Nitazoxanide for the treatment of liver dysfunction

Abstract

The present invention relates to a compound selected from nitazoxanide, tizoxanide, tizoxanide glucuronide and pharmaceutically acceptable salts thereof for use in a method for the treatment of liver dysfunction.

Description

[Technical Field]

[0001] The present invention relates to a compound selected from nitazoxanide, tizoxanide, tizoxanide glucuronide and pharmaceutically acceptable salts thereof for use in a method for the treatment of liver dysfunction. [Background technology]

[0002] The liver is one of the vital organs that plays an important role in metabolism. Its functions are mainly classified as circulatory, excretory, metabolic, defense-detoxification, and hematological. Impairment of any of these functions can result in various symptoms characteristic of liver disease, such as fatigue, feelings of worthlessness, loss of appetite, jaundice, and mild fever. Prolonged liver dysfunction can lead to diseases such as hepatitis, cirrhosis, and liver cancer. Furthermore, the liver is involved in drug clearance through various mechanisms and pathways (e.g., cytochrome P450 [CYP] enzyme pathway, glucuronidation, biliary excretion), and liver dysfunction, dysfunction, disease, or abnormalities can alter drug clearance. Furthermore, when a subject has liver damage, toxic substances normally removed by the liver accumulate in the blood, impairing brain function.

[0003] Therefore, it is of utmost importance to provide therapeutic strategies for treating liver dysfunction. Summary of the Invention [Means for solving the problem]

[0004] The present invention relates to a compound selected from nitazoxanide (NTZ), tizoxanide (TZ), tizoxanide glucuronide (TZG) and pharmaceutically acceptable salts thereof for use in a method for treating liver dysfunction.

[0005] In one particular embodiment, the subject has mild, moderate or severe liver dysfunction according to the Child-Pugh score.

[0006] In another specific embodiment, the subject has nonalcoholic steatohepatitis (NASH) and liver dysfunction. In particular, the subject may have NASH and moderate or severe liver dysfunction.

[0007] In yet another embodiment, the compound is nitazoxanide. In a further embodiment, the nitazoxanide is for oral administration, particularly formulated as a tablet. In yet another embodiment, the subject is administered a tablet containing 500 mg of nitazoxanide twice daily. [Brief explanation of the drawings]

[0008] [Figure 1] Figure 1 is a set of photographs of Picrosirius Red Fast Green stained liver cross sections from a bile duct ligated (BDL) rat model with LPS-induced liver injury administered with either NTZ or vehicle. [Figure 2] FIG. 2 is a set of graphs showing the effect of NTZ on plasma transaminase levels in a BDL+LPS-induced liver injury rat model. [Figure 3] FIG. 3 is a set of graphs showing the effect of NTZ on liver function markers in a BDL+LPS-induced liver injury rat model. [Figure 4] FIG. 4 is a graph showing the effect of NTZ on LPS-induced urea increase. [Figure 5] FIG. 5 is a graph showing the effect of NTZ on LPS-induced circulating cytokines. [Figure 6] FIG. 6 is a graph showing the effect of NTZ on LPS-induced brain edema. DETAILED DESCRIPTION OF THE INVENTION

[0009] Liver dysfunction or liver failure is a condition in which the liver's normal function is impaired. Liver damage and liver failure are different conditions. Liver damage refers to a state in which liver function is reduced but not completely lost. Liver damage may refer to a partial loss of liver function and may manifest as elevated liver enzymes, mild jaundice, or other mild symptoms. Liver failure, such as acute liver failure and acute-chronic liver failure, is a more serious condition in which the liver loses its function. Liver failure results in a severe and often life-threatening breakdown of liver function, accompanied by significant biochemical abnormalities and multiple organ failure. Although the prognosis for liver damage is generally better, especially if the underlying cause is identified and promptly managed, liver failure is a serious medical emergency with a high risk of death.

[0010] Provided herein is a therapeutic strategy for treating liver dysfunction. More specifically, the present invention relates to a compound selected from nitazoxanide (NTZ), tizoxanide (TZ), tizoxanide glucuronide (TZG) and pharmaceutically acceptable salts thereof for use in a method for treating liver dysfunction.

[0011] In certain embodiments, the compound is selected from NTZ, TZ, and pharmaceutically acceptable salts thereof. In further embodiments, the compound is selected from NTZ and pharmaceutically acceptable salts thereof. In yet other embodiments, the compound is NTZ.

[0012] In the context of the present invention, a therapeutically effective amount of a compound is administered to a subject. A "therapeutically effective amount" refers to an amount of a drug effective to achieve a desired therapeutic result. The amount of a therapeutically effective drug may vary depending on factors such as the individual's disease state, age, sex, and weight, as well as the drug's ability to elicit a desired response in the individual. A therapeutically effective amount is also an amount in which the toxic or detrimental effects of the drug are outweighed by the therapeutically beneficial effects. The effective amount and administration regimen of a drug depend on the disease or condition being treated and can be determined by one skilled in the art. A physician with ordinary skill in the art can easily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician may start administering the drug employed in the pharmaceutical composition at a level lower than that required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. Generally, an appropriate dose of the composition of the present invention is the amount of the compound that is the lowest dose effective to produce a therapeutic effect according to a particular administration regimen. Such an effective amount generally depends on the factors described above.

[0013] The frequency and / or dosage of administration can be adapted by those skilled in the art depending on the patient's function, pathology, dosage form, etc. Typically, the compound can be administered at a dose comprised between 0.01 mg / day and 4000 mg / day, for example, 50 mg / day and 2000 mg / day, for example, 100 mg / day and 2000 mg / day, particularly between 100 mg / day and 1000 mg / day. In certain embodiments, the compound is administered at a dose of about 1000 mg / day, particularly 1000 mg / day. In certain embodiments, the compound is administered orally at a dose of about 1000 mg / day, particularly 1000 mg / day, particularly as a tablet. Administration can be once a day or several times a day as needed. In one embodiment, the compound is administered at least once a day, for example, once a day, twice a day, or three times a day. In certain embodiments, the compound is administered once or twice a day. In particular, oral administration can be achieved by taking a tablet containing a compound at a dose of about 1000 mg, particularly a 1000 mg dose, once a day during a meal, such as breakfast, lunch, or dinner. In a different embodiment, the tablet is orally administered twice a day, for example by administering a first tablet containing a compound at a dose of about 400 mg, about 500 mg, or about 600 mg, particularly 500 mg, during one meal, and a second tablet containing a compound at a dose of about 500 mg, particularly 500 mg, during another meal on the same day.

[0014] The compounds used in the present invention can be formulated into pharmaceutical compositions that further comprise one or several pharmaceutically acceptable excipients or vehicles (e.g., physiological saline, physiological solution, isotonic solution, etc.) that are compatible with pharmaceutical use and are well known to those skilled in the art. These compositions can also further comprise one or several agents or vehicles selected from dispersing agents, solubilizing agents, stabilizers, preservatives, etc. Useful agents or vehicles for these formulations (liquid and / or injectable and / or solid formulations) are, inter alia, methylcellulose, hydroxymethylcellulose, carboxymethylcellulose, polysorbate 80, mannitol, gelatin, lactose, vegetable oils, acacia, liposomes, etc.

[0015] These compositions can be formulated in the form of injection suspensions, syrups, gels, oils, ointments, pills, tablets, suppositories, powders, gelcaps, capsules, aerosols, etc., and even by using galenical forms or devices that ensure a prolonged and / or slow release. For this type of preparation, agents such as cellulose, carbonates or starch can be advantageously used.

[0016] NTZ, TZ, or TZG can be in the form of a pharmaceutically acceptable salt, particularly an acid salt or a basic salt suitable for pharmaceutical use. Salts of NTZ, TZ, and TZG include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable base addition salts, pharmaceutically acceptable metal salts, ammonium salts, and alkylated ammonium salts. These salts can be obtained during the final purification step of the compound or by incorporating the salt into a previously purified compound.

[0017] The compounds for use in the present invention can be administered by different routes and in different forms. For example, the compounds can be administered via oral, parenteral systemic routes, by inhalation, nasal spray, intranasal injection, or injection, such as intravenous, intramuscular, subcutaneous, transdermal, topical, intraarterial, etc. Of course, the administration route will be adapted to the form of the drug according to procedures well known to those skilled in the art.

[0018] In certain embodiments, the compound is formulated as a tablet. In another specific embodiment, the compound is orally administered. In another specific embodiment, the compound is NTZ formulated into a tablet for oral administration. In yet another specific embodiment, the tablet contains 400 to 600 mg of NTZ, more specifically 500 mg of NTZ.

[0019] In certain embodiments, the compound is for use as a single active ingredient for the treatment of liver dysfunction. In yet another embodiment, the compound is for use in combination with different active ingredients, for example, different compounds useful for treating liver dysfunction or different compounds useful for treating at least one symptom of liver dysfunction or different compounds useful for treating a condition that has caused or will cause liver dysfunction, such as a condition selected from liver infection, liver fibrosis, cirrhosis, non-alcoholic fatty liver disease, or non-alcoholic steatohepatitis.

[0020] The compounds for use in the present invention are administered to treat liver dysfunction in a subject in need thereof. As used herein, the term "subject" refers to a mammal, preferably a human subject.

[0021] The Child-Pugh classification is the most widely used method for classifying liver function. The Child-Pugh classification groups subjects based on two clinical features (encephalopathy and ascites) and three laboratory parameters (serum albumin, serum bilirubin, and prothrombin time). Liver dysfunction is classified into groups A, B, and C, or "mild," "moderate," and "severe," corresponding to scores of 5-6, 7-9, and 10-15, respectively. In certain embodiments, subjects have mild, moderate, or severe liver dysfunction as assessed by the Child-Pugh scoring system, which is well known in the art. In different specific embodiments, subjects have moderate or severe liver dysfunction, more specifically, severe liver dysfunction. In further specific embodiments, subjects have nonalcoholic steatohepatitis (NASH) and liver dysfunction. In yet another embodiment, subjects have NASH and moderate or severe liver dysfunction. In a further embodiment, the subject has non-alcoholic steatohepatitis (NASH) and severe liver dysfunction.

[0022] As used herein, the term "treatment" refers to both therapeutic and prophylatic or preventative measures, the purpose of which is to prevent or slow (alleviate) undesirable physiological changes or abnormalities. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, stabilization (particularly not worsening) of the pathological condition, slowing or halting the progression of the disease, and amelioration or remission of the pathological condition. In particular, for purposes of the present invention, treatment aims to slow the progression of liver dysfunction and reduce the risk of further complications. It can also include prolonging survival compared to expected survival if not treated.

[0023] In certain embodiments, the compound is used to reduce the mortality rate associated with liver dysfunction.The compound can also be used to slow or stop the progression of liver dysfunction.In particular, the compound can be used to prevent, slow or stop the progression of liver dysfunction in subjects with mild or moderate liver dysfunction, especially moderate liver dysfunction, and especially to prevent, slow or stop the progression to severe liver dysfunction.In particular, the compound can be used to reverse liver dysfunction from severe to moderate or mild liver dysfunction.In yet another specific embodiment, the compound can be used to reverse liver dysfunction from moderate to mild liver dysfunction. [Example]

[0024] Example 1: Evaluation of the efficacy of NTZ against BDL+LPS-induced liver injury in rats Materials and Methods The aim of this study was to evaluate the efficacy of NTZ in preventing LPS-induced inflammation, liver dysfunction, and cerebral edema in fibrotic rats subjected to BDL surgery.

[0025] BDL surgery was performed on 30 Sprague-Dawley rats (Janvier). After anesthesia, a midline abdominal incision was made to expose the liver and duodenum. The main bile duct was identified and dissected. The bile duct was then ligated in two locations: the first ligation was performed in the middle of the bile duct, and the second ligation was performed above the entrance to the pancreatic duct. To prevent recanalization, the bile duct was then transected midway. On day 14 after surgery, blood samples were collected from the sublingual vein to measure markers of liver dysfunction (serum aspartate aminotransferase (AST), total bile acids, and bilirubin), and the animals were assigned to treatment groups. Two rats that developed BDL were excluded at the end of the study due to abnormal blood parameters (a 10–20% surgical failure rate is expected in this model). Two unoperated experimental animals were included as healthy controls.

[0026] Twenty or 21 days after BDL surgery, liver dysfunction was induced by intraperitoneal administration of 1 μg / kg of LPS (Escherichia coli O111:B4). Nine BDL rats were administered phosphate-buffered saline (PBS, Fisher Scientific, USA) instead of LPS and served as BDL controls.

[0027] Body weight and food consumption were monitored twice weekly for the duration of the study.

[0028] During the fibrosis induction period, each experimental animal was observed once daily to monitor clinical signs. Observations included changes in the skin, hair coat, and eyes, the occurrence of secretions and excretions, and autonomic nervous activity (lacrimation, pore formation, abnormal breathing patterns). Changes in gait and posture, repetitive behaviors (e.g., excessive grooming, repetitive circling), or bizarre behaviors (self-injurious behavior, backward walking) were also monitored. Experimental animals were euthanized if they lost more than 25% of their body weight for three or more consecutive days, stopped eating, showed a deterioration in their general condition, or began to vocalize.

[0029] After LPS administration, each experimental animal was continuously observed for 7 hours to assess the inflammatory response and pain level (animal appearance - changes in fur and skin color -, activity level, alertness - response to stimuli, eyelid opening, activity, locomotion and behavior).

[0030] NTZ 100 mg / kg or vehicle (1% carboxymethylcellulose (C4888, Sigma-Aldrich), 0.1% tween 80 (P8074, Sigma-Aldrich)) was orally administered 1 hour before LPS injection.

[0031] [Table 1]

[0032] NTZ is highly light sensitive, so it was protected from light.

[0033] For oral administration, NTZ powder was dissolved in 1% CMC and 0.1% Tween 80 to a concentration of 10 mg / ml in an amber glass bottle, homogenized with a Polytron, and sonicated for 10 seconds at 10% power. The NTZ was kept under magnetic stirring until it was administered to rats at 10 ml / kg.

[0034] The LPS solution was prepared in a microbiological safety cabinet to obtain a sterile solution for administration to rats. The LPS solution was dissolved in phosphate-buffered saline (PBS) at 0.5 μg / ml, aliquoted, and stored frozen until the day of the experiment. 2 ml / kg of LPS was administered to rats.

[0035] All surviving animals were euthanized 3 hours after LPS injection for plasma and tissue analysis. At the end of the study, plasma levels of liver function markers and cytokines, as well as cerebral edema, were assessed.

[0036] result Assessment of fibrosis level In the livers of mice that underwent BDL surgery, peribiliary fibrosis was observed, as demonstrated by Sirius red staining (Fig. 1 ).

[0037] As expected, neither LPS nor NTZ affected the rate of liver fibrosis during short-term administration (data not shown).

[0038] Levels of liver and kidney function markers in plasma BDL surgery induced severe liver damage and altered liver function, which was further augmented by LPS injection. The effects of NTZ on the levels of liver and kidney function markers in plasma were evaluated.

[0039] Plasma transaminases ALAT and ASAT, markers of hepatocellular injury, were increased in the BDL group compared with the non-pathological group. LPS further increased plasma ASAT and ALAT levels by 5.7-fold and 3.9-fold, respectively. NTZ treatment significantly reduced ALAT by 101% (p = 0.03) and ASAT by 100% (p = 0.01) compared with the ACLF-Veh condition (Figure 2).

[0040] Plasma levels of liver function markers, total bile acids, total bilirubin, albumin, and GGT, were also altered by LPS administration in BDL rats (Fig. 3). NTZ treatment tended to attenuate the LPS-induced changes in these markers.

[0041] LPS injection also altered renal function, as indicated by an increase in urea concentration (Fig. 4), confirming that organs other than the liver are affected in this model. NTZ treatment also prevented LPS-induced renal dysfunction by reducing plasma urea by 84% (p = 0.007) (Fig. 4).

[0042] Circulating cytokine levels in plasma Circulating cytokine levels were measured in the blood of experimental animals collected 3 hours after LPS injection. Although LPS injection induced a strong cytokine increase of 228-fold for IL6, 91-fold for TNFα, and 143-fold for IL-1β, NTZ reduced circulating IL-6 by 93%, TNFα by 94%, and IL-1β by 91% (Fig. 5).

[0043] Cerebral edema Finally, LPS injection induced cerebral edema (+0.78% in water volume), whereas NTZ completely restored water volume to the level of BDL and healthy experimental animals (-111% compared to the BDL condition, p=0.006) (Figure 6).

[0044] conclusion BDL surgery induces severe liver damage and altered liver function, as demonstrated by elevated levels of AST (3.8-fold), total bile acids (3.8-fold), total bilirubin (165-fold), gamma-glutamyltransferase (GGT) (4-fold), and urea (1.3-fold) compared to healthy controls.

[0045] Injection of LPS into BDL rats further increased the levels of AST (5.7-fold) and urea (1.4-fold) compared with BDL rats, and also induced an increase in ALT (3.9-fold) and a decrease in albumin concentration (-11%).

[0046] NTZ treatment suppressed LPS-induced increases in AST (-100%), ALT (-101%), and urea (-84%). These effects were associated with a significant effect on systemic inflammation. LPS injection induced a strong cytokine increase of 228-fold for IL6, 91-fold for TNFα, and 143-fold for IL-1β. NTZ reduced circulating IL-6 by 93%, TNFα by 94%, and IL-1β by 91%. Furthermore, brain edema (+0.78% in water volume) was induced in these experimental animals, but NTZ completely restored water volume to the levels observed in BDL and healthy rats.

[0047] Taken together, these results demonstrate that NTZ has the effect of rapidly suppressing LPS-induced liver and brain damage as well as systemic inflammation in rats with liver dysfunction.

[0048] Example 2: Study Design to Evaluate Nitazoxanide in the Treatment of Liver Dysfunction To evaluate the efficacy and safety of nitazoxanide in patients with hepatic dysfunction.

[0049] There are many methods for classifying the severity of liver dysfunction. In this study, the Child-Pugh classification (CP classification) was chosen because it is the most widely used and is supported and accepted by regulatory authorities such as the US FDA and the European Medicines Evaluation Agency.

[0050] Liver dysfunction is classified as moderate or severe using the CP system. Parameters for determining the CP class of each subject with liver dysfunction are collected at screening.

[0051] [Table 2]

[0052] Chronic liver dysfunction is classified into Child-Pugh (CP) classes A to C by adding up the scores of the five parameters in Table 2. Mild impairment (CP-A): 5-6 points, moderate impairment (CP-B): 7-9 points, and severe impairment (CP-C): 10-15 points.

[0053] a In this study, hepatic encephalopathy was - Grade 0: consciousness, personality, and neurological examination are normal or EEG is normal; - Grade 1: restlessness, sleep disturbance, irritability / hyperactivity, tremor, dysgraphia or EEG of 5 cycles per second (cps), - Grade 2: lethargy, temporal disorientation, inappropriate, asterixis, ataxia or slow triphasic EEG; - Grade 3: somnolence, stupor, spatial disorientation, hyperreflexia, rigidity or slower waves; - Grade 4: Unarousable coma, no personality / behavior, decerebrate or slow delta activity 2-3 cps, Grades are assigned according to the following criteria.

[0054] b Ascites - None: If palpation or ultrasound examination is performed, ascites cannot be detected by ultrasound examination; - Mild: Palpation is suspicious for the presence of ascites, but if performed, ultrasound measurable ascites; - Moderate: Ascites is detectable by both palpation and ultrasound examination; - Severe: Requires paracentesis and does not respond to drug treatment; - Subjects with a history of severe ascites who are receiving diuretics such as furosemide to prevent recurrence should receive points according to the severity of their original ascites. are graded according to the following criteria.

[0055] c Subjects with grade 3 or 4 hepatic encephalopathy cannot be enrolled in the study. However, subjects with a history of grade 3 or 4 hepatic encephalopathy and taking medication to prevent recurrence of encephalopathy (lactulose, neomycin, or rifaximin) can participate in the study and receive a score of stage 3 or 4 encephalopathy.

[0056] Each enrolled patient will receive a tablet containing 500 mg of nitazoxanide twice daily.

[0057] Example 3: Safety of nitazoxanide in patients with impaired hepatic function The study design was an open-label, non-randomized, two-center, multiple-dose, parallel-group study to evaluate the PK, safety, and tolerability of NTZ 500 mg administered BID for 7 days in male and female patients with moderate and severe hepatic impairment, compared with matched male and female controls with healthy hepatic function.

[0058] The objective of this study was to evaluate the effect of hepatic impairment on the PK of tizoxanide (TZ, the active metabolite of NTZ) after repeated oral administration of NTZ 500 mg BID for 7 days in subjects with moderate and severe hepatic impairment and subjects with normal hepatic function.

[0059] The Child-Pugh (CP) score ( ) is used to measure liver function to assess the degree of liver dysfunction on the PK of NTZ. * ), serum albumin, serum total bilirubin, international normalized ratio (INR), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) parameters were considered.

[0060] ( * ) CP scores were not calculated for matched healthy controls, and analysis was limited to patients with liver dysfunction.

[0061] Subjects were selected based on their CP score at screening. - Group 1: Normal liver function - Group 2: Moderate liver dysfunction (CP class B) - Group 3: Severe liver dysfunction (CP class C) were assigned to groups.

[0062] A total of 25 subjects were included in this study, including 10 healthy subjects assigned to the control group, 9 subjects assigned to the moderate hepatic dysfunction group, and 6 subjects assigned to the hepatorenal dysfunction group, and the subjects received at least one type of NTZ.

[0063] On Day 1, study subjects took one 500 mg tablet of NTZ with 240 mL (8 oz) of water 30 minutes after the start of a standardized breakfast. Food was withheld for at least 4 hours after each dose. Blood PK samples were collected pre-dose (completed in a fasted state before the start of a standardized breakfast) and at T1h, T2h, T3h, T4h, T5h, T6h, T7h, T8h, T10h, and T12h post-dose.

[0064] From days 2 to 6, subjects received nitazoxanide 500 mg (1 tablet) in the morning and evening for 6 consecutive days, with the final dose administered on the morning of day 7. Pre-dose blood PK samples were collected in the fasting state each morning from days 2 to 6, before the start of a standardized breakfast.

[0065] On Day 7, blood PK samples were collected pre-dose (completed in a fasted state before the start of a standardized breakfast) and at T1 h, T2 h, T3 h, T4 h, T5 h, T6 h, T7 h, T8 h, T10 h, T12 h, T14 h, and T16 h post-dose. Post-dose PK samples at T18 h, T24 h, and T48 h were collected on Days 8 and 9, respectively.

[0066] The primary analysis of total TZ geometric means and geometric mean ratios (GMR) (90% CI) to the control group for the disorder and control groups at steady state is shown in Table 3 .

[0067] [Table 3]

[0068] The primary analysis aimed to evaluate the PK parameters (C) of total NTZ after repeated oral administration of NTZ 500 mg BID for 7 days to subjects with moderate or severe hepatic impairment and subjects with normal hepatic function. max , AUC 0-12 and AUC 0-t The purpose of this study was to evaluate the differences between the two.

[0069] In subjects with moderate hepatic impairment, AUC and C max No statistically significant differences were observed between the control group and the control group. Given that the GMRs were between 0.80 and 1.00, differences in subjects with moderate liver dysfunction are unlikely, even if they could not be formally demonstrated due to limited sample size.

[0070] In subjects with severe hepatic impairment, a statistically significant difference in AUC was observed between the control group and the control group. The GMR was between 1.64 and 1.79, with a 90% CI not including 1.00. max The GMR was estimated to be 1.19, which was not statistically different from the control group.

[0071] Parameters of total TZ between subjects with moderate liver dysfunction and control subjects, and C of subjects with severe liver dysfunctionmax No differences were observed in the AUC. However, subjects with severe hepatic impairment showed a modest increase in AUC, which was statistically significant.

[0072] Secondary analyses of total TZ accumulation rates are shown in Table 4 .

[0073] [Table 4]

[0074] The secondary analysis objective was to measure the AUC after a single (Day 1) and repeated 7-day (BID) oral administration. 0-12 and C max The objective of this study was to identify the accumulation of

[0075] No interaction between the factors of administration day and administration group was observed for any of the parameters. Therefore, accumulation was considered to be independent of the degree of liver dysfunction, and evaluation was performed for all groups combined.

[0076] In total TZ, C max and AUC 0―12 Although statistically significant accumulation was observed in the 7th day and the 1st day, the degree of accumulation was limited. max AUC is approximately 1.4. 0-12 was about 1.6.

[0077] Sensitivity analysis confirmed that moderate hepatic impairment likely had no effect on the PK of total TZ. Severe hepatic impairment also significantly affected C max Although it does not appear to affect the variability of the variability, it may increase the AUC by approximately 1.5-fold.

[0078] Liver function markers {serum albumin, serum total bilirubin, INR, AST, and ALT (values ​​obtained at screening)} and PK parameters (C max and AUC 0-12 ) were investigated and evaluated using graphical and correlation analysis techniques.

[0079] Both Pearson correlation coefficients (indicating linear trends) and Spearman correlation coefficients (indicating monotonic trends) were calculated. The correlation coefficient (ρ) was used to appropriately measure the most likely relationship, and only strong correlations (i.e., ρ ≥ 0.75) were considered for further modeling.

[0080] The relationship between hepatic function and PK parameters is summarized in Table 5.

[0081] [Table 5]

[0082] The results showed that most of the liver function markers had poor (ρ<0.25) or weak (0.25≦ρ<0.5) correlations with the PK parameters of TZ or TZ Glu (total and free). max A moderate linear correlation (ρ = 0.51) was found between urinary tract infection and bilirubin, but the correlation was weak (ρ < 0.75) and insufficient for further modeling.

[0083] For tizoxanide, the time to reach maximum concentration was consistent between groups and days (median t max Although there was moderate to high inter-individual variability, the total TZ exposure on days 1 and 7 was higher in the severely impaired liver group than in the other groups (C max , AUC 0-12 and AUC 0-∞ The GM ratio was approximately 0.8-1.0 times between the moderate group and the control group, and approximately 1.1-1.8 times between the severe group and the control group. 0-∞ The extrapolation rate was determined to be less than 20%.

[0084] The elimination phase was comparable between groups on day 1, but tended to be slower on day 7 in the severely impaired liver group (GM on day 1). t1 / 2The GM time on the 7th day was approximately 2 hours in the severely impaired group. t1 / 2 The trough concentration generally increased with the degree of liver dysfunction.

[0085] In urine, the percentage of the administered dose recovered over 12 hours on both Days 1 and 7 was less than 1% regardless of the treatment group, and there was a large degree of inter-individual variability. Renal clearance was also low in all treatment groups regardless of the number of days, with values ​​ranging from 0.002 to 0.030 L / h and a large degree of inter-individual variability.

[0086] Peak exposure (C max In the statistical analysis (primary analysis) of the 2016 study, the area under the curve (AUC) from 0 to 12 hours was 0-12 ), and the area under the curve from time 0 to the last quantifiable concentration (AUC 0-t ) showed no difference between the moderate hepatic impairment group and the control group, with GMRs ranging from 0.80 to 1.25, suggesting no relevant differences. In the severe hepatic impairment group, only the AUC showed a statistically significant difference, with GMRs ranging from 1.64 to 1.79.

[0087] The sensitivity analysis for total TZ was consistent with the primary analysis. The trends observed in PK parameters were consistent, confirming that moderate hepatic impairment likely does not affect the PK of total TZ. However, in severely impaired subjects, C max Although it is unlikely to affect the C max and AUC 0-12 The ratio of day 7 to day 1 was C max AUC is approximately 1.4. 0-12 was about 1.6.

[0088] The clinical trials have shown that nitazoxanide is safe and is metabolized to the active metabolite nitazoxanide.

[0089] Example 4: Efficacy of nitazoxanide in patients with impaired liver function This study was conducted to evaluate the efficacy of nitazoxanide 500 mg twice daily in patients with impaired liver function. Based on the results reported in Example 1, it is expected that this treatment will improve the subjects' condition.

[0090] This study is an interventional, proof-of-concept, Phase 2a, randomized, open-label, controlled, parallel-group clinical trial to evaluate the safety, pharmacokinetics, and efficacy of nitazoxanide (NTZ) 500 mg orally administered twice daily in patients receiving standard of care (SOC) compared with patients with Acute-On-Chronic Liver Failure (ACLF) who received SOC alone.

[0091] The study consisted of three periods: a 72-hour screening period, followed by a 7-day treatment period, and a safety follow-up period up to 90 days after the start of treatment.

[0092] Patients will be randomly assigned to receive nitazoxanide 500 mg orally twice daily (BID) on a background of standard of care (SOC) or SOC alone for 7 days each.

[0093] Standard of Care (SOC) is the standard medical management of patients with ACLF according to local medical practice at a participating medical institution. Medical treatment at that institution is at the discretion of the attending physician and takes into account the patient's overall clinical assessment, the precipitating event, and the nature and severity of organ dysfunction. Interventions may include, but are not limited to, supportive care with fluid therapy, including albumin infusion as needed; antibiotics for suspected or confirmed infection; nutritional management; bowel management; thromboprophylaxis; and organ system support, including circulatory system support, oxygen therapy, noninvasive or invasive respiratory support; laxatives and nonabsorbable antibiotics for hepatic encephalopathy; and dialysis for renal failure. SOC may also include liver transplantation, depending on the individual patient's clinical condition and local medical practice.

[0094] The primary objective was to evaluate the safety of nitazoxanide (NTZ) in patients with ACLF and liver dysfunction.

[0095] The secondary objective is - To evaluate the pharmacokinetics of NTZ's main metabolites (tizoxanide and tizoxanide glucuronide) in patients with ACLF. - To evaluate the impact of NTZ on clinical disease progression using applicable prognostic criteria in patients with ACLF; - To assess the impact of NTZ on clinical outcomes, including 28- and 90-day mortality after liver transplantation; is.

[0096] Other objectives are to assess the effect of NTZ treatment on inflammatory markers in these patients and to assess the effect of NTZ on the intestinal microbiota.

[0097] In this study, approximately 30 patients were randomly assigned to NTZ+SOC:SOC in a 2:1 ratio. - Group A: NTZ + SOC - Group B: SOC are randomly assigned to

[0098] Safety information, clinical prognostic scores, markers of renal and liver function, gut microbiota profiles, and inflammatory markers will be assessed at screening, days 1 to 7 (active treatment phase), days 8, 14, 21, 28, and 90 (follow-up visit).

[0099] PK measurements of NTZ and metabolites will be evaluated on days 1, 7, and 8 (NTZ+SOC group only).

[0100] Clinical outcomes, including liver transplantation and mortality, will be monitored throughout the study and up to 97 days.

[0101] Exclusion criteria: 1) Patients with cirrhosis who developed decompensation at any point in the postoperative period after partial liver resection or major non-hepatic surgery. 2) Patients with uncontrolled infection or sepsis. Patients with infection may be enrolled in this study if they have been administered antimicrobial therapy, as deemed appropriate by the principal investigator, for at least 48 hours prior to randomization and have demonstrated an adequate response. 3) Patients with ACLF grade 3 4) Patients with a MELD-Na score of more than 25 5) Patients with hepatic encephalopathy grade III (coma) or grade IV (coma) according to the West Haven criteria. 6) Patients with clinical evidence of disseminated intravascular coagulation. 7) Patients who require administration of cardiac inotropes due to cardiovascular dysfunction. 8) Patients who are judged by the principal investigator to have evidence of significant and / or uncontrollable bleeding. 9) Patients currently using or expected to use a mechanical ventilator 10) Patients with active malignancies (expected survival time is less than 1 year) or a history of malignancies other than hepatocellular carcinoma (HCC) that meet the Milan criteria, or patients with curatively treated skin cancer (basal cell carcinoma or squamous cell carcinoma), unless adequately treated or in complete remission for 5 years or more. 11) Known hypersensitivity to nitazoxanide or use of nitazoxanide within 30 days prior to screening 12) Hemoglobin concentration less than 9 g / dl 13) All patients undergoing dialysis 14) Patients currently using warfarin. Patients are allowed to use warfarin if they have not used warfarin within 5 days prior to the start of screening. 15) Receiving systemic corticosteroid therapy within 30 days of screening; 16) Participating in any other interventional study (drug or medical device) or using any other investigational product within 30 days of screening 17) History of digestive disorders that cause abnormal intestinal absorption (e.g., celiac disease, inflammatory bowel disease, etc.) 18) Patients with serious systemic or critical illnesses other than liver disease, including coronary artery disease, cerebrovascular disease, pulmonary disease, renal failure, and severe mental illness, who are judged by the investigator to be unable to participate in and complete this study. 19) Pregnant or lactating women or women planning to become pregnant during the study period 20) Positive for anti-human immunodeficiency virus (HIV) antibodies 21) Individuals who are deemed by the investigator to be unsafe to participate in the study; 22) Patients are registered on the UNOS liver transplant list. 23) positive test result for illegal drugs (excluding marijuana) unless the subject uses these drugs as prescription medications and has investigator approval; 24) Positive alcohol test, excluding patients with alcoholic hepatitis; 25) A history of serious drug abuse within one year prior to screening, or a history of recreational use of soft drugs (excluding marijuana) within one month prior to screening, or a history of hard drug use (cocaine, phencyclidine [PCP], opioid derivatives including heroin, amphetamine derivatives, etc.) within three months prior to screening. Patients who fall under any of the following categories will not be able to participate in the study.

[0102] Evaluation criteria: Primary endpoint: The primary endpoints were the incidence of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and treatment discontinuation for safety reasons up to 90 days.

[0103] Secondary endpoints: Safety endpoints: a. Laboratory measurements (chemistry, hematology, and coagulation tests). b. Physical examination, vital signs, and electrocardiogram (ECG).

[0104] Pharmacokinetic endpoints: Following a single oral dose (Day 1) and at steady state (expected to reach steady state by Day 7), TZ and TZ glucuronide are expressed as free and total concentrations, as appropriate. - Maximum plasma concentration (C max ), - Area under the plasma concentration-time curve (AUC) from 0 to 12 hours (AUC 0-12 ), - AUC from time 0 to the last quantifiable concentration (AUC 0-t ), - Maximum plasma concentration observation time (T max ), - apparent terminal plasma elimination half-life (t 1 / 2 ). Secondary efficacy endpoints - Change from baseline in MELD-Na, CLIF-C ACLF score, CLIF-C organ failure score, ACLF grade, Child-Turcotte-Pugh (CTP) score, and West Haven criteria. - Clinical outcomes - other hepatic clinical events such as ascites, gastrointestinal bleeding, liver transplantation, 28-day mortality, and 90-day mortality PK parameters of

Claims

1. A compound selected from nitazoxanide (NTZ), tizoxanide (TZ), tizoxanide glucuronide (TZG) and pharmaceutically acceptable salts thereof for use in a method for treating liver dysfunction.

2. The compound of claim 1, wherein the subject has mild liver dysfunction according to the Child-Pugh score.

3. The compound according to claim 1, wherein the subject has moderate liver dysfunction according to the Child-Pugh score.

4. The compound of claim 1, wherein the subject has severe liver dysfunction according to the Child-Pugh score.

5. 5. The compound of any one of claims 1 to 4, wherein the subject has non-alcoholic steatohepatitis (NASH) and liver dysfunction.

6. 6. The compound of claim 5, wherein the subject has NASH and moderate liver dysfunction.

7. 6. The compound of claim 5, wherein the subject has NASH and severe liver dysfunction.

8. 8. The compound of any one of claims 1 to 7, wherein the compound is nitazoxanide.

9. 9. The compound of claim 8, wherein the nitazoxanide is for oral administration.

10. 10. The compound of claim 9, wherein the nitazoxanide is formulated into a tablet.

11. 11. The compound of claim 10, wherein the subject is administered a tablet containing 500 mg of nitazoxanide twice daily.

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