl, C 1-6 Alkyl group, C 1-6 Alkylaminosulfonyl, C 1-6 alkoxycarbonyl, carbamoyl, N-(C 1-6 alkyl)carbamoyl, N,N-(C 1-6 Alkyl) carbamoyl, benzyl, benzyloxycarbonyl, benzoyl, and phenylaminosulfonyl; and "Heteroaryl" is a fully unsaturated monocyclic or bicyclic ring containing 3 to 12 atoms (at least one of which is selected from nitrogen, sulfur and oxygen), and unless otherwise stated, the heteroaryl group may be carbon or nitrogen linked. Wherein, "heterocyclic group" is a saturated, partially saturated, or unsaturated monocyclic or bicyclic ring containing 3-12 atoms (at least one of which is selected from nitrogen, sulfur, and oxygen). Unless otherwise stated, the heterocyclic group may be carbon or nitrogen-linked, wherein the -CH2- group may optionally be replaced by a -C(O)- group, and the cyclic sulfur atom may optionally be oxidized to form an S-oxide; and The "carbocyclic group" is a saturated, partially saturated, or unsaturated monocyclic or bicyclic carbon ring containing 3-12 atoms; the -CH2- group may optionally be replaced by a -C(O) group; Or a pharmaceutically acceptable salt thereof or an in vivo hydrolyzable ester or amide formed on an available carboxyl or hydroxyl group.

[0212] 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-benzothiazazaporide; 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-benzothiazazaporide; 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-benzothiazazopyr; 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-benzothiazazopyr; 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-benzothiazazopyr; 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-benzothiazazopyr; 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-benzothiazazopyr; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxy-2-(R)-hydroxypropyl)carbamoyl]benzyl 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-benzothiodiazazoline; 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-benzothiodiazazoline;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-benzothiazazepine; 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-benzothiazazopyr;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-benzothiazazopyr; 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-benzothiazazopyr; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio -8-[N-{(R)-α-carboxy-4-hydroxybenzyl}carbamoylmethoxy]-2,3,4,5-tetrahydro-1,2,5-benzothiazazolide; 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-benzothiazazolide or a salt thereof.

[0213] In some embodiments, the compound of formula V is or or .

[0214] In some embodiments, the ASBTI suitable for the methods described herein is a compound of formula VI: VI in: R v and R w Independently selected from hydrogen or C 1-6 alkyl; R 1 and R 2 One of them is selected from hydrogen or C. 1-6 Alkyl group, and another one selected from C4. 1-6 alkyl; R x and Ry Independently selected from 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 hydroxyl or C 1-6 Alkoxy; R z Selected from halogen, nitro, cyano, hydroxyl, amino, carboxyl, carbamoyl, mercapto, aminosulfonyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkyl group, C 1-6 Alkyloxy group, N-(C 1-6 Alkyl)amino, N,N-(C) 1-6 alkyl)2amino, C 1-6 Alkylamino, N-(C 1-6 alkyl)carbamoyl, N,N-(C 1-6 alkyl)2-carbamoyl, C 1-6 Alkyl S(O)a (where a is 0 to 2), C 1-6 alkoxycarbonyl, N-(C 1-6 alkyl)aminosulfonyl and N,N-(C 1-6 alkyl)2-aminosulfonyl; n is 0-5; R 4 and R 5 One of them is the group of formula (VIA): VIA R 3 and R 6 and R 4 and R 5 The other group is independently selected from hydrogen, halogen, nitro, cyano, hydroxyl, amino, carboxyl, carbamoyl, mercapto, aminosulfonyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkyl group, C 1-6 Alkyloxy group, N-(C 1-6 Alkyl)amino, N,N-(C) 1-6 alkyl)2amino, C 1-6 Alkylamino, N-(C 1-6 alkyl)carbamoyl, N,N-(C 1-6 alkyl)2-carbamoyl, C 1-6 Alkyl S(O)a (where a is 0 to 2), C1-6 alkoxycarbonyl, N-(C 1-6 alkyl)aminosulfonyl and N,N-(C 1-6 alkyl)2-aminosulfonyl; wherein R 3 and R 6 and R 4 and R 5 The other one can optionally be on carbon by one or more R 17 replace; X is —O—, —N(R) a —、—S(O) b —or—CH(R) a —; where R a Is it hydrogen or C? 1-6 Alkyl group, and b is 0-2; Ring A is aryl or heteroaryl; wherein ring A is optionally surrounded on a carbon atom by one or more atoms selected from R. 18 Substituents of the substituents; R 7 It is hydrogen, C 1-6 Alkyl, carbocyclic or heterocyclic; wherein R 7 Carbon is optionally marked with one or more atoms selected from R 19 The nitrogen may be substituted with a substituent; and if the heterocyclic group contains a -NH- group, the nitrogen may optionally be selected from R. 20 Substitution of groups; R 8 Is it hydrogen or C? 1-6 alkyl; R 9 Is it hydrogen or C? 1-6 alkyl; R 10 It is hydrogen, halogen, nitro, cyano, hydroxyl, amino, carbamoyl, mercapto, aminosulfonyl, hydroxyaminocarbonyl, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 Alkoxy, C 1-10 Alkyl group, C 1-10 Alkyloxy group, N-(C 1-10 Alkyl)amino, N,N-(C) 1-10 alkyl)2amino, N,N,N-(C 1-10 alkyl)3-amino, C 1-10 Alkylamino, N-(C 1-10 alkyl)carbamoyl, N,N-(C 1-10 alkyl)2-carbamoyl, C 1-10 Alkyl S(O) a (where a is 0 to 2), N—(C 1-10 alkyl)aminosulfonyl, N,N-(C1-10 alkyl)2-aminosulfonyl, N-(C 1-10 alkyl)aminosulfonylamino, N,N-(C 1-10 alkyl)2-aminosulfonylamino, C 1-10 alkoxycarbonylamino, carbocyclic, carbocyclic C 1-10 Alkyl, heterocyclic, heterocyclic C 1-10 Alkyl, carbocyclo-(C 1-10 Alkylene) p -R 21 —(C 1-10 Alkylene) q -or heterocyclic group-(C 1-10 Alkylene) r -R 22 —(C 1-10 Alkylene) s -; where R 10 Carbon is optionally marked with one or more atoms selected from R 23 The nitrogen may be substituted with a substituent; and if the heterocyclic group contains a -NH- group, the nitrogen may optionally be selected from R. 24 Substitution of the group; or R 10 It is a group of formula (VIB): VIB in: R 11 Is it hydrogen or C? 1-6 alkyl; R 12 and R 13 Independently selected from hydrogen, halogen, nitro, cyano, hydroxyl, amino, carbamoyl, mercapto, aminosulfonyl, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 Alkoxy, C 1-10 Alkyl group, C 1-10 Alkyloxy group, N-(C 1-10 Alkyl)amino, N,N-(C) 1-10 alkyl)2amino, C 1-10 Alkylamino, N-(C 1-10 alkyl)carbamoyl, N,N-(C 1-10 alkyl)2-carbamoyl, C 1-10 Alkyl S(O) a (where a is 0 to 2), N—(C 1-10 alkyl)aminosulfonyl, N,N-(C 1-10 alkyl)2-aminosulfonyl, N-(C 1-10 alkyl)aminosulfonylamino, N,N-(C 1-10alkyl)2-aminosulfonylamino, carbocyclic or heterocyclic; wherein R 12 and R 13 It can be independently and optionally coated on carbon with one or more elements selected from R. 25 The nitrogen may be substituted with a substituent; and if the heterocyclic group contains a -NH- group, the nitrogen may optionally be selected from R. 26 Substitution of groups; R 14 Selected from hydrogen, halogen, nitro, cyano, hydroxyl, amino, carbamoyl, mercapto, aminosulfonyl, hydroxyaminocarbonyl, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 Alkoxy, C 1-10 Alkyl group, C 1-10 Alkyloxy group, N-(C 1-10 Alkyl)amino, N,N-(C) 1-10 alkyl)2amino, N,N,N-(C 1-10 alkyl)3-amino, C 1-10 Alkylamino, N-(C 1-10 alkyl)carbamoyl, N,N-(C 1-10 alkyl)2-carbamoyl, C 1-10 Alkyl S(O) a (where a is 0 to 2), N—(C 1-10 alkyl)aminosulfonyl, N,N-(C 1-10 alkyl)2-aminosulfonyl, N-(C 1-10 alkyl)aminosulfonylamino, N,N-(C 1-10 alkyl)2-aminosulfonylamino, C 1-10 alkoxycarbonylamino, carbocyclic, carbocyclic C 1-10 Alkyl, heterocyclic, heterocyclic C 1-10 Alkyl, carbocyclo-(C 1-10 Alkylene) p -R 27 —(C 1-10 Alkylene) q -or heterocyclic group-(C 1-10 Alkylene) r -R 28 —(C 1-10 Alkylene) s -; where R 14 Optionally, one or more atoms selected from R can be deposited on carbon. 29 The nitrogen may be substituted with a substituent; and if the heterocyclic group contains a -NH- group, the nitrogen may optionally be selected from R. 30 Substitution of the group; or R 14 It is a group of formula (VIC): VIC R 15 Is it hydrogen or C? 1-6 alkyl; R 16 Is it hydrogen or C? 1-6 Alkyl; wherein R 16 Optionally, one or more atoms selected from R can be deposited on carbon. 31 Substitution of groups; n is 1-3; where R 7 The values ​​can be the same or different; R 17 R 18 R 19 R 23 R 25 R 29 Or R 31 Independently selected from halogen, nitro, cyano, hydroxy, carbamoyl, mercapto, aminosulfonyl, hydroxyaminocarbonyl, amidine, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 Alkoxy, C 1-10 Alkyl group, C 1-10 Alkyloxy, (C 1-10 alkyl)3-methylsilyl, N-(C) 1-10 Alkyl)amino, N,N-(C) 1-10 alkyl)2amino, N,N,N-(C 1-10 alkyl)3-amino, C 1-10 Alkylamino, N-(C 1-10 alkyl)carbamoyl, N,N-(C 1-10 alkyl)2-carbamoyl, C 1-10 Alkyl S(O) a (where a is 0 to 2), N—(C 1-10 alkyl)aminosulfonyl, N,N-(C 1-10 alkyl)2-aminosulfonyl, N-(C 1-10 alkyl)aminosulfonylamino, N,N-(C 1-10 alkyl)2-aminosulfonylamino, C 1-10 alkoxycarbonylamino, carbocyclic, carbocyclic C 1-10 Alkyl, heterocyclic, heterocyclic C 1-10 Alkyl, carbocyclo-(C 1-10 Alkylene) p -R 32 —(C 1-10 Alkylene) q -or heterocyclic group-(C 1-10 Alkylene) r-R 33 —(C 1-10 Alkylene) s -; where R 17 R 18 R 19 R 23 R 25 R 29 Or R 31 It can be independently and optionally coated on carbon with one or more R 34 Substitution; and wherein if the heterocyclic group contains a -NH- group, the nitrogen may optionally be selected from R 35 Substitution of groups; R 21 R 22 R 27 R 28 R 32 Or R 33 Independently selected from —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 —; where R 36 Selected from hydrogen or C 1-6 Alkyl group, and x is 0-2; p, q, r, and s are independently selected from 0 to 2; R 34 Selected from halogen, hydroxyl, cyano, carbamoyl, urea, amino, nitro, carbamoyl, mercapto, aminosulfonyl, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy, ethoxy, vinyl, allyl, ethynyl, formyl, acetyl, formamido, acetamido, acetoxy, methylamino, dimethylamino, N-methylcarbamoyl, N,N-dimethylcarbamoyl, methylthio, methanesulfonyl, methanesulfonyl, N-methylaminosulfonyl, N,N-dimethylaminosulfonyl, N-methylaminosulfonylamino and N,N-dimethylaminosulfonylamino; R 20 R 24 R 26 R 30 Or R 35 Selected independently from C 1-6 Alkyl, C 1-6 Alkyl group, C 1-6 alkylsulfonyl, C 1-6 alkoxycarbonyl, carbamoyl, N-(C1-6 alkyl)carbamoyl, N,N-(C 1-6 Alkyl) carbamoyl, benzyl, benzyloxycarbonyl, benzoyl, and benzenesulfonyl; Or a pharmaceutically acceptable salt, solvate, or solvate of such salt, or an in vivo hydrolyzable ester formed on its available carboxyl or hydroxyl group, or an in vivo hydrolyzable amide formed on its available carboxyl group.

[0215] In some embodiments, the compound of formula VI has the structure of formula VID: VID in: R 1 and R 2 Selected independently from C 1-6 Alkyl; R 4 and R 5 One of them is the group of formula (VIE): VIE R 3 and R 6 and R 4 and R 5 The other group is independently selected from hydrogen, halogen, nitro, cyano, hydroxyl, amino, carboxyl, carbamoyl, mercapto, aminosulfonyl, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Alkyl group, C 1-4 Alkyloxy group, N-(C 1-4 Alkyl)amino, N,N-(C) 1-4 alkyl)2amino, C 1-4 Alkylamino, N-(C 1-4 alkyl)carbamoyl, N,N-(C 1-4 alkyl)2-carbamoyl, C 1-4 Alkyl S(O) a (where a is 0 to 2), C 1-4 alkoxycarbonyl, N-(C 1-4 alkyl)aminosulfonyl and N,N-(C 1-4 alkyl)2-aminosulfonyl; wherein R 3 and R 6 and R 4 and R 5 The other one can optionally be on carbon by one or more R 14 replace; R 7 It is a carboxyl group, sulfonyl group, sulfinyl group, phosphonoyl group, -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 Selected independently from C 1-6 Alkyl; or R 7 It is a group of formula (VIF): VIF R 8 and R 9 Independently, it is hydrogen and C 1-4 Alkyl or saturated cyclic groups, or R 8 and R 9 Together they form C 2-6 Alkylene; wherein R 8 and R 9 Or R 8 and R 9 Together they can be independently and optionally bonded to carbon by one or more atoms selected from R. 15 The nitrogen may be replaced by one or more R substituents; and if the saturated cyclic group contains a -NH- moiety, the nitrogen may optionally be replaced by one or more R substituents. 20 replace; R 10 Is it hydrogen or C? 1-4 Alkyl; wherein R 10 Carbon is optionally marked with one or more atoms selected from R 24 Substituents of the substituents; R 11 It is hydrogen, C 1-4 Alkyl, carbocyclic or heterocyclic; wherein R 11 Optionally, carbon is coated with one or more R-type carbon atoms. 16 The nitrogen may be replaced by one or more R substituents; and if the heterocyclic group contains a -NH- moiety, the nitrogen may optionally be replaced by one or more R substituents. 21 replace; R 12 Is it hydrogen or C? 1-4 Alkyl, carbocyclic or heterocyclic; wherein R 12 Optionally, carbon is coated with one or more R-type carbon atoms. 17 The nitrogen may be replaced by one or more R substituents; and if the heterocyclic group contains a -NH- moiety, the nitrogen may optionally be replaced by one or more R substituents. 22 replace; R 13 It is a carboxyl group, sulfonyl group, sulfinyl group, phosphonoyl group, -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 Selected independently from C 1-6 alkyl; m is 1-3; where R 8 and R 9 The values ​​can be the same or different; n is 1-3; where R 11 The values ​​can be the same or different; p is 1-3; where R 12 The values ​​can be the same or different; R 14 and R 16 Independently selected from halogen, nitro, cyano, hydroxyl, amino, carboxyl, carbamoyl, mercapto, aminosulfonyl, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Alkyl group, C 1-4 Alkyloxy group, N-(C 1-4 Alkyl)amino, N,N-(C) 1-4 alkyl)2amino, C 1-4 Alkylamino, N-(C 1-4 alkyl)carbamoyl, N,N-(C 1-4 alkyl)2-carbamoyl, C 1-4 Alkyl S(O) a (where a is 0 to 2), C 1-4 alkoxycarbonyl, N-(C 1-4 alkyl)aminosulfonyl and N,N-(C 1-4 alkyl)2-aminosulfonyl; wherein R 14 and R 16 It can be independently and optionally coated on carbon with one or more R 18 replace; R 15 and R 17 Independently selected from halogen, nitro, cyano, hydroxyl, amino, carboxyl, carbamoyl, mercapto, aminosulfonyl, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Alkyl group, C 1-4 Alkyloxy group, N-(C 1-4 Alkyl)amino, N,N-(C) 1-4alkyl)2amino, C 1-4 Alkylamino, N-(C 1-4 alkyl)carbamoyl, N,N-(C 1-4 alkyl)2-carbamoyl, C 1-4 Alkyl S(O) a (where a is 0 to 2), C 1-4 alkoxycarbonyl, N-(C 1-4 alkyl)aminosulfonyl and N,N-(C 1-4 Alkyl)2-aminosulfonyl, carbocyclic, heterocyclic, sulfonyl, sulfinyl, amidine, phosphonyl, -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 Selected independently from C 1-6 Alkyl; wherein R 15 and R 17 It can be independently and optionally coated on carbon with one or more R 19 Substitution; and wherein if the heterocyclic group contains a -NH- moiety, the nitrogen may optionally be replaced by one or more R... 23 replace; R 18 R 19 and R 25 Independently selected from halogen, hydroxyl, cyano, carbamoyl, urea, amino, nitro, carboxyl, carbamoyl, mercapto, aminosulfonyl, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy, ethoxy, vinyl, allyl, ethynyl, methoxycarbonyl, formyl, acetyl, formamido, acetamido, acetoxy, methylamino, dimethylamino, N-methylcarbamoyl, N,N-dimethylcarbamoyl, methylthio, methanesulfonyl, methanesulfonyl, N-methylaminosulfonyl, and N,N-dimethylaminosulfonyl; R 20 R 21 R 22 R 23 and R 26 C is independent 1-4 Alkyl, C 1-4 Alkyl group, C 1-4 alkylsulfonyl, aminosulfonyl, N-(C 1-4 alkyl)aminosulfonyl, N,N-(C 1-4 alkyl)2-aminosulfonyl, C 1-4 Alkoxycarbonyl, carbamoyl, N-(C1-4 alkyl)carbamoyl, N,N-(C 1-4 Alkyl)2-carbamoyl, benzyl, phenethyl, benzoyl, phenylsulfonyl, and phenyl; R 24 Selected from halogen, nitro, cyano, hydroxy, amino, carboxyl, carbamoyl, mercapto, aminosulfonyl, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Alkyl group, C 1-4 Alkyloxy group, N-(C 1-4 Alkyl)amino, N,N-(C) 1-4 alkyl)2amino, C 1-4 Alkylamino, N-(C 1-4 alkyl)carbamoyl, N,N-(C 1-4 alkyl)2-carbamoyl, C 1-4 Alkyl S(O) a (where a is 0 to 2), C 1-4 alkoxycarbonyl, N-(C 1-4 alkyl)aminosulfonyl and N,N-(C 1-4 alkyl)2-aminosulfonyl, carbocyclic, heterocyclic; wherein R 24 It can be independently and optionally coated on carbon with one or more R 25 Substitution; and wherein if the heterocyclic group contains a -NH- moiety, the nitrogen may optionally be replaced by one or more R... 26 replace; Any saturated cyclic group is a fully or partially saturated monocyclic or bicyclic ring containing 3 to 12 atoms, wherein 0 to 4 atoms are selected from nitrogen, sulfur, or oxygen, and they may be carbon or nitrogen linked. Any heterocyclic group therein is a saturated, partially saturated, or unsaturated monocyclic or bicyclic ring containing 3-12 atoms, wherein at least one atom is selected from nitrogen, sulfur, or oxygen, and they may be carbon or nitrogen linked, wherein the —CH2— group may optionally be substituted with -C(O)-, or the cyclic sulfur atom may optionally be oxidized to form an S-oxide; and Any of the carbocyclic groups is a saturated, partially saturated or unsaturated monocyclic or bicyclic carbocyclic ring containing 3 to 12 atoms, wherein the —CH2— group may optionally be replaced by —C(O)—. Or its pharmaceutically acceptable salt.

[0216] 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-benzothiazazepine; 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-benzothiazazepine. - benzothiazazaporium; 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-benzothiazaporium; 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-benzothiazaporium; or salts thereof.

[0217] In some embodiments, any of the compounds described herein are covalently conjugated with bile acids using any suitable method. In some embodiments, the compounds described herein are covalently bonded with cyclodextrins or biodegradable polymers (e.g., polysaccharides).

[0218] In some embodiments, the compounds described herein are not systemically absorbed. Furthermore, this document provides compounds that inhibit bile salt recirculation in an individual's gastrointestinal tract. In some embodiments, the compounds described herein may not be transported from the intestinal lumen and / or interact with ASBTs. In some embodiments, the compounds described herein do not affect fat digestion and / or absorption or affect fat digestion and / or absorption minimally. In some embodiments, administration of a therapeutically effective amount of any of the compounds described herein does not cause gastrointestinal disturbances or lactic acidosis in an individual. In some embodiments, the compounds described herein are administered orally. In some embodiments, ASBTIs are released in the distal ileum. ASBTIs compatible with the methods described herein may be direct inhibitors, allosteric inhibitors, or partial inhibitors of apical sodium-dependent bile acid transporters.

[0219] In some embodiments, compounds that inhibit ASBT or any reversible bile acid transporter are described in EP1810689, U.S. Patent Nos. 6,458,851, 7,413,536, 7514,421, U.S. Application Publication Nos. 2002 / 0147184, 2003 / 0119809, 2003 / 0149010, 2004 / 0014806, 2004 / 0092500, 2004 / 0180861, 2004 / 0180860, 2005 / 0031651, 2006 / 0069080, 2006 / 0199797, and 2006 / 0241121. 2007 / 0065428, 2007 / 0066644, 2007 / 0161578, 2007 / 0197628, 2007 / 0203183, 2007 / 0254952, 2008 / 0070888, 2008 / 0070892, 2008 / 00 70889, 2008 / 0070984, 2008 / 0089858, 2008 / 0096921, 2008 / 0161400, 2008 / 0167356, 2008 / 0194598, 2008 / 0255202, 2008 / 0261990, WO W O2006 / 122186, WO2006 / 124713, WO2007 / 050628, WO2007 / 101531, WO2007 / 134862, WO2007 / 140934, WO2007 / 140894, WO2008 / 028590 The compounds described in WO2008 / 033431, WO2008 / 033464, WO2008 / 031501, WO2008 / 031500, WO2008 / 033465, WO2008 / 034534, WO2008 / 039829, WO2008 / 064788, WO2008 / 064789, WO2008 / 088836, WO2008 / 104306, WO2008 / 124505 and WO2008 / 130616; the compounds described therein that inhibit reversible bile acid transport are hereby incorporated herein by reference.

[0220] In some embodiments, compounds that inhibit ASBT or any restorative bile acid transporter are 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, DE 19825804, WO00 / 38725, WO00 / 38726, WO00 / 38727 (including those compounds having the 2,3,4,5-tetrahydro-1-benzothiophene-1,1-dioxide structure), WO00 / 38728, WO01 / 66533, WO02 / 50051, EP0864582 (For example, (3R,5R)-3-butyl-3-ethyl-1,1-dioxa-5-phenyl-2,3,4,5-tetrahydro-1,4-benzo-thiazepin-8-yl(β-D-glucopyranoic acid), WO94 / 24087, WO98 / 07749, WO98 / 56757, WO99 / 32478, WO99 / 35135, WO00 / 20392, WO00 / 20393, WO00 / 20410, WO00 / 20437, WO01 / 34570, WO00 / 35889, WO01 / 68637, W) O01 / 68096, WO02 / 08211, WO03 / 020710, WO03 / 022825, WO03 / 022830, WO03 / 0222861, JP10072371, US 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;Compounds described in 5,070,103, 6,114,322, 6,020,330, 7,179,792, EP251315, EP417725, EP489-423, EP549967, EP573848, EP624593, EP624594, EP624595, EP869121, EP1070703, WO04 / 005247, *Drugs of the Future*, 24, 425-430 (1999), *Journal of Medicinal Chemistry*, 48, 5837-5852, (2005), and *Current Medicinal Chemistry*, 13, 997-1016. Compounds with IBAT activity disclosed in (2006) are described herein; compounds that inhibit reversible bile acid transport as described therein are incorporated herein by reference.

[0221] In some embodiments, the compound that inhibits ASBT or any restorative bile acid transporter is benzothiophene, benzothiazolinone (including 1,2-benzothiazolinone; 1,4-benzothiazolinone; 1,5-benzothiazolinone; and / or 1,2,5-benzothiazolinone). In some embodiments, compounds that inhibit ASBT or any restorative bile acid transporters include, but are not limited to, S-8921 (disclosed in EP597107, 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-hydroxy-1,1-dioxo-1-benzothiazolinone-5-yl]phenoxy]butyl]4-aza-1-azabicyclo[2.2.2]octane methanesulfonate), SC-635 (Searle); 2164U90 (3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazolinone-1,1-dioxide); BARI-1741 (Aventis SA), AZD 7508 (Astra Zeneca); barixibat (11-(D-glucosamine)-N-{2-[(1S,2R,3S)-3-hydroxy-3-phenyl-2-(2-pyridinyl)-1-(2-pyridylamino)propyl]phenyl}undecanoamide) and combinations thereof. In some embodiments, ASBTI is: .

[0222] In some embodiments, the compounds described herein have one or more chiral centers. Therefore, all stereoisomers are contemplated herein. In various embodiments, the compounds described herein exist in optically active or racemic forms. It should be understood that the compounds of the present invention encompass racemic, optically active, regioisomeric, and stereoisomeric forms or combinations thereof having the therapeutically useful properties described herein. Preparation of the optically active form is achieved in any suitable manner, including, as a non-limiting example, by resolving the racemic form via recrystallization, by synthesis from an optically active starting material, by chiral synthesis, or by chromatographic separation using a chiral stationary phase. In some embodiments, a mixture of one or more isomers is used as the therapeutic compound described herein. In some embodiments, the compounds described herein contain one or more chiral centers. These compounds can be prepared by any means, including enantioselective synthesis and / or separation of mixtures of enantiomers and / or diastereomers. Separation of the compound and its isomers can be achieved by any means, including, as a non-limiting example, chemical processes, enzymatic processes, stepwise crystallization, distillation, chromatography, etc.

[0223] In some embodiments, ASBTI is (Macixibat, LUM-001, SHP625, lopixibat chloride) or alternative pharmaceutically acceptable salts thereof.

[0224] In some embodiments, ASBTI is (Voxibat, (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]thiazo-5-yl)-phenyl]-ureido}-3,5-dihydroxy-tetrahydro-pyran-2-ylmethyl) hydrogen sulfate) or a pharmaceutically acceptable salt thereof.

[0225] In some embodiments, ASBTI is or (LUM-002; SHP626; SAR548304; Vosibart potassium) or alternative pharmaceutically acceptable salts thereof.

[0226] In various embodiments, ASBTI is (Ovispart; AZD8294; WHO10706; AR-H064974; SCHEMBL946468; A4250; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-a-[N-((S)-1-carboxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiazazepine) or a pharmaceutically acceptable salt thereof.

[0227] In some embodiments, ASBTI is (Elobisibart; 2-[[(2R)-2-[[2-[(3,3-dibutyl-7-methylsulfonyl-1,1-dioxo-5-phenyl-2,4-dihydro-1λ6,5-benzothiazazo-8-yl)oxy]acetyl]amino]-2-phenylacetyl]amino]acetic acid or a pharmaceutically acceptable salt thereof.)

[0228] In some embodiments, ASBTI is (GSK2330672; linerixibat; 3-((((3R,5R)-3-butyl-3-ethyl-7-(methoxy)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazazo-8-yl)methyl)amino)glutaric acid) or a pharmaceutically acceptable salt thereof.)

[0229] In some embodiments, the ASBTI described herein is synthesized as described in, for example, WO 96 / 05188, U.S. Patent Nos. 5,994,391; 7,238,684; 6,906,058; 6,020,330; and 6,114,322.

[0230] In some embodiments, the ASBTI used in the methods or compositions of the present invention is macibart (SHP625), vocibart (SHP626), or osticocibart (A4250) or a pharmaceutically acceptable salt thereof.

[0231] In some embodiments, the ASBTI used in the methods or compositions of the present invention is macibat or a pharmaceutically acceptable salt thereof.

[0232] In some embodiments, the ASBTI used in the methods or compositions of the present invention is vosibarb or a pharmaceutically acceptable salt thereof.

[0233] In some embodiments, the ASBTI used in the methods or compositions of the present invention is osthibart or a pharmaceutically acceptable salt thereof.

[0234] In some embodiments, the ASBTI used in the methods or compositions of the present invention is erobixibart or a pharmaceutically acceptable salt thereof.

[0235] In some embodiments, the ASBTI used in the methods or compositions of the present invention is GSK2330672 or a pharmaceutically acceptable salt thereof.

[0236] In some embodiments, ASBTI may comprise a mixture of different ASBTIs; for example, ASBTI may be a composition comprising macibat, vocibat, ovivcibat, GSK2330672, erobicibat or various combinations thereof.

[0237] method This article provides a method for treating or improving cholestatic liver disease in patients who require it, wherein the patients have BSEP deficiency. The method comprises administering a apical sodium-dependent bile acid transport inhibitor (ASBTI) to the patient.

[0238] In some embodiments, cholestatic liver disease includes progressive familial intrahepatic cholestasis (PFIC), type 1 PFIC, type 2 PFIC, type 3 PFIC, Alagille syndrome, Durbin-Johnson syndrome, biliary atresia, post-Kasai biliary atresia, post-liver transplant biliary atresia, post-liver transplant cholestasis, liver transplant-related liver disease, intestinal failure-related liver disease, bile acid-mediated liver injury, pediatric primary sclerosing cholangitis, and MRP2. Deficiency syndrome, neonatal sclerosing cholangitis, obstructive cholestasis in children, non-obstructive cholestasis in children, extrahepatic cholestasis in children, intrahepatic cholestasis in children, primary intrahepatic cholestasis in children, secondary intrahepatic cholestasis in children, benign recurrent intrahepatic cholestasis (BRIC), type 1 BRIC, type 2 BRIC, type 3 BRIC, total parenteral nutrition-related cholestasis, paraneoplastic cholestasis, Stauffer syndrome, drug-related cholestasis, infection-related cholestasis, or cholelithiasis. In some embodiments, cholestatic liver disease is a pediatric form of liver disease.

[0239] In some embodiments, cholestatic liver disease is characterized by one or more of the following symptoms: jaundice, pruritus, cirrhosis, hypercholesterolemia, neonatal respiratory distress syndrome, pneumonia, increased serum bile acid concentration, increased liver bile acid concentration, increased serum bilirubin concentration, hepatocellular damage, liver scarring, liver failure, hepatomegaly, xanthomas, malabsorption, splenomegaly, diarrhea, pancreatitis, hepatocellular necrosis, giant cell formation, hepatocellular carcinoma, gastrointestinal bleeding, portal hypertension, hearing loss, fatigue, loss of appetite, anorexia, foul odor, dark urine, loose stools, steatorrhea, developmental arrest, and / or renal failure.

[0240] In some embodiments, the patient has biliary atresia.

[0241] In some embodiments, the patient has intrahepatic cholestasis of pregnancy (ICP).

[0242] In some embodiments, the method of the present invention comprises non-systemic administration of a therapeutically effective amount of ASBTI. In some embodiments, the method comprises contacting the gastrointestinal tract (including the distal ileum and / or colon and / or rectum) of the individual in need with ASBTI. In various embodiments, the method of the present invention causes a reduction in intracellular bile acids in intestinal cells, or a reduction in damage to hepatocytes or intestinal structures caused by cholestasis or cholestatic liver disease.

[0243] In various embodiments, the method of the present invention comprises delivering a therapeutically effective amount of any ASBTI described herein to the ileum or colon of an individual.

[0244] In various embodiments, the subject suffers from a condition associated with, caused by, or partially caused by BSEP deficiency. In some embodiments, conditions associated with, caused by, or partially caused by BSEP deficiency include neonatal hepatitis, primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), PFIC 2, benign recurrent intrahepatic cholestasis (BRIC), intrahepatic cholestasis of pregnancy (ICP), drug-induced cholestasis, oral contraceptive-induced cholestasis, biliary atresia, or combinations thereof.

[0245] In various embodiments, the method of the present invention comprises reducing damage to hepatocytes or intestinal structures or cells caused by cholestasis or cholestatic liver disease, comprising administering a therapeutically effective amount of ASBTI. In some embodiments, the method of the present invention comprises reducing intracellular bile acids / salts by administering a therapeutically effective amount of ASBTI to an individual in need of it.

[0246] In some embodiments, the method of the present invention provides inhibition of bile salt recirculation when administered to an individual of any of the compounds described herein. In some embodiments, the ASBTIs described herein are systemically absorbed upon administration. In some embodiments, the ASBTIs described herein are not systemically absorbed. In some embodiments, the ASBTIs described herein are administered to an individual orally. In some embodiments, the ASBTIs described herein are delivered and / or released in the distal ileum of an individual.

[0247] In various embodiments, contacting the distal ileum of an individual with an ASBTI (e.g., any ASBTI described herein) inhibits bile acid reuptake and increases the concentration of bile acids / salts near L-cells in the distal ileum and / or colon and / or rectum, thereby reducing intestinal bile acids, reducing serum and / or hepatic bile acid levels, alleviating total serum bile acid load, and / or mitigating damage to ileal structures caused by cholestasis or cholestatic liver disease. Without being limited to any particular theory, lowering serum and / or hepatic bile acid levels may improve hypercholesterolemia and / or cholestatic diseases.

[0248] The compounds described herein may be administered in any suitable manner, including, by way of non-limiting example, oral, enteral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, oral, topical, rectal, or transdermal administration. Any compound or composition described herein may be administered in a method or formulation suitable for treating a newborn or infant. Any compound or composition described herein may be administered in the form of an oral formulation (e.g., solid or liquid) for treating a newborn or infant. Any compound or composition described herein may be administered before, with, or after food intake.

[0249] In some embodiments, the compounds described herein or compositions comprising the compounds are administered for preventative and / or therapeutic treatment. In therapeutic applications, the composition is administered to an individual who already suffers from the disease or condition in an amount sufficient to cure or at least partially suppress the symptoms of the disease or condition. In various cases, the effective amount for this purpose depends on the severity and course of the disease or condition, prior treatment, the individual's health status, weight, and response to the drug, as well as the judgment of the treating physician.

[0250] In preventative applications, the compounds described herein or compositions containing those compounds may be administered to individuals susceptible to a particular disease, disability, or condition, or otherwise at risk of such a disease, disability, or condition. In some embodiments of this use, the precise amount of compound administered depends on the individual's health status, weight, etc. Furthermore, in some cases, the effective amount for this use when the compounds or compositions described herein are administered to an individual depends on the severity and course of the disease, disability, or condition, prior treatment, the individual's health status and response to the medication, and the judgment of the treating physician.

[0251] In some embodiments of the method of the present invention, where an individual’s condition does not improve after administration of a selected dose of the compound or composition described herein, the compound or composition described herein may optionally be administered chronically, i.e., for an extended period of time, including throughout the individual’s lifespan, in order to improve or otherwise control or limit the symptoms of the individual’s disorder, disease or condition.

[0252] In some embodiments of the method of the present invention, the effective amount of a given agent varies according to one or more of a number of factors, such as a particular compound, a disease or condition and its severity, characteristics of the subject or host requiring treatment (e.g., weight), and is determined based on specific circumstances surrounding the case, including, for example, the specific agent to be administered, the route of administration, the condition to be treated, and the subject or host to be treated. In some embodiments, the administered dose includes at most the highest tolerable dose. In some embodiments, the administered dose includes at most the highest tolerable dose for a newborn or infant.

[0253] In various embodiments of the method of the invention, the desired dose is conveniently available in the form of a single dose or fractional dose administered simultaneously (or over a short period of time) or at appropriate intervals, for example, in the form of sub-dose administered twice, three, four, or more times daily. In various embodiments, a single dose of ASBTI is administered every 6 hours, every 12 hours, every 24 hours, every 48 hours, every 72 hours, every 96 hours, every 5 days, every 6 days, or weekly. In some embodiments, the total single dose of ASBTI is within the range described below.

[0254] In various embodiments of the method of the present invention, where the patient’s condition has indeed improved, ASBTI may optionally be administered continuously, at the physician’s discretion; alternatively, the dosage of the drug to be administered may be temporarily reduced or temporarily discontinued for a certain period of time (i.e., a “drug holiday”). The length of the drug holiday may optionally vary between 2 days and 1 year, and includes, by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days. Dosage reduction during medication breaks includes 10%-100% of the original dose, and by way of example only, includes 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 range described below.

[0255] Once improvement in the patient's condition has been observed, a maintenance dose may be administered if necessary. Subsequently, as a function of symptoms, the dose or frequency of administration, or both, may be reduced to the level that preserves the improvement in the disease, disorder, or condition. In some embodiments, the patient requires intermittent treatment on a long-term basis in the event of any recurrence of symptoms.

[0256] In some cases, numerous variables exist regarding individual treatment regimens, and considerable deviations from these recommendations are considered within the scope described herein. The dosages described herein may optionally vary depending on many variables, such as, by way of non-limiting example, the activity of the compound used, the disease or condition to be treated, the mode of administration, the individual subject's requirements, the severity of the disease or condition to be treated, and the physician's judgment.

[0257] The toxicity and efficacy of such treatment regimens may optionally be determined by pharmaceutical procedures in cell cultures or laboratory animals, including but not limited to determining LD50. 50 (The dose that would be fatal to 50% of the population) and ED 50 (The dose effective for 50% of the population). The dose ratio of toxicity to therapeutic effect is the therapeutic index, which can be expressed as LD50. 50 With ED 50 The ratio between [specific values]. Compounds exhibiting a high therapeutic index are preferred. In some embodiments, data obtained from cell culture assays and animal studies were used to formulate a series of doses for human use. In specific embodiments, the doses of the compounds described herein are within the range of ED (extra-exposure prophylaxis) with minimal toxicity. 50 The cyclic concentration range is specified. The dosage may optionally vary within this range, depending on the dosage form and route of administration.

[0258] In some embodiments, the composition used or applied comprises one or more of an absorption inhibitor, a carrier, and a cholesterol absorption inhibitor, an enteric peptide, a peptidase inhibitor, a spreading agent, and a wetting agent.

[0259] In some embodiments of the method of the present invention, the composition for preparing an oral dosage form or for oral administration comprises an absorption inhibitor, a suitable oral carrier, optionally a cholesterol absorption inhibitor, optionally an enteroendocrine peptide, optionally a peptidase inhibitor, optionally a spreading agent, and optionally a wetting agent. In some embodiments, the orally administered composition induces an anorectal reaction. In specific embodiments, an anorectal reaction is an increase in the secretion of one or more enteroendocrine secretions by cells in the colon and / or rectum (e.g., L cells of the epithelial layer of the colon, ileum, rectum, or a combination thereof). In some embodiments, the anorectal reaction 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 a period between 24 and 48 hours, while in other embodiments, the anorectal reaction lasts for a period longer than 48 hours.

[0260] Genotyping In various embodiments, BSEP deficiency is progressive familial intrahepatic cholestasis (PFIC 2), benign recurrent intrahepatic cholestasis, or intrahepatic cholestasis of pregnancy. In various embodiments, the patient has residual BSEP function. In various embodiments, the patient has at least approximately 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 25%, 20%, 5%, 2.5%, or 1% BSEP function relative to a healthy individual without cholestatic liver disease. In various embodiments, the patient has a maximum of approximately 99%, 95%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 25%, 20%, 5%, or 2.5% BSEP function relative to a healthy individual without cholestatic liver disease. BSEP deficiency can lead to impaired or reduced bile flow or bile stasis.

[0261] In various embodiments, BSEP deficiency is caused by… ABCB11 Caused by mutations in genes. In various embodiments... ABCB11 The mutation in the gene is a non-truncated mutation. Generally speaking, ABCB11 Truncated mutations in genes can result in the encoding of BSEP lacking residual function (“severe” mutations). In various embodiments, ABCB11 Genes include mutations, but do not include any truncated mutations. ABCB11 Gene mutations can be missense or nonsense mutations, insertions, or deletions. In some embodiments, ABCB11 The gene includes the E297G or D482G mutation, which may alternatively be referred to as a “mild” mutation or “mild PFIC 2”. In some embodiments, ABCB11 The gene contains a missense mutation, but does not include the E297G or D482G missense mutations, and is instead referred to as a “moderate” mutation or “moderate PFIC 2”. ABCB11 Genes may include E297G, D482G, substitutional missense mutations, insertions, deletions, and various combinations thereof. In various embodiments, substitutional missense mutations may be selected from Byrne et al. ABCB11 Missense mutations and single nucleotide polymorphisms in bile salt export pumps impair bile salt output pump processing and function or disrupt messenger ribonucleic acid precursor splicing. ABCB11ImpairBile Salt Export Pump Processing and Function or Disruption Pre-Messenger RNA Splicing), Hepatology Hepatology) One of the mutations listed in 49:553-567 (2009) (which is incorporated herein by reference in its entirety for all purposes).

[0262] In various embodiments, the patient has a complete loss of BSEP activity. In various embodiments, the patient with a complete loss of BSEP activity is associated with a mutation (e.g., a truncated or frameshift mutation) that results in a complete loss of the BSEP-encoding activity. ABCB11 The gene is homozygous. In various embodiments, the patient has residual BSEP activity. In various embodiments, the patient with residual BSEP activity is associated with a mutation that results in the complete loss of the encoded BSEP activity. ABCB11 The gene is heterozygous (e.g., has a truncated mutation). ABCB11 Genes and wild type ABCB11 Patients with genes or those carrying truncated mutations ABCB11 Genes and mutations encoding BSEP ABCB11 Patients with the gene (possessing residual BSEP activity but with reduced activity relative to wild-type BSEP). In some embodiments, patients with residual BSEP activity are those with mutations that result in residual BSEP activity and reduced BSEP activity relative to wild-type. ABCB11 The gene is homozygous (e.g., has the same or different missense mutations). ABCB11 Patients with the gene). In some embodiments, patients with residual BSEP activity are those with mutations that result in residual BSEP activity and reduced BSEP activity relative to wild type. ABCB11 The gene is heterozygous (e.g., has wild-type). ABCB11 Genes and those with missense mutations ABCB11 (Patients with genetic predispositions).

[0263] In various embodiments, the method includes determining the patient's genotype. Determining the genotype may include any of the various methods known in the art for determining a patient's gene sequence, including, as non-limiting examples, restriction fragment length polymorphism (RFLP) identification of genomic DNA, random amplification polymorphism (RAP) detection of genomic DNA, amplified fragment length polymorphism (APLP) detection, polymerase chain reaction (PCR), DNA sequencing, allele-specific oligonucleotide probes, hybridization with DNA microarrays or beads, and various combinations thereof. In various embodiments, determining the genotype includes determining... ABCB11 The sequence of a gene.

[0264] In some embodiments, the method includes determining a genotype, which includes identification and characterization. ABCB11 Mutations in genes. Determining a genotype may include determining... ABCB11 A portion or all of the gene sequence. Genotyping may further include determining... ABCB11 Sequence or determination of the genomic region surrounding the gene ABCB11 The sequence of one or more introns and / or exons of a gene. Genotyping can include identifying the patient's... ABCB11 Characterized by one, more, or all mutations in the gene encoding alleles. ABCB11 Genes. In various embodiments, determining the genotype includes determining... ABCB11 Does the gene have truncated mutations, insertions, deletions, missense mutations, E297G mutations, D482G mutations, splice site mutations, nonsense mutations, frameshift mutations, or any combination thereof?

[0265] dose In various embodiments, the patient is a pediatric patient aged 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 years of age. In some embodiments, the pediatric patient is a newborn, a preterm newborn, an infant, a toddler, a preschool child, a school-aged child, a pre-pubescent child, a post-pubescent child, an adolescent, or a adolescent under the age of 18. In some embodiments, the pediatric patient is a newborn, a preterm newborn, an infant, a toddler, a preschool child, or a school-aged child. In some embodiments, the pediatric patient is a newborn, a preterm newborn, an infant, a toddler, or a preschool child. In some embodiments, the pediatric patient is a newborn, a preterm newborn, an infant, or a toddler. In some embodiments, the pediatric patient is a newborn, a preterm newborn, or an infant. In some embodiments, the pediatric patient is a newborn. In some embodiments, the pediatric patient is an infant. In some embodiments, the pediatric patient is a toddler.

[0266] In some embodiments, the patient is an adult aged 18, 20, 30, 40, 50, 60, or 70 years or older.

[0267] In various embodiments, ASBTI is macibart, oscibart, or a pharmaceutically acceptable salt thereof.

[0268] In various embodiments, the efficacy and safety of ASBTI administration to patients are monitored by measuring serum levels of 7α-hydroxy-4-cholesten-3-one (7αC4), sBA concentration, the 7αC4:sBA ratio (7αC4:sBA), serum bilirubin concentration, serum ALT concentration, serum AST concentration, or combinations thereof. In various embodiments, the efficacy of ASBTI administration is measured by monitoring observer-reported pruritus report outcome (ITCHRO(OBS)) scores, HRQoL (e.g., PedsQL) scores, CSS scores, height Z-scores, weight Z-scores, or various combinations thereof. In various embodiments, the method includes monitoring serum levels of 7α-hydroxy-4-cholesten-3-one (7αC4), sBA concentration, the 7αC4:sBA ratio (7αC4:sBA), serum bilirubin concentration, serum ALT concentration, serum AST concentration, or combinations thereof. In various embodiments, the method includes monitoring observer-reported itch report outcome (ITCHRO(OBS)) scores, HRQoL (e.g., PedsQL) scores, CSS scores, height Z-scores, weight Z-scores, or various combinations thereof.

[0269] In some embodiments, ASBTI is administered at a dose of 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, 200 µg / kg, 240 µg / 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, 1500 µg / kg, 1,600 µg / kg, 1,700 µg / kg, 1,800 µg / kg, 1,900 µg / kg or 2,000 µg / kg.In some embodiments, the ASBTI is present at no more than 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, 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, 200 µg / kg, 240 µg / kg, 280 µg / kg, 300 µg / kg, 250µg / 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 or 2,100 µg / kg. In some embodiments, ASBTI is administered at doses of about or at least about 0.5 mg / day, 1 mg / day, 2 mg / day, 3 mg / day, 4 mg / day, 5 mg / day, 6 mg / day, 7 mg / day, 8 mg / day, 9 mg / day, 10 mg / day, 11 mg / day, 12 mg / day, 13 mg / day, 14 mg / day, 15 mg / day, 16 mg / day, 17 mg / day, 18 mg / day, 19 mg / day, 20 mg / day, 30 mg / day, 40 mg / day, 50 mg / day, 60 mg / day, 70 mg / day, 80 mg / day, 90 mg / day, 100 mg / day, 150 mg / day, 200 mg / day, 300 mg / day, 500 mg / day, 600 mg / day, 700 mg / day, 800 mg / day, 900 mg / day, and 1000 mg / day.In various embodiments, ASBTI was administered at doses not exceeding about 1 mg / day, 2 mg / day, 3 mg / day, 4 mg / day, 5 mg / day, 6 mg / day, 7 mg / day, 8 mg / day, 9 mg / day, 10 mg / day, 11 mg / day, 12 mg / day, 13 mg / day, 14 mg / day, 15 mg / day, 16 mg / day, 17 mg / day, 18 mg / day, 19 mg / day, 20 mg / day, 30 mg / day, 40 mg / day, 50 mg / day, 60 mg / day, 70 mg / day, 80 mg / day, 90 mg / day, 100 mg / day, 150 mg / day, 200 mg / day, 300 mg / day, 500 mg / day, 600 mg / day, 700 mg / day, 800 mg / day, 900 mg / day, 1,000 mg / day, and 1,100 mg / day.

[0270] In some embodiments, ASBTI is administered at a dose of about 140 g / kg / day to about 1400 g / kg / day. In various embodiments, ASBTI was administered at approximately or at least about 0.5 µg / kg / day, 1 µg / kg / day, 2 µg / kg / day, 3 µg / kg / day, 4 µg / kg / day, 5 µg / kg / day, 6 µg / kg / day, 7 µg / kg / day, 8 µg / kg / day, 9 µg / kg / day, 10 µg / kg / day, 15 µg / kg / day, 20 µg / kg / day, 25 µg / kg / day, 30 µg / kg / day, 35 µg / kg / day, 40 µg / kg / day, 45 µg / kg / day, 50 µg / kg / day, 100 µg / kg / day, 140 µg / kg / day, 150 µg / kg / day, 200 µg / kg / day, 240 µg / kg / day, 280 µg / kg / day, 300 µg / kg / day. Doses can be administered at the following rates: 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, or 1,300 µg / kg / day.In various embodiments, ASBTI was used at rates not exceeding approximately 1 µg / kg / day, 2 µg / kg / day, 3 µg / kg / day, 4 µg / kg / day, 5 µg / kg / day, 6 µg / kg / day, 7 µg / kg / day, 8 µg / kg / day, 9 µg / kg / day, 10 µg / kg / day, 15 µg / kg / day, 20 µg / kg / day, 25 µg / kg / day, 30 µg / kg / day, 35 µg / kg / day, 40 µg / kg / day, 45 µg / kg / day, 50 µg / kg / day, 100 µg / kg / day, 140 µg / kg / day, 150 µg / kg / day, 200 µg / kg / day, 240 µg / kg / day, 280 µg / kg / day, 300 µg / kg / day, 250 µg / kg / day, 28 ... Doses can be administered at the following rates: 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 was administered at doses ranging from 0.5 µg / kg / day to approximately 500 µg / kg / day, from approximately 0.5 µg / kg / day to approximately 250 µg / kg / day, from approximately 1 µg / kg / day to approximately 100 µg / kg / day, from approximately 10 µg / kg / day to approximately 50 µg / kg / day, from approximately 10 µg / kg / day to approximately 100 µg / kg / day, from approximately 0.5 µg / kg / day to approximately 2000 µg / kg / day, from approximately 280 µg / kg / day to approximately 1400 µg / kg / day, from approximately 420 µg / kg / day to approximately 1400 µg / kg / day, from approximately 250 µg / kg / day to approximately 550 µg / kg / day, from approximately 560 µg / kg / day to approximately 1400 µg / kg / day, from approximately 700 µg / kg / day to approximately 1400 µg / kg / day, and from approximately 560 µg / kg / day to approximately 1200 µg / kg / day. µg / kg / day, approximately 700 µg / kg / day to approximately 1200 µg / kg / day, approximately 560 µg / kg / day to approximately 1000 µg / kg / day, approximately 700 µg / kg / day to approximately 1000 µg / kg / day, approximately 800 µg / kg / day to approximately 1000 µg / kg / day, approximately 200 µg / kg / day to approximately 600 µg / kg / day, approximately 300 µg / kg / day to approximately 600 µg / kg / day, approximately 400 µg / kg / day to approximately 500 µg / kg / day, approximately 400 µg / kg / day to approximately 600 µg / kg / day, approximately 400 µg / kg / day to approximately 700 µg / kg / day, approximately 400 µg / kg / day to approximately 800 µg / kg / day, approximately 500 µg / kg / day to approximately 800 µg / kg / day, approximately 500 µg / kg / day to approximately 800 µg / kg / day, approximately 500 µg / kg / day Doses of approximately µg / kg / day to about 900 µg / kg / day, approximately 600 µg / kg / day to about 900 µg / kg / day, approximately 700 µg / kg / day to about 900 µg / kg / day, approximately 200 µg / kg / day to about 600 µg / kg / day, approximately 800 µg / kg / day to about 900 µg / kg / day, approximately 100 µg / kg / day to about 1500 µg / kg / day, approximately 300 µg / kg / day to about 2000 µg / kg / day, or approximately 400 µg / kg / day to about 2000 µg / kg / day are administered.

[0271] 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 doses of approximately 0.5 µg / kg to approximately 2000 µg / kg, approximately 0.5 µg / kg to approximately 1500 µg / kg, approximately 100 µg / kg to approximately 700 µg / kg, approximately 5 µg / kg to approximately 100 µg / kg, approximately 10 µg / kg to approximately 500 µg / kg, approximately 50 µg / kg to approximately 1400 µg / kg, approximately 300 µg / kg to approximately 2000 µg / kg, approximately 60 µg / kg to approximately 1200 µg / kg, approximately 70 µg / kg to approximately 1000 µg / kg, approximately 70 µg / kg to approximately 700 µg / kg, approximately 80 µg / kg to approximately 1000 µg / kg, approximately 80 µg / kg to approximately 800 µg / kg, and approximately 100 µg / kg to approximately 800 µg / kg. Administered at doses of µg / kg, from 100 µg / kg to about 600 µg / kg, from 150 µg / kg to about 700 µg / kg, from 150 µg / kg to about 500 µg / kg, from 200 µg / kg to about 400 µg / kg, from 200 µg / kg to about 300 µg / kg, or from 300 µg / kg to about 400 µg / kg.

[0272] 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 doses of approximately 1 mg / day to approximately 500 mg / day, approximately 1 mg / day to approximately 300 mg / day, approximately 1 mg / day to approximately 200 mg / day, approximately 2 mg / day to approximately 300 mg / day, approximately 2 mg / day to approximately 200 mg / day, approximately 4 mg / day to approximately 300 mg / day, approximately 4 mg / day to approximately 200 mg / day, approximately 4 mg / day to approximately 150 mg / day, approximately 5 mg / day to approximately 150 mg / day, approximately 5 mg / day to approximately 100 mg / day, approximately 5 mg / day to approximately 80 mg / day, approximately 5 mg / day to approximately 50 mg / day, approximately 5 mg / day to approximately 40 mg / day, approximately 5 mg / day to approximately 30 mg / day, approximately 5 mg / day to approximately 20 mg / day, approximately 5 mg / day to approximately 15 mg / day, approximately 10 mg / day to approximately 100 mg / day, approximately 10 mg / day to approximately 80 mg / day, and approximately 10 mg / day to approximately 50 mg / day. Administered at doses of approximately 10 mg / day to approximately 40 mg / day, approximately 10 mg / day to approximately 20 mg / day, approximately 20 mg / day to approximately 100 mg / day, approximately 20 mg / day to approximately 80 mg / day, approximately 20 mg / day to approximately 50 mg / day, or approximately 20 mg / day to approximately 40 mg / day, or approximately 20 mg / day to approximately 30 mg / day.

[0273] In various embodiments, the dose of ASBTI is a first dose level. In various embodiments, the dose of ASBTI is a second dose level. In some embodiments, the second dose level is greater than the first dose level. In some embodiments, the second dose level is about or at least about 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, or 100 times or multiples of the first dose level. In some embodiments, the second dose level does not exceed about 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, or 150 times or multiples of the first dose level.

[0274] In various embodiments, ASBTI is administered once daily (QD) at one of the above-described doses or within one of the above-described dose ranges. In various embodiments, ASBTI is administered twice daily (BID) at one of the above-described doses or within one of the above-described dose ranges. In various embodiments, ASBTI doses are administered daily, every other day, twice weekly, or once weekly.

[0275] In various embodiments, ASBTI is applied periodically for a period of approximately or at least approximately 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 applied for a period of no more than approximately 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 applied periodically for a period of about 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, or 10 years. In various embodiments, ASBTI is applied periodically for a period of no more than about 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 15 years.

[0276] Dosage adjustment In various embodiments, the method includes adjusting the dose of ASBTI administered to the patient. The adjustment includes determining the patient's 7αC4:sBA ratio at baseline (e.g., before ASBTI administration or before adjusting (e.g., increasing) the dose of ASBTI), and further determining the 7αC4:sBA ratio after administering ASBTI at a first dose or adjusting (e.g., increasing) the dose 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 times, then an increase is made. The dose of ASBTI is increased until the ratio increases by at least about 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 75, 100, 150, 200, 300, 500, 750, 1,000, 2,000, 3,000, 4,000, 5,000, or 10,000 times relative to baseline. In various embodiments, the dose of ASBTI is increased or decreased to achieve and maintain a specific 7αC4:sBA ratio.

[0277] In various embodiments, the adjustment includes if the 7αC4:sBA ratio is initially increased 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 times, and then begins to decrease or reduce... If the dose of ASBTI is 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 75, 100, 150, 200, 300, 500, 750, 1,000, 2,000, 3,000, 4,000, 5,000, or 10,000 times or more lower than the baseline, the dose of ASBTI should be increased from the first dose level to a second dose level greater than the first dose level. Increase the dose level until the 7αC4:sBA A ratio increases from baseline to at least 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 75, 100, 150, 200, 300, 500, 750, 1,000, 2,000, 3,000, 4,000, 5,000, or 10,000 times.

[0278] In some embodiments, the adjustment includes administering a first dose of ASBTI to the patient. 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 times, a second dose of ASBTI higher than the first dose is administered to the patient. Continue to increase the dose administered to the patient 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 times.

[0279] In various embodiments, the 7αC4:sBA ratio is measured approximately daily, every two weeks, weekly, every two months, monthly, every two months, every three months, every four months, every five months, every six months, or annually, and the dose of ASBTI is adjusted as needed each time the ratio is measured.

[0280] Predicting patient response based on genotype In one aspect of the invention, a predictive method is provided for predicting a patient's response to treatment for cholestatic liver disease. The treatment includes administering ASBTI to a patient requiring such treatment. The method includes determining the patient's genotype as described above and predicting the patient's response to treatment based on that genotype. In various embodiments, the patient has BSEP deficiency. In some embodiments, the patient has PFIC 2.

[0281] In various embodiments, the prediction method includes predicting if ABCB11 If a gene contains a truncated mutation, the patient will not respond to ASBTI administration. In some embodiments, the method includes predicting if... ABCB11 If a gene contains a mutation that results in the absence of any residual BSEP activity in a patient (i.e., complete loss of BSEP activity), the patient will not respond to ASBTI administration. In some embodiments, the method includes predicting whether a patient has a genotype corresponding to complete absence or loss of BSEP activity (e.g., a genotype that does not include BSEP activity). ABCB11 If the genomic sequence of the untruncated allele of the gene is not specified, then the patient will not respond to ASBTI administration. In various embodiments, the prediction method includes if... ABCB11 The gene contains mutations that lead to residual BSEP activity and ABCB11 If the gene does not contain mutations that result in the absence of BSEP activity, then the patient is predicted to respond to ASBTI administration. Those skilled in the art will understand that if the patient has at least one functional... ABCB11 If the gene's genome is affected, the patient will have residual BSEP activity.

[0282] In some embodiments, the prediction method includes predicting if ABCB11 If the gene contains an E297G mutation or a D482G mutation, the method further includes predicting whether the patient will respond to ASBTI administered at the first-day dose. Additionally, if... ABCB11 If the gene contains a substitutional missense mutation instead of the E287G or D482G mutation, the method further includes predicting that the patient will respond to administration of ASBTI at a second-day dose, wherein the second-day dose is greater than the first-day dose. If a patient is predicted to respond to ASBTI administration, the method further includes administering ASBTI to the patient at either the first-day dose or the second-day dose. In various embodiments, if a patient is predicted not to respond to ASBTI treatment, ASBTI is not administered to the patient.

[0283] Treatment methods using genotype information In one aspect of the invention, a method is provided for treating or improving cholestatic liver disease in a patient who requires it, wherein the patient has BSEP deficiency. The method includes determining the patient's genotype as described above. As described above, the method further includes using the patient's genotype to predict whether the patient will respond to treatment with ASBTI. The method further includes administering ASBTI to the patient if a response to ASBTI administration is predicted. In various embodiments, BSEP deficiency is PFIC2.

[0284] In various embodiments, the method of the present invention includes if ABCB11 If the gene contains an E297G or D482G mutation, the first dosing regimen of ASBTI is followed. If the ABCB11 gene contains a missense mutation but does not contain an E297G or D482G mutation, the second dosing regimen of ASBTI is followed. In some embodiments, the first dosing regimen includes administering a first-day dose of ASBTI, and the second dosing regimen includes administering a second total-day dose of ASBTI, wherein the first total-day dose is greater than the second total-day dose.

[0285] In various embodiments, the first dosing regimen is not equivalent to the second dosing regimen in terms of frequency of administration, dosage, or combination thereof. The first and second dosing regimens may include any of the various dosing frequencies listed above, any of the various dosage levels listed above administered to the patient, and various combinations thereof.

[0286] Cholestatic liver disease Symptom relief or changes in disease-related laboratory measurements In various embodiments of the method described above, administration of ASBTI leads to a reduction in symptoms of cholestatic liver disease or a change in disease-related laboratory measurements (i.e., improvement in the patient's condition), which is maintained for about or at least about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, or 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, symptom relief or changes in disease-related laboratory measurements include a decrease in sBA concentration, an increase in serum 7αC4 concentration, an increase in the 7αC4:sBA ratio, an increase in fBA excretion, relief of pruritus, a decrease in ALT levels, an increase in a quality of life checklist score, an increase in a fatigue-related quality of life checklist score, or various combinations thereof. In various embodiments, symptom relief or changes in disease-related laboratory measurements are determined relative to baseline levels. That is, symptom relief or changes in disease-related laboratory measurements are determined relative to symptom measurements or prior to 1) changing the dose level of ASBTI administered to the patient, 2) changing the dosing regimen followed by the patient, 3) initiating ASBTI administration, or 4) any other various changes made with the aim of reducing the patient's symptoms or changes in disease-related laboratory measurements. In various embodiments, symptom relief or changes in disease-related laboratory measurements are statistically significant reductions.

[0287] In some embodiments, the patient is a pediatric patient, and the reduction of symptoms or changes in disease-related laboratory measurements include an increase in growth. In some embodiments, the increase in growth is measured relative 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 relative to baseline 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, or 0.29. 0.3, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, 0.4, 0.41, 0.42, 0.43, 0.44, 0.45, 0.46, 0.47, 0.48, 0.49, 0.5, 0.51, 0.52, 0.53, 0.54, 0.55, 0.56, 0.57, 0.58, 0.59, 0.6, 0.7, 0.8, or 0.9. In some embodiments, the height Z-score, weight Z-score, or both gradually increase during a period of approximately or at least approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 48, 50, 60, 70, or 72 weeks of ASBTI administration.

[0288] In various embodiments, administration of ASBTI resulted in an increase in serum 7αC4 concentration. In various embodiments, the serum 7αC4 concentration increased relative to baseline by about or at least about 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, or 500 times or multiples. In various embodiments, the serum 7αC4 concentration increased relative to baseline 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%.

[0289] In various embodiments, administration of ASBTI resulted in an increase in the 7αC4:sBA ratio relative to baseline of approximately or at least about 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 75, 100, 150, 200, 300, 500, 750, 1,000, 2,000, 3,000, 4,000, 5,000, or 10,000 times.

[0290] 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 relative to baseline 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%. In various embodiments, fBA excretion increases relative to baseline by about or at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100 times or multiples. In some embodiments, fBA excretion increases relative to baseline by about or at least about 100 µmol, 150 µmol, 200 µmol, 250 µmol, 300 µmol, 400 µmol, 500 µmol, 600 µmol, 700 µmol, 800 µmol, 900 µmol, 1,000 µmol, or 1,500 µmol. In various embodiments, administration of ASBTI results in a dose-dependent increase in fBA excretion, such that administration of a higher dose of ASBTI results in a correspondingly higher level of fBA excretion. In various embodiments, ASBTI is administered at a dose sufficient to cause an increase in bile acid secretion relative to baseline of at least about 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100 times or multiples.

[0291] 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, ITCHRO score, CSS score, or a combination thereof. In various embodiments, administration of ASBTI results in a reduction of the ITCHRO (OBS) score on a scale of 1 to 4 relative to baseline of about or at least about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.25, 2.5, or 3. In various embodiments, administration of ASBTI results in a reduction of the ITCHRO score on a scale of 1 to 10 by 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 reduction of the ITCHRO (OBS) score, the ITCHRO score, or both to zero. In various embodiments, administration of ASBTI results in a reduction of the ITCHRO (OBS) score or the ITCHRO score to 1.0 or lower. In various embodiments, application of ASBTI results in a CSS score reduction relative to baseline of about or at least about 0.1, 0.2, 0.3, 0.4, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.25, 2.5, or 3. In various embodiments, application of ASBTI results in a CSS score reduction to zero. In various embodiments, application of ASBTI results in a CSS score, ITCHRO (OBS) score, ITCHRO score, or a combination thereof reducing the score relative to baseline by about or at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. In various embodiments, a decrease in CSS score, ITCHRO (OBS) score, ITCHRO score, or a combination thereof relative to baseline was 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.

[0292] In various embodiments, administration of ASBTI results in an increase in a quality of life inventory score, or an increase in a fatigue-related quality of life inventory score. The quality of life inventory score may 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 a fatigue-related PedsQL score relative to baseline of about or at least about 5%, 10%, 15%, 20%, 25%, 30%, 45%, or 50%.

[0293] In various embodiments, administration of ASBTI resulted in approximately 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, ... Symptom reduction or changes in disease-related laboratory measurements at 3 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.

[0294] In various embodiments, serum bilirubin concentrations were observed at approximately 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, and 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 or approximately before that at the baseline level before application, or at the normal level.

[0295] In various embodiments, serum ALT concentrations were observed at approximately 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, and 26 weeks. The ASBTI administration results in a decrease in ALT levels relative to baseline of approximately 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, or 15% compared to baseline. The ASBTI administration is administered at approximately 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52 weeks or 1 year prior to administration, or at normal levels. In some embodiments, ASBTI administration results in a decrease in ALT levels relative to baseline of approximately 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, or 15%.

[0296] In various embodiments, serum ALT concentration, serum AST concentration, serum bilirubin concentration, or various combinations thereof, are measured at approximately 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, and 23 weeks. Weeks 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, or 1 year prior to application, within the normal range or at the pre-application baseline level. In various embodiments, administration of ASBTI did not result in serum bilirubin concentrations, serum AST concentrations, serum ALT concentrations, serum alkaline phosphatase concentrations, or combinations thereof, at least for 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. Statistically significant changes from baseline within timeframes of 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52 weeks, or 1 year.

[0297] Pharmaceutical Composition In some embodiments, ASBTI is administered as a pharmaceutical composition (or composition) containing ASBTI. Any composition described herein may be formulated for ileal, rectal, and / or colonic delivery. In more specific embodiments, the composition is formulated for non-systemic or local delivery to the rectum and / or colon. It should be understood that, as used herein, delivery to the colon includes delivery to the S-shaped colon, transverse colon, and / or ascending colon. In more specific embodiments, rectal administration is formulated for non-systemic or local delivery to the rectum and / or colon. In other specific embodiments, oral administration is formulated for non-systemic or local delivery to the rectum and / or colon.

[0298] In some embodiments, this document provides a pharmaceutical composition comprising a therapeutically effective amount of any of the compounds described herein. In some cases, the pharmaceutical composition comprises an ASBT inhibitor (e.g., any ASBTI described herein).

[0299] In some embodiments, pharmaceutical compositions are formulated in a conventional manner using one or more physiologically acceptable carriers, said carriers comprising, for example, excipients and adjuvants that facilitate the processing of the active compound into a formulation suitable for pharmaceutical use. In some embodiments, the appropriate formulation depends on the chosen route of administration. A summary of the pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmaceuticals. The Science and Practice of Pharmacy ), 19th edition (Easton, Pennsylvania: Mack Publishing Co., 1995); Hoover, John E., Remington Pharmaceutical Sciences ( Remington's Pharmaceutical Sciences ), Mack Publishing Co., Easton, Pennsylvania, 1975; Liberman, HA and Lachman, L., Eds., Pharmaceutical Dosage Forms ( Pharmaceutical Dosage Forms ), Mareel Decker, New York, 1980; and drug dosage forms and drug delivery systems ( Pharmaceutical Dosage Forms and Drug Delivery Systems The seventh edition (Lippincott Williams & Wilkins, 1999) can be found in the entirety of this article for all purposes.

[0300] As used herein, a pharmaceutical composition refers to a mixture of the compound described herein with other chemical components such as carriers, stabilizers, diluents, dispersants, suspending agents, thickeners, and / or excipients. In some cases, the pharmaceutical composition facilitates the application of the compound to an individual or cell. In some embodiments of the methods of carrying out the treatment or use provided herein, a therapeutically effective amount of the compound described herein is applied in the form of a pharmaceutical composition to an individual suffering from a disease, disorder, or condition to be treated. In certain embodiments, the individual is a person. As discussed herein, the compound described herein may be used alone or in combination with one or more other therapeutic agents.

[0301] In some embodiments, the pharmaceutical formulations described herein are administered to an individual in any manner, including one or more of a variety of routes of administration, such as, as a non-limiting example, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, oral, local, rectal, or transdermal administration routes.

[0302] In some embodiments, the pharmaceutical compositions described herein comprise one or more of the compounds described herein as active ingredients in the form of a free acid or free base or a pharmaceutically acceptable salt. In some embodiments, the compounds described herein are used as N-oxides or in crystalline or amorphous forms (i.e., polymorphs). In some cases, the compounds described herein are present in tautomer forms. All tautomers are included within the scope of the compounds presented herein. In some embodiments, the compounds described herein are present in unsolvated or solvated forms, wherein the solvated forms comprise any pharmaceutically acceptable solvent, such as water, ethanol, etc. The solvated forms of the compounds presented herein are also considered to be those described herein.

[0303] In some embodiments, "carrier" includes pharmaceutically acceptable excipients and is selected based on compatibility with compounds described herein, such as any compound of formulas I-VI, and the release profile properties of the desired dosage form. Exemplary carrier materials include, for example, binders, suspending agents, disintegrants, fillers, surfactants, solubilizers, stabilizers, lubricants, wetting agents, diluents, etc. See, for example, Remington: Pharmaceutical Science and Practice, 19th edition (Easton, PA: Mack Publishing, 1995); Hoover, John E., Remington Pharmaceutical Science, Mack Publishing, Easton, PA, 1975; Lieberman, HA and Lackman, L., Eds. Pharmaceutical Dosage Forms, Mareel Decker, New York, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th edition (Lipincott Williams and Wilkins, 1999), all of which are incorporated herein by reference in their entirety for all purposes.

[0304] Furthermore, in some embodiments, the pharmaceutical compositions described herein are formulated into dosage forms. Therefore, in some embodiments, this document provides a dosage form comprising the compounds described herein, suitable for individual administration. In some embodiments, suitable dosage forms include, as non-limiting examples, aqueous oral dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, solid oral dosage forms, aerosols, controlled-release formulations, rapidly melting formulations, effervescent formulations, lyophilized formulations, tablets, powders, pills, sugar-coated pills, capsules, delayed-release formulations, extended-release formulations, pulsatile-release formulations, multi-particle formulations, and mixed immediate-release and controlled-release formulations.

[0305] In some embodiments, this document provides a composition comprising an enteroendocrine peptide secretion enhancer and optionally a pharmaceutically acceptable carrier for relieving symptoms of cholestasis or cholestatic liver disease in an individual.

[0306] In some embodiments, the composition comprises an enteroendocrine peptide secretion enhancer and an absorption inhibitor. In specific embodiments, the absorption inhibitor is an inhibitor that inhibits the absorption of a specific enteroendocrine peptide secretion enhancer (or at least one) bound thereto. In some embodiments, the composition comprises an enteroendocrine peptide secretion enhancer, an absorption inhibitor, and a carrier (e.g., a suitable oral or rectal carrier, depending on the intended mode of administration). In some embodiments, the composition comprises an enteroendocrine peptide secretion enhancer, an absorption inhibitor, a carrier, and one or more of a cholesterol absorption inhibitor, an enteroendocrine peptide, a peptidase inhibitor, a spreading agent, and a wetting agent.

[0307] In other embodiments, the compositions described herein are administered orally for the non-systemic delivery of ASBTI to the rectum and / or colon, including the S-shaped colon, transverse colon, and / or ascending colon. In specific embodiments, as a non-limiting example, the compositions formulated for oral administration are enteric-coated or formulated into oral dosage forms such as tablets and / or capsules.

[0308] Absorption inhibitors In some embodiments, the compositions described herein formulated for non-systemic delivery of ASBTI include absorption inhibitors. As used herein, absorption inhibitors include agents or groups of agents that inhibit bile acid / salt absorption.

[0309] Suitable bile acid absorption inhibitors (also described herein as absorption inhibitors) may include, as non-limiting examples, anion exchange matrices, polyamines, quaternary ammonium-containing polymers, quaternary ammonium salts, polyallylamine polymers and copolymers, colesevelam, colesevelam hydrochloride, cholestaGel (a polymer of N,N,N-trimethyl-6-(2-propenylamino)-1-hexylamine chloride and (chloromethyl)ethylene oxide, 2-propen-1-amine and N-2-propenyl-1-decylamine hydrochloride), cyclodextrins, chitosan, chitosan derivatives, bile acid-binding carbohydrates, bile acid-binding lipids, bile acid-binding proteins and protein materials, and bile acid-binding antibodies and albumins. Suitable cyclodextrins include those that bind bile acids / salts, such as, as non-limiting examples, β-cyclodextrin and hydroxypropyl-β-cyclodextrin. Suitable proteins include proteins that bind bile acids / salts, such as, as non-limiting examples, bovine serum albumin, ovalbumin, casein, alpha-acid glycoprotein, gelatin, soy protein, peanut protein, almond protein, and wheat plant protein.

[0310] In some embodiments, the absorption inhibitor is cholestyramine. In a specific embodiment, cholestyramine is combined with bile acids. Cholestyramine (an ion exchange resin) is a styrene polymer containing quaternary ammonium groups crosslinked by divinylbenzene. In other embodiments, the absorption inhibitor is colestipol. In a specific embodiment, colestipol is combined with bile acids. Colestipol (an ion exchange resin) is a copolymer of diethylenetriamine and 1-chloro-2,3-epoxypropane.

[0311] In some embodiments of the compositions and methods described herein, ASBTI is linked to an absorption inhibitor, while in other embodiments, ASBTI and the absorption inhibitor are separate molecular entities.

[0312] Cholesterol absorption inhibitors In some embodiments, the compositions described herein optionally include at least one cholesterol absorption inhibitor. Suitable cholesterol absorption inhibitors include, as non-limiting examples, ezetimibe (SCH 58235), ezetimibe analogs, ACT inhibitors, stigmastanyl phosphorylcholine, stigmastanyl phosphorylcholine analogs, β-lactam cholesterol absorption inhibitors, sulfated polysaccharides, neomycin, sponin, phytosterols, phytosterol formulations FM-VP4, sitosterol, β-sitosterol, acyl-CoA:cholesterol-O-acyltransferase (ACAT) inhibitors, avasimibe, impritapide, steroidal glycosides, etc. Suitable ezetimibe analogs include, as non-limiting examples, SCH 48461, SCH 58053, etc. Suitable ACT inhibitors include, as non-limiting examples, trimethoxy fatty acid anilines such as Cl-976, 3-[decyldimethylsilyl]-N-[2-(4-methylphenyl)-1-phenylethyl]-propionamide, methyllinoleamide, etc. β-lactam cholesterol absorption inhibitors include, as non-limiting examples, βR-4S)-1,4-bis-(4-methoxyphenyl)-3-β-phenylpropyl)-2-azacyclobutanone, etc.

[0313] peptidase inhibitors In some embodiments, the compositions described herein optionally comprise at least one peptidase inhibitor. Such peptidase inhibitors include, but are not limited to, dipeptidyl peptidase-4 inhibitors (DPP-4), neutral endopeptidase inhibitors, and invertase inhibitors. As non-limiting examples, suitable dipeptidyl peptidase-4 inhibitors (DPP-4) include vildagliptin, (2S)-1-{2-[β-hydroxy-1-adamantyl)amino]acetyl}pyrrolidine-2-carboxynitrile sitagliptin, (3R)-3-amino-1-[9-(trifluoromethyl)-1,4,7,8-tetraazabicyclo[4.3.0]non-6,8-dien-4-yl]-4-(2,4,5-trifluorophenyl)but-1-one; saxagliptin and (1S,3S,5S)-2-[(2S)-2-amino-2-β-hydroxy-1-adamantyl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carboxynitrile. These neutral endopeptidase inhibitors include, but are not limited to, candoxatrilat and ecadotril.

[0314] Spreading agent / wetting agent In some embodiments, the compositions described herein optionally comprise a spreading agent. In some embodiments, a spreading agent is used to improve the spreading of the composition in the colon and / or rectum. As a non-limiting example, suitable spreading agents include hydroxyethyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol, colloidal silica, propylene glycol, cyclodextrin, microcrystalline cellulose, polyvinylpyrrolidone, polyoxyethylated glycerol ester, polycarbophil, di-n-octyl ether, Cetiol™ OE, fatty alcohol polyalkylene glycol ether, Aethoxal™ B, 2-ethylhexyl palmitate, Cegesoft™ C 24, and isopropyl fatty acid esters.

[0315] In some embodiments, the compositions described herein optionally comprise a wetting agent. In some embodiments, the wetting agent is used to improve the wettability of the composition in the colon and rectum. As a non-limiting example, suitable wetting agents include surfactants. In some embodiments, as a non-limiting example, the surfactant is selected from polysorbates (e.g., 20 or 80), stearyl heptanoate, and surfactants with a chain length of C0. 12 -C 18 Saturated fatty alcohols in the form of caprylic / decanoic acid esters, isostearyl diglyceride isostearic acid, sodium lauryl sulfate, isopropyl myristate, isopropyl palmitate, and mixtures of isopropyl myristate / isopropyl stearate / isopropyl palmitate.

[0316] Vitamins In some embodiments, the method provided herein further comprises administering one or more vitamins.

[0317] In some embodiments, the vitamins are vitamins 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, and menaquinone.

[0318] In some embodiments, the vitamin is a fat-soluble vitamin, such as vitamins A, D, E, K, retinol, beta-carotene, cholecalciferol, tocopherol, and phylloquinone. In a preferred embodiment, the fat-soluble vitamin is tocopherol polyethylene glycol succinate (TPGS).

[0319] Bile acid chelating agents / binding agents In some embodiments, the unstable bile acid chelator is an enzyme-dependent bile acid chelator. In some embodiments, the enzyme is a bacterial enzyme. In some embodiments, the enzyme is a bacterial enzyme found in high concentrations in the human colon or rectum, relative to concentrations found in the small intestine. Examples of microbiota activation systems include formulations comprising glycosidic conjugates (e.g., conjugates of D-galactoside, β-D-xylanopyranoside, etc.) comprising pectin, galactomannan, and / or azo hydrogels and / or activators. Examples of gastrointestinal microbiota enzymes include bacterial glycosidases, such as, for example, D-galactosidase, β-D-glucosidase, α-L-arabinofuranoside, β-D-xylanopyranoside, etc.

[0320] In some embodiments, the unstable bile acid chelating agent is a time-dependent bile acid chelating agent. In some embodiments, the unstable bile acid chelating agent releases bile acids or is degraded after chelation for 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 seconds. In some embodiments, the unstable bile acid chelating agent releases bile acids or is degraded after chelation for 15, 20, 25, 30, 35, 40, 45, 50, or 55 seconds. In some embodiments, the unstable bile acid chelating agent releases bile acids or is degraded after chelation for 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 minutes. In some embodiments, the unstable bile acid chelating agent releases bile acids or is degraded after chelation for approximately 15, 20, 25, 30, 35, 45, 50, or 55 minutes. In some embodiments, the unstable bile acid chelating agent releases bile acids or is degraded after chelation for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours. In some embodiments, the unstable bile acid chelating agent releases bile acids or is degraded after chelation for 1, 2, or 3 days.

[0321] In some embodiments, the unstable bile acid chelating agent has a low affinity for bile acids. In some embodiments, the unstable bile acid chelating agent has a high affinity for primary bile acids and a low affinity for secondary bile acids.

[0322] In some embodiments, the unstable bile acid chelating agent is a pH-dependent bile acid chelating agent. In some embodiments, the pH-dependent bile acid chelating agent has a high affinity for bile acids at pH 6 or lower and a low affinity for bile acids at pH above 6. In some embodiments, the pH-dependent bile acid chelating agent has a high affinity for bile acids at pH 6.5 or lower and a low affinity for bile acids at pH above 6.5. In some embodiments, the pH-dependent bile acid chelating agent has a high affinity for bile acids at pH 7 or lower and a low affinity for bile acids at pH above 7. In some embodiments, the pH-dependent bile acid chelating agent has a high affinity for bile acids at pH 7.1 or lower and a low affinity for bile acids at pH above 7.1. In some embodiments, the pH-dependent bile acid chelator exhibits high affinity for bile acids at pH 7.2 or lower and low affinity at pH above 7.2. In some embodiments, the pH-dependent bile acid chelator exhibits high affinity for bile acids at pH 7.3 or lower and low affinity at pH above 7.3. In some embodiments, the pH-dependent bile acid chelator exhibits high affinity for bile acids at pH 7.4 or lower and low affinity at pH above 7.4. In some embodiments, the pH-dependent bile acid chelator exhibits high affinity for bile acids at pH 7.5 or lower and low affinity at pH above 7.5. In some embodiments, the pH-dependent bile acid chelator exhibits high affinity for bile acids at pH 7.6 or lower and low affinity at pH above 7.6. In some embodiments, the pH-dependent bile acid chelator exhibits high affinity for bile acids at pH 7.7 or lower and low affinity for bile acids at pH above 7.7. In some embodiments, the pH-dependent bile acid chelator exhibits high affinity for bile acids at pH 7.8 or lower and low affinity for bile acids at pH above 7.8. In some embodiments, the pH-dependent bile acid chelator degrades at pH above 6. In some embodiments, the pH-dependent bile acid chelator degrades at pH above 6.5. In some embodiments, the pH-dependent bile acid chelator degrades at pH above 7. In some embodiments, the pH-dependent bile acid chelator degrades at pH above 7.1. In some embodiments, the pH-dependent bile acid chelator degrades at pH above 7.2. In some embodiments, the pH-dependent bile acid chelator degrades at pH above 7.3. In some embodiments, the pH-dependent bile acid chelator degrades at pH above 7.4. In some embodiments, the pH-dependent bile acid chelator degrades at pH values ​​above 7.5.In some embodiments, the pH-dependent bile acid chelating agent degrades at pH values ​​above 7.6. In some embodiments, the pH-dependent bile acid chelating agent degrades at pH values ​​above 7.7. In some embodiments, the pH-dependent bile acid chelating agent degrades at pH values ​​above 7.8. In some embodiments, the pH-dependent bile acid chelating agent degrades at pH values ​​above 7.9.

[0323] In some embodiments, the unstable bile acid chelating agent is lignin or modified lignin. In some embodiments, the unstable bile acid chelating agent is a polycationic polymer or copolymer. In some embodiments, the unstable bile acid chelating agent 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-azaonium residues; one or more N,N,N-trialkyl-N-alkenyl-azaonium residues; one or more alkenylamine residues; or combinations thereof. In some embodiments, the bile acid binder is cholestyramine, and various compositions comprising cholestyramine, which are described, for example, in U.S. Patent 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 herein by reference in their entirety for all purposes). In some embodiments, the bile acid binder is colestipol or colesvelan.

[0324] 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 some embodiments, the compositions described herein are formulated for rectal or oral administration. In some embodiments, such formulations are administered rectally or orally, respectively. In some embodiments, the compositions described herein are combined with a device for locally delivering the composition to the rectum and / or colon (S-shaped colon, transverse colon, or ascending colon). In some embodiments, for rectal administration, the compositions described herein are formulated as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas. In some embodiments, for oral administration, the compositions described herein are formulated for both oral administration and intestinal delivery to the colon.

[0325] In some embodiments, the compositions or methods described herein are non-systemic. In some embodiments, the compositions described herein deliver ASBTI to the distal ileum, colon, and / or rectum rather than systemically (e.g., a significant portion of the enteroendocrine peptide secretion enhancer is not systemically absorbed). In some embodiments, the oral compositions described herein deliver ASBTI to the distal ileum, colon, and / or rectum rather than systemically (e.g., a significant portion of the enteroendocrine peptide secretion enhancer is not systemically absorbed). In some embodiments, the rectal compositions described herein deliver ASBTI to the distal ileum, colon, and / or rectum rather than systemically (e.g., a significant portion of the enteroendocrine peptide secretion enhancer is not systemically absorbed). In some embodiments, the non-systemic compositions described herein deliver less than 90% w / w of ASBTI systemically. In some embodiments, the non-systemic compositions described herein deliver less than 80% w / w of ASBTI systemically. In some embodiments, the non-systemic compositions described herein deliver less than 70% w / w of ASBTI systemically. In some embodiments, the non-systemic composition described herein delivers less than 60% w / w ASBTI systemically. In some embodiments, the non-systemic composition described herein delivers less than 50% w / w ASBTI systemically. In some embodiments, the non-systemic composition described herein delivers less than 40% w / w ASBTI systemically. In some embodiments, the non-systemic composition described herein delivers less than 30% w / w ASBTI systemically. In some embodiments, the non-systemic composition described herein delivers less than 25% w / w ASBTI systemically. In some embodiments, the non-systemic composition described herein delivers less than 20% w / w ASBTI systemically. In some embodiments, the non-systemic composition described herein delivers less than 15% w / w ASBTI systemically. In some embodiments, the non-systemic composition described herein delivers less than 10% w / w ASBTI systemically. In some embodiments, the non-systemic composition described herein delivers less than 5% w / w ASBTI systemically. In some embodiments, systemic absorption is determined in any suitable manner, including total circulating volume, amount cleared after administration, etc.

[0326] In some embodiments, the compositions and / or formulations described herein are administered at least once daily. In some embodiments, the formulations containing ASBTI are administered at least twice daily, while in other embodiments, the formulations containing ASBTI are administered at least three times daily. In some embodiments, the formulations containing ASBTI are administered up to five times daily. It should be understood that, in some embodiments, the administration regimen of the compositions containing ASBTI described herein is determined by taking into account various factors such as the patient's age, sex, and diet.

[0327] The concentration of ASBTI applied in the formulations described herein ranges from about 1 mM to about 1 M. In some embodiments, the concentration of ASBTI applied in the formulations described herein ranges from about 1 mM to about 750 mM. In some embodiments, the concentration of ASBTI applied in the formulations described herein ranges from about 1 mM to about 500 mM. In some embodiments, the concentration of ASBTI applied in the formulations described herein ranges from about 5 mM to about 500 mM. In some embodiments, the concentration of ASBTI applied in the formulations described herein ranges from about 10 mM to about 500 mM. In some embodiments, the concentration of ASBTI applied in the formulations described herein ranges from about 25 mM to about 500 mM. In some embodiments, the concentration of ASBTI applied in the formulations described herein ranges from about 50 mM to about 500 mM. In some embodiments, the concentration of ASBTI applied in the formulations described herein ranges from about 100 mM to about 500 mM. In some embodiments, the concentration of ASBTI applied in the formulation described herein ranges from about 200 mM to about 500 mM.

[0328] In some embodiments, the compositions and methods described herein provide efficacy (e.g., in reducing microbial growth and / or alleviating cholestasis or cholestatic liver disease) by targeting the distal gastrointestinal tract (e.g., distal ileum, colon and / or rectum) with reduced doses of enteroendocrine peptide secretion enhancers (e.g., compared to oral doses not targeting the distal gastrointestinal tract).

[0329] Rectal administration preparation The pharmaceutical compositions described herein for the non-systemic delivery of the compounds described herein to the rectum and / or colon are formulated as rectal enemas, rectal foams, rectal gels, and rectal suppositories for rectal administration. The components of such formulations are described herein. It should be understood that, as used herein, pharmaceutical compositions and formulations are or comprise of formulations as described herein. In some embodiments, rectal formulations comprise rectal enemas, foams, gels, or suppositories.

[0330] In some embodiments, the liquid carrier medium or co-solvent in the compositions and / or formulations described herein includes, as a 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-imidazolium ketone, propylene carbonate, 1,2-butylene carbonate, 2,3-butylene carbonate, dimethyl sulfoxide, diethyl sulfoxide, hexamethylphosphoramide, acetone aldehyde dimethyl acetal, dimethyl isosorbide, and combinations thereof.

[0331] In some embodiments, stabilizers used in the compositions and / or formulations described herein include, but are not limited to, polyoxyethylene saturated fatty acid metaglycerides.

[0332] In some embodiments, the surfactants / emulsifiers used in the compositions and / or formulations described herein include, as a non-limiting example, mixtures of cetearyl alcohol and sorbitol esterified with polyoxyethylene fatty acids, polyoxyethylene fatty ethers, polyoxyethylene fatty acid esters, fatty acids, sulfated fatty acids, phosphorylated fatty acids, sulfosuccinates, amphoteric surfactants, nonionic poloxamer, nonionic meroxaprol, petroleum derivatives, fatty amines, polysiloxane derivatives, sorbitol fatty acid esters, lauryl ether-4, PEG-2 dilaurate, stearic acid, sodium lauryl sulfate, dioctyl sulfosuccinate, cocoazopropionic acid, poloxamer 188, meroxaprol 258, triethanolamine, dimethyl silicone oil, polysorbate 60, sorbitol monostearate, pharmaceutically acceptable salts thereof, and combinations thereof.

[0333] In some embodiments, the nonionic surfactants used in the compositions and / or formulations described herein include, as non-limiting examples, phospholipids, alkyl poly(ethylene oxide), poloxamer (e.g., poloxamer 188), polysorbates, sodium dioctyl sulfosuccinate, Brij™-30 (lauryl ether-4), Brij™-58 (cetyl ether-20), and Brij™-78 (stearyl ether-20), Brij™-721 (stearyl ether-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), and Pluronic™ F87. Pluronic™ polymers include Pluronic™ F98 (Pluronic™ 288), Pluronic™ L62 (Pluronic™ 182), Pluronic™ L64 (Pluronic™ 184), Pluronic™ F68 (Pluronic™ 188), Pluronic™ L81 (Pluronic™ 231), Pluronic™ L92 (Pluronic™ 282), Pluronic™ L101 (Pluronic™ 331), Pluronic™ P103 (Pluronic™ 333), Pluracare™ F 108 NF (Pluronic™ 338), and Pluracare™ F 127 NF (Pluronic™ 407), as well as combinations thereof. Pluronic™ polymers are commercially available from BASF, the USA, and Germany.

[0334] In some embodiments, the anionic surfactants used in the compositions and / or formulations described herein include, as non-limiting examples, sodium lauryl sulfate, sodium dodecyl sulfate (SDS), ammonium lauryl sulfate, alkyl sulfates, alkylbenzene sulfonates, and combinations thereof.

[0335] In some embodiments, the cationic surfactants used in the compositions and / or formulations described herein include, as non-limiting examples, benzalkonium chloride, benzyltrimethylammonium bromide, hexadecyl trimethylammonium bromide, other alkyltrimethylammonium salts, hexadecylpyridinium chloride, polyethoxylated tallow, and combinations thereof.

[0336] In some embodiments, the thickeners used in the compositions and / or formulations described herein include, as non-limiting examples, natural polysaccharides, semi-synthetic polymers, synthetic polymers, and combinations thereof. Natural polysaccharides include, as non-limiting examples, gum arabic, agar, alginate, carrageenan, guar gum, gum arabic, tragacanth gum, pectin, dextran, gellan gum, and xanthan gum. Semi-synthetic polymers include, as non-limiting examples, cellulose esters, modified starch, modified cellulose, carboxymethyl cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, and hydroxypropyl methyl cellulose. Synthetic polymers include, as non-limiting examples, polyoxyethylene, polyvinyl alcohol, polyacrylamide, polyacrylate, carboxymethyl polymethylene (carbomer), polyvinylpyrrolidone (polyvinyl acetate), polyvinyl acetate, polyethylene glycol, and poloxamer. Other thickeners include, as non-limiting examples, polyethylene glycol isostearate, cetyl alcohol, polyethylene glycol 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.).

[0337] In some embodiments, the chelating agents used in the compositions and / or formulations described herein include, as a non-limiting example, ethylenediaminetetraacetic acid (EDTA) or its salts, phosphates, and combinations thereof.

[0338] In some embodiments, the concentration of one or more chelating agents used in the rectal formulation 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).

[0339] In some embodiments, the preservatives used in the compositions and / or formulations described herein include, as non-limiting examples, parabens, ascorbyl palmitate, benzoic acid, butylated hydroxyanisole, butylated hydroxytoluene, chlorobutanol, ethylenediamine, ethylparaben, methylparaben, butylene glycol paraben, propylparaben, monothioglycerol, phenol, phenethyl alcohol, propylparaben, sodium benzoate, sodium propionate, sodium formaldehyde sulfoxylate, sodium metabisulfite, sorbic acid, sulfur dioxide, maleic acid, propyl gallate, benzalkonium chloride, benzyl chloride, benzyl alcohol, chlorhexidine acetate, chlorhexidine gluconate, sorbic acid, potassium sorbitol, chlorobutanol, phenoxyethanol, hexadecylpyridinium chloride, phenylmercuric nitrate, thimerosal, and combinations thereof.

[0340] In some embodiments, the antioxidants used in the compositions and / or formulations described herein include, as non-limiting examples, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphite, thioglycerol, propyl gallate, sodium ascorbate, sodium sulfite, sodium bisulfite, sodium formaldehyde sulfoxylate, potassium metabisulfite, sodium metabisulfite, oxygen, quinones, tert-butylhydroquinone, isoascorbic acid, olive oil, pentasodium glutarate, valeric acid, tocopherol, tocopheryl acetate, and combinations thereof.

[0341] In some embodiments, the concentration of one or more antioxidants used in the rectal formulation described herein is sufficient to achieve the desired results, for example, about 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.4% or 0.5% (w / v).

[0342] Lubricants used in the compositions and / or formulations described herein include, as a non-limiting example, natural or synthetic fats or oils (e.g., triglycerides, etc.). In some embodiments, lubricants include, as a non-limiting example, glycerin (also known as glycerine, glycerol, 1,2,3-propanetriol, and trihydroxypropane), polyethylene glycol (PEG), polypropylene glycol, polyisobutylene, polyethylene oxide, betaine, behenol, sorbitol, mannitol, lactose, polydimethylsiloxane, and combinations thereof.

[0343] In some embodiments, mucosal adhesion and / or bioadhesion polymers are used in the compositions and / or formulations described herein as agents for inhibiting the absorption of enteroendocrine peptide secretion enhancers across the rectal or colonic mucosa. Bioadhesion or mucosal adhesion polymers include, as non-limiting examples, hydroxypropyl cellulose, polyethylene oxide homopolymers, polyvinyl ether-maleic acid copolymers, methylcellulose, ethylcellulose, propylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, polycarbofibril, polyvinylpyrrolidone, carbopol, polyurethane, polyethylene oxide-polypropylene oxide copolymers, sodium carboxymethylcellulose, polyethylene, polypropylene, lectins, xanthan gum, alginate, sodium alginate, polyacrylic acid, chitosan, hyaluronic acid and its ester derivatives, vinyl acetate homopolymers, calcium polycarbofibril, gelatin, natural gums, karaya gum, tragacanth gum, alginate, chitosan, starch, pectin, and combinations thereof.

[0344] In some embodiments, the buffers / pH adjusters used in the compositions and / or formulations described herein include, as non-limiting examples, phosphoric acid, sodium dihydrogen phosphate or potassium phosphate, triethanolamine (TRIS), BICINE, HEPES, Trizma, glycine, histidine, arginine, lysine, asparagine, aspartic acid, glutamine, glutamic acid, carbonates, bicarbonates, potassium metaphosphate, potassium phosphate, disodium acetate, acetic acid, acetate, citric acid, anhydrous sodium citrate, sodium citrate dihydrate, and combinations thereof. In some embodiments, an acid or base is added to adjust the pH. Suitable acids or bases include, as non-limiting examples, HCl, NaOH, and KOH.

[0345] In some embodiments, the concentration of one or more buffers used in the rectal formulation described herein is sufficient to achieve or maintain the physiologically required pH, for example, about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.8%, 0.9% or 1.0% (w / w).

[0346] The tension modifiers used in the compositions and / or formulations described herein include, as non-limiting examples, sodium chloride, potassium chloride, sodium phosphate, mannitol, sorbitol, or glucose.

[0347] Oral administration for colon delivery In some aspects, compositions or formulations containing one or more of the compounds described herein are administered orally for the local delivery of ASBTI or the compounds described herein to the colon and / or rectum. Unit dosage forms of such compositions include pills, tablets, or capsules formulated for intestinal delivery to the colon. In some embodiments, such pills, tablets, or capsules contain the compositions described herein encapsulated or embedded in microspheres. In some embodiments, the microspheres include, as non-limiting examples, chitosan microcore HPMC capsules and cellulose acetate butyrate (CAB) microspheres. In some embodiments, the oral dosage form is prepared using conventional methods known to those skilled in the art of pharmaceutical formulation. For example, in some embodiments, standard tablet processing procedures and equipment are used to manufacture the tablets. An exemplary method for forming tablets is by directly pressing a powdered, crystalline, or granular composition containing an active agent, alone or in combination with one or more carriers, additives, etc. In alternative embodiments, wet granulation or dry granulation processes are used to prepare the tablets. In some embodiments, tablets are molded rather than pressed, starting from a wet or other readily handleable material.

[0348] In some embodiments, the preparation of tablets for oral administration comprises various excipients, including, as non-limiting examples, binders, diluents, lubricants, disintegrants, fillers, stabilizers, surfactants, preservatives, colorants, flavorings, etc. In some embodiments, the binder is used to impart cohesive qualities to the tablet, ensuring that the tablet remains intact after compression. Suitable binder materials include, as non-limiting examples, starches (including corn starch and pregelatinized starch), gelatin, sugars (including sucrose, glucose, dextrose, and lactose), polyethylene glycol, propylene glycol, waxes, and natural and synthetic gums, such as sodium alginate, gum arabic, polyvinylpyrrolidone, cellulose polymers (including hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, etc.), magnesium aluminum silicate (Veegum), and combinations thereof. In some embodiments, a diluent is used to increase the volume of the tablet, thereby providing tablets of a practical size. Suitable diluents include, as non-limiting examples, dicalcium phosphate, calcium sulfate, lactose, cellulose, kaolin, mannitol, sodium chloride, dry starch, powdered sugar, and combinations thereof. In some embodiments, a lubricant is used to facilitate tablet manufacturing; examples of suitable lubricants include, as non-limiting examples, vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and cocoa butter, glycerin, magnesium stearate, calcium stearate, stearic acid, and combinations thereof. In some embodiments, a disintegrant is used to facilitate tablet disintegration and includes, as non-limiting examples, starch, clay, cellulose, alginate, gum, crosslinking polymers, and combinations thereof. Fillers include, as non-limiting examples, materials such as silica, titanium dioxide, alumina, talc, kaolin, powdered cellulose, and microcrystalline cellulose, and soluble materials such as mannitol, urea, sucrose, lactose, glucose, sodium chloride, and sorbitol. In some embodiments, a stabilizer is used to inhibit or delay drug degradation reactions (including, for example, oxidation reactions). In some embodiments, the surfactant is anionic, cationic, amphoteric, or nonionic.

[0349] In some embodiments, ASBTI or other compounds described herein may be administered orally together with a carrier suitable for delivery to the distal gastrointestinal tract (e.g., distal ileum, colon, and / or rectum).

[0350] In some embodiments, the compositions described herein comprise ASBTI or other compounds described herein bound to a matrix (e.g., a matrix comprising hydroxypropyl methylcellulose) that allows controlled release of the active agent in the distal portion of the ileum and / or colon. In some embodiments, the compositions comprise a pH-sensitive polymer (e.g., the MMX™ matrix from Cosmo Pharmaceuticals) that allows 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 methacrylates, such as Carbopol® polymers) that contain acidic groups (e.g., -COOH, -SO3H) and swell at the alkaline pH of the intestine (e.g., about 7 to about 8). In some embodiments, 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 degradable poly(dl-lactide-co-glycolic acid) (PLGA) core is suitable for delivering an enteroendocrine peptide secretion enhancer to the distal ileum. In some embodiments, dosage forms containing enteroendocrine peptide secretion enhancers are coated with enteric polymers (e.g., Eudragit® S-100, cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, anionic polymers of methacrylic acid, methacrylates, etc.) for site-specific delivery to the distal ileum and / or colon. In some embodiments, bacterial activation systems are adapted for targeted delivery to the distal portion of the ileum. Examples of microbiota activation systems include dosage forms containing active agents such as pectin, galactomannan, and / or azo hydrogels and / or glycoside conjugates (e.g., conjugates of D-galactoside, β-D-xylanopyranoside, etc.). Examples of gastrointestinal microbiota enzymes include bacterial glycosidases, such as, for example, D-galactosidase, β-D-glucosidase, α-L-arabinofuranoside, β-D-xylanopyranoside, etc.

[0351] The pharmaceutical compositions described herein optionally include additional therapeutic compounds described herein and one or more pharmaceutically acceptable additives, such as compatible carriers, binders, fillers, suspending agents, flavoring agents, sweeteners, disintegrants, dispersants, surfactants, lubricants, colorants, diluents, solubilizers, wetting agents, plasticizers, stabilizers, penetration enhancers, defoamers, antioxidants, preservatives, or one or more combinations thereof. In some aspects, standard coating procedures, such as those described in Remington Pharmaceutical Sciences, 20th edition (2000), are used to provide a film coating around the formulation of the compound of formula I. In one embodiment, the compound described herein is in particulate form, and some or all of the particles of the compound are coated. In some 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 neither microencapsulated nor coated.

[0352] In a further embodiment, tablets or capsules containing ASBTI or other compounds described herein are coated with a film for delivery to a target site in the gastrointestinal tract. Examples of enteric coatings include, but are not limited to, hydroxypropyl methylcellulose, polyvinylpyrrolidone, hydroxypropyl cellulose, polyethylene glycol 3350, 4500, 8000, methylcellulose, pseudoethylcellulose, amylopectin, etc.

[0353] Pediatric Dosage Forms and Compositions In some embodiments, this document provides pediatric dosage forms or compositions comprising a therapeutically effective amount of any of the compounds described herein. In some cases, the pharmaceutical composition comprises an ASBT inhibitor (e.g., any ASBTI described herein).

[0354] In some embodiments, suitable dosage forms for pediatric dosage formulations or compositions include, as non-limiting examples, aqueous or non-aqueous oral dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, solutions, controlled-release formulations, instantaneous formulations, effervescent formulations, lyophilized formulations, chewable tablets, gummies, orally disintegrating tablets, powders for reconstitution into suspensions or solutions, sprayable oral powders or granules, sugar-coated pills, delayed-release formulations, extended-release formulations, pulsatile-release formulations, multi-particle formulations, and mixed instant-release and controlled-release formulations. In some embodiments, this document provides a pharmaceutical composition wherein the pediatric dosage form is selected from solutions, syrups, suspensions, elixirs, powders for reconstitution into suspensions or solutions, dispersible / effervescent tablets, chewable tablets, gummies, lollipops, freezer pops, tablets, oral strips, orally disintegrating tablets, orally disintegrating strips, sachets, and sprinkleable powders or granules.

[0355] In another aspect, this document provides a pharmaceutical composition wherein at least one excipient is a flavoring agent or sweetener. In some embodiments, this document provides a coating. In some embodiments, this document provides a flavor-masking technique selected from coating drug particles with a flavor-neutral polymer via spray drying, wet granulation, fluidized bed formation, and microencapsulation; molten wax coating with a mixture of molten wax and other pharmaceutical adjuvants; retention of drug particles by complexation, flocculation, or coagulation of aqueous polymer dispersions; adsorption of drug particles on resins and inorganic carriers; and solid dispersions wherein the drug and one or more flavor-neutral compounds are melted and cooled, or co-precipitated by solvent evaporation. In some embodiments, this document provides a delayed or sustained-release formulation comprising drug particles or granules in a rate-controlled polymer or matrix.

[0356] Suitable sweeteners include sucrose, glucose, fructose, or potent sweeteners, i.e., agents that have a high sweetness compared to sucrose (e.g., at least 10 times sweeter than sucrose). Suitable potent sweeteners include aspartame, saccharin, sodium or potassium or calcium saccharin, acesulfame potassium, sucralose, alitame, xylitol, cyclamate, neomate, neohesperidine dihydrochalcone or mixtures thereof, thaumatin, palatinit, stevioside, rebaudioside, and Magnasweet®. Based on the liquid composition at reconstitution, the total concentration of the sweetener can effectively range from zero to about 300 mg / ml.

[0357] To improve the palatability of the liquid composition during reconstruction in an aqueous medium, one or more masking agents can be added to the composition to mask the taste of the ASBT inhibitor. The masking agent can be a sweetener, a flavoring agent, or a combination thereof. The masking agent typically comprises up to about 0.1% or 5% by weight of the total pharmaceutical composition. In a preferred embodiment of the invention, the composition contains both a sweetener and a flavoring agent.

[0358] Flavoring agents, as used herein, are substances that enhance the flavor or aroma of a composition. Suitable natural or synthetic flavoring agents may 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 that may be used in the formulations described herein include, for example, gum arabic syrup, acesulfame K, arabinose, anise, apple, aspartame, banana, Bavarian cream, berries, blackcurrant, caramel, calcium citrate, camphor, caramel, cherry, cherry cream, chocolate, cinnamon, bubble gum, citrus, citrus punch, citrus cream, marshmallow, cocoa, cola, chilled cherry, chilled citrus, cyclosulfonates, cylamate, glucose, eucalyptus ( eucalyptus Eugenol, fructose, fruit punch, ginger, glycyrrhetinic acid ester, licorice ( glycyrrhiza / licorice syrup, grapes, grapefruit, honey, isomalt, lemon, lime, lemon butter, monoammonium glyrrhizinate (MagnaSweet®), maltol, mannitol, maple, marshmallow, menthol, mint milk, mixed berries, neohesperidin DC, neotame, orange, pear, peach, mint, mint butter, Prosweet® powder, raspberry, root juice soda, rum, saccharin, safrole, sorbitol, spearmint, spearmint butter, strawberry, strawberry butter, stevia steviaThe following are permitted flavorings: sucralose, sucrose, sodium saccharin, saccharin, aspartame, acesulfame potassium, mannitol, talin, sylitol, sucralose, sorbitol, Swiss cream, tagatose, orange, somatian, tutti fruitti, vanilla, walnut, watermelon, wild cherry, wintergreen, xylitol, or any combination of these flavorings, such as anise-menthol, cherry-anise, cinnamon-orange, cherry-cinnamon, chocolate-mint, honey-lemon, lemon-lime, lemon-mint, mint-eucalyptus, orange cream, vanilla-mint, and mixtures thereof. Flavorings may be used alone or in combination of two or more. In some embodiments, the aqueous liquid dispersion comprises a sweetener or flavoring agent at a concentration ranging from about 0.001% to about 5.0% of the 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% of the 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% of the 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% of the volume of the aqueous dispersion. In still another embodiment, the aqueous liquid dispersion comprises a sweetener or flavoring agent at a concentration ranging from about 0.01% to about 0.5% of the volume of the aqueous dispersion.

[0359] In some embodiments, the pediatric pharmaceutical compositions described herein comprise one or more of the compounds described herein as active ingredients in the form of a free acid or free base or a pharmaceutically acceptable salt. In some embodiments, the compounds described herein are used as N-oxides or in crystalline or amorphous forms (i.e., polymorphs). In some cases, the compounds described herein are present as tautomers. All tautomers are included within the scope of the compounds presented herein. In some embodiments, the compounds described herein are present in unsolvated or solvated forms, wherein the solvated forms comprise any pharmaceutically acceptable solvent, such as water, ethanol, etc. The solvated forms of the compounds presented herein are also considered to be those described herein.

[0360] In some embodiments, the “carrier” for a pediatric pharmaceutical composition comprises a pharmaceutically acceptable excipient and is selected based on compatibility with the compounds described herein (e.g., compounds of any of formulas I-VI) and the release profile properties of the desired dosage form. Exemplary carrier materials include, for example, binders, suspending agents, disintegrants, fillers, surfactants, solubilizers, stabilizers, lubricants, wetting agents, diluents, etc. See, for example, Remington: The Science and Practice of Pharmaceuticals, 19th edition (Easton, PA: Mack Publishing, 1995); Hoover, John E., Remington Pharmaceutical Sciences, Mack Publishing, Easton, PA, 1975; Lieberman, HA and Lackman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th edition (Lipincott Williams and Wilkins, 1999), all of which are incorporated herein by reference in their entirety for all purposes.

[0361] Furthermore, in some embodiments, the pediatric pharmaceutical compositions described herein are formulated into dosage forms. Therefore, in some embodiments, this document provides a dosage form comprising the compounds described herein, suitable for individual administration. In some embodiments, suitable dosage forms include, as non-limiting examples, aqueous oral dispersants, liquids, gels, syrups, elixirs, slurries, suspensions, solid oral dosage forms, aerosols, controlled-release formulations, instantaneous formulations, effervescent formulations, lyophilized formulations, tablets, powders, pills, sugar-coated pills, capsules, delayed-release formulations, extended-release formulations, pulsatile-release formulations, multi-particle formulations, and mixtures of immediate-release and controlled-release formulations.

[0362] In some aspects, pediatric compositions or formulations containing one or more of the compounds described herein are administered orally for the local delivery of ASBTI or the compounds described herein to the colon and / or rectum. Unit dosage forms of such compositions include pills, tablets, or capsules formulated for intestinal delivery to the colon. In some embodiments, such pills, tablets, or capsules contain the composition described herein encapsulated or embedded in microspheres. In some embodiments, the microspheres include, as non-limiting examples, chitosan microcore HPMC capsules and cellulose acetate butyrate (CAB) microspheres. In some embodiments, the oral dosage form is prepared using conventional methods known to those skilled in the art of pharmaceutical formulation. For example, in some embodiments, standard tablet processing procedures and equipment are used to manufacture the tablets. An exemplary method for forming tablets is by directly pressing a powdered, crystalline, or granular composition containing an active agent, alone or in combination with one or more carriers, additives, etc. In alternative embodiments, wet granulation or dry granulation methods are used to prepare the tablets. In some embodiments, tablets are molded rather than pressed, starting from a wet or other readily handleable material.

[0363] In some embodiments, the preparation of tablets for oral administration contains various excipients, including, as non-limiting examples, binders, diluents, lubricants, disintegrants, fillers, stabilizers, surfactants, preservatives, colorants, flavorings, etc. In some embodiments, the binder is used to impart cohesive qualities to the tablet, ensuring that the tablet remains intact after compression. Suitable binder materials include, as non-limiting examples, starches (including corn starch and pregelatinized starch), gelatin, sugars (including sucrose, glucose, dextrose, and lactose), polyethylene glycol, propylene glycol, waxes, and natural and synthetic gums, such as gum arabic sodium alginate, polyvinylpyrrolidone, cellulose polymers (including hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, etc.), magnesium aluminum silicate, and combinations thereof. In some embodiments, a diluent is used to increase the volume of the tablet, thereby providing tablets of a practical size. Suitable diluents include, as non-limiting examples, dicalcium phosphate, calcium sulfate, lactose, cellulose, kaolin, mannitol, sodium chloride, dry starch, powdered sugar, and combinations thereof. In some embodiments, a lubricant is used to facilitate tablet manufacturing; examples of suitable lubricants include, as non-limiting examples, vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and cocoa butter, glycerin, magnesium stearate, calcium stearate, stearic acid, and combinations thereof. In some embodiments, a disintegrant is used to facilitate tablet disintegration and includes, as non-limiting examples, starch, clay, cellulose, alginate, gum, crosslinking polymers, and combinations thereof. Fillers include, as non-limiting examples, materials such as silica, titanium dioxide, alumina, talc, kaolin, powdered cellulose, and microcrystalline cellulose, and soluble materials such as mannitol, urea, sucrose, lactose, glucose, sodium chloride, and sorbitol. In some embodiments, a stabilizer is used to inhibit or delay drug degradation reactions (including, for example, oxidation reactions). In some embodiments, the surfactant is anionic, cationic, amphoteric, or nonionic surfactant.

[0364] In some embodiments, ASBTI or other compounds described herein may be administered orally together with a carrier suitable for delivery to the distal gastrointestinal tract (e.g., distal ileum, colon, and / or rectum).

[0365] In some embodiments, the pediatric compositions described herein comprise ASBTI or other compounds described herein bound to a matrix (e.g., a matrix comprising hydroxypropyl methylcellulose) that allows controlled release of the active agent in the distal portion of the ileum and / or colon. In some embodiments, the composition comprises a pH-sensitive polymer (e.g., MMX™ matrix from Cosmo Pharmaceuticals) that allows 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 methacrylates, such as Carbopol® polymers) that contain acidic groups (e.g., -COOH, -SO3H) and swell at the alkaline pH of the intestine (e.g., about 7 to about 8). In some embodiments, 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 degradable poly(dl-lactide-co-glycolic acid) (PLGA) core is suitable for delivering an enteroendocrine peptide secretion enhancer to the distal ileum. In some embodiments, dosage forms containing enteroendocrine peptide secretion enhancers are coated with enteric polymers (e.g., Eudragit® S-100, cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, anionic polymers of methacrylic acid, methacrylates, etc.) for site-specific delivery to the distal ileum and / or colon. In some embodiments, bacterial activation systems are adapted for targeted delivery to the distal portion of the ileum. Examples of microbiota activation systems include dosage forms containing active agents such as pectin, galactomannan, and / or azo hydrogels and / or glycoside conjugates (e.g., conjugates of D-galactoside, β-D-xylanopyranoside, etc.). Examples of gastrointestinal microbiota enzymes include bacterial glycosidases, such as, for example, D-galactosidase, β-D-glucosidase, α-L-arabinofuranoside, β-D-xylanopyranoside, etc.

[0366] The pediatric pharmaceutical compositions described herein optionally include additional therapeutic compounds described herein and one or more pharmaceutically acceptable additives, such as compatible carriers, binders, fillers, suspending agents, flavoring agents, sweeteners, disintegrants, dispersants, surfactants, lubricants, colorants, diluents, solubilizers, wetting agents, plasticizers, stabilizers, penetration enhancers, defoamers, antioxidants, preservatives, or one or more combinations thereof. In some aspects, standard coating procedures, such as those described in Remington Pharmaceutical Sciences, 20th edition (2000), are used to provide a film coating around the formulation of the compound of formula I. In one embodiment, the compound described herein is in particulate form, and some or all of the particulates of the compound are coated. In some embodiments, some or all of the particulates of the compound described herein are microencapsulated. In some embodiments, the particulates of the compound described herein are neither microencapsulated nor coated.

[0367] In a further embodiment, tablets or capsules containing ASBTI or other compounds described herein are coated with a film for delivery to a target site in the gastrointestinal tract. Examples of enteric coatings include, but are not limited to, hydroxypropyl methylcellulose, polyvinylpyrrolidone, hydroxypropyl cellulose, polyethylene glycol 3350, 4500, 8000, methylcellulose, pseudoethylcellulose, amylopectin, etc.

[0368] Solid dosage form for pediatric use The solid dosage form of the present invention for pediatric administration can be manufactured using standard manufacturing techniques. Non-limiting examples of oral solid dosage forms for pediatric administration are described below.

[0369] Effervescent composition The effervescent composition of the present invention can be prepared using techniques well known in the pharmaceutical field.

[0370] Effervescent formulations comprise an effervescent couple of an alkaline component and an acidic component, which arrive in the presence of water to generate gas. In some embodiments, the alkaline component may comprise, for example, an alkali metal or alkaline earth metal carbonate or bicarbonate. The acidic component may comprise, for example, an aliphatic carboxylic acid or a salt thereof, such as citric acid. The alkaline and acidic components may each constitute, for example, 25% to 55% (w / w) of the effervescent composition independently. The ratio of the acidic component to the alkaline component may be in the range of 1:2 to 2:1.

[0371] The effervescent compositions of the present invention may be formulated with additional pharmaceutically acceptable carriers or excipients, as appropriate. For example, one or more taste masking agents may be used. Dyes may also be used, as pediatric patients often prefer colored drug combinations. The compositions may be in the form of, for example, tablets, granules or powders, or granules or powders present in sachets.

[0372] Chewable tablets The chewable tablets of the present invention can be prepared using techniques well-known in the pharmaceutical field.

[0373] Chewable tablets are tablets designed to disintegrate in the mouth through chewing or sucking, thus giving the active ingredient more opportunities to come into contact with bitter taste receptors on the tongue.

[0374] One approach to overcoming this problem is to absorb the active ingredient ont...

Claims

1. A method for treating or improving cholestatic liver disease in a subject in need, wherein the subject suffers from bile salt output pump (BSEP) deficiency, the method comprising administering a apical sodium-dependent bile acid transport inhibitor (ASBTI) to the subject.

2. The method according to claim 1, wherein the ASBTI is (Mashibat) (Voshibat) (Ovichbart) (Erobishbart) (GSK2330672), or a pharmaceutically acceptable salt thereof.

3. The method of claim 2, wherein the ASBTI is a macibatide or a pharmaceutically acceptable salt of its alternative.

4. The method of claim 2, wherein the ASBTI is vosibarb or a pharmaceutically acceptable salt thereof.

5. The method of claim 2, wherein the ASBTI is ostigbar or a pharmaceutically acceptable salt thereof.

6. The method of claim 2, wherein the ASBTI is erobixibart or a pharmaceutically acceptable salt thereof.

7. The method of claim 2, wherein the ASBTI is GSK2330672 or a pharmaceutically acceptable salt thereof.

8. The method according to any one of claims 1 to 7, wherein the cholestatic liver disease is progressive familial intrahepatic cholestasis type 2 (PFIC 2), benign recurrent intrahepatic cholestasis (BRIC), intrahepatic cholestasis of pregnancy (ICP), or biliary atresia.

9. The method according to any one of claims 1 to 8, wherein the subject has residual BSEP function.

10. The method according to any one of claims 1 to 9, wherein the BSEP deficiency results in impaired or reduced bile flow or bile stasis.

Images