Pharmacology: Mechanism of Action:
Ursodiol, a naturally occurring hydrophilic bile acid, derived from cholesterol, is present as a minor fraction of the total human bile acid pool. Oral administration of ursodiol increases this fraction in a dose related manner, to become the major biliary acid, replacing/displacing toxic concentrations of endogenous hydrophobic bile acids that tend to accumulate in cholestatic liver disease.
Multiple mechanisms of action at the cellular and molecular level in addition to the replacement and displacement of toxic bile acids include cytoprotection of the injured bile duct epithelial cells (cholangiocytes) against toxic effects of bile acids, inhibition of apoptosis of hepatocytes, immunomodulatory effects via a number of mechanisms including decreasing expression of MHC class I proteins on hepatocytes and cholangiocytes, and stimulation of bile secretion by hepatocytes and cholangiocytes.
The cholesterol-lowering effect observed following the administration of ursodiol in patients with primary biliary cirrhosis could be related to an improvement of cholestasis, modifications in cholesterol metabolism, or both. Changes in the endogenous bile acid composition induced by ursodiol might be the common denominator of these two mechanisms.
During chronic administration, ursodiol becomes a major biliary and plasma bile acid. At a chronic dose of 13-15 mg/kg/day, ursodiol constitutes 30-50% of biliary and plasma bile acids.
Comparative Bioavailability Studies: Single-Dose Crossover Comparative Bioavailability Study of pms-URSODIOL C 2 x 250 mg Tablets, was performed vs. Axcan Pharma Inc., URSO 2 x 250 mg Tablets, Administered as 2 x 250 mg Tablet in Healthy Subjects Under Fasting Conditions. Bioavailability data were measured and the results are summarized in the following table: See Table 1.
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Study demographics and trial design: See Table 2.
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U.S. Study: A multicenter, randomized, double-blind, placebo-controlled study was conducted to evaluate the efficacy of ursodeoxycholic acid at a dose of 13-15 mg/kg/day, administered in 4 divided doses in 180 patients with PBC. Upon completion of the double-blind portion, all patients entered an open-label, active treatment, extension phase.
Treatment failure, the main efficacy end point measured during this study, was defined as death, need for liver transplantation, histologic progression by two stages or to cirrhosis, development of varices, ascites or encephalopathy, marked worsening of fatigue or pruritus, inability to tolerate the drug, doubling of serum bilirubin and voluntary withdrawal. After two years of double-blind treatment, the incidence of treatment failure was significantly reduced in the ursodiol group (n=89) as compared to the placebo group (n=91). Time to treatment failure was also significantly delayed in the ursodiol treated group, regardless of either histologic stage or baseline bilirubin levels (>1.8 or ≤1.8 mg/dL).
Using a definition of treatment failure which excluded doubling of serum bilirubin and voluntary withdrawal, time to treatment failure was significantly delayed in the ursodiol group. In comparison with placebo, treatment with ursodiol resulted in a significant improvement in the following serum hepatic biochemistries when compared to baseline: total bilirubin, AST, alkaline phosphatase and IgM.
Canadian Study: A second study conducted in Canada randomized 222 PBC patients to ursodiol 14 mg/kg/day (n=111) or placebo (n=111), in a double-blind manner during a two-year period. At two years, a statistically significant difference between the two treatments, in favor of ursodiol, was demonstrated by the following: reduction in the proportion of patients exhibiting a more than 50% increase in serum bilirubin; median percent decrease in bilirubin, transaminases and alkaline phosphatase, incidence of treatment failure, and time to treatment failure. The definition of treatment failure included: discontinuing the study for any reason, a total serum bilirubin level greater than or equal to 1.5 mg/dL or increasing to a level equal to or greater than two times the baseline level, and the development of ascites or encephalopathy.
Evaluation of patients at 4 years or longer was inadequate due to the high dropout rate and small number of patients. Therefore, death, need for liver transplantation, histological progression by two stages or to cirrhosis, development of varices, ascites or encephalopathy, marked worsening of fatigue or pruritus, inability to tolerate the drug, doubling of serum bilirubin and voluntary withdrawal were not assessed.
Multinational Study: A two-year multicenter, multinational (France-Canada), double-blind study was conducted to compare the efficacy of ursodiol versus placebo in primary biliary cirrhosis. Patients with histologically confirmed biliary cirrhosis were randomized to receive either ursodiol 13-15 mg/kg/day (n=72), or placebo (n=73). Treatment failure was defined as a doubling of bilirubin levels (>70 mcmol/L) or the occurrence of severe complications (ascites or variceal bleeding) or an adverse event.
The results showed that treatment failed in six patients in the ursodiol group, as compared with thirteen in the placebo group (p<0.01). A single patient in each group withdrew because of minor adverse effects. After two years of treatment, the proportion of patients with clinically overt disease decreased only in the ursodiol group (p<0.02). The patients treated with ursodiol had significant improvements in serum levels of bilirubin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, γ-glutamyltransferase, cholesterol, and IgM (all p<0.01); the antimitochondrial antibody titer (p<0.01); and the Mayo risk score (p<0.001). In a follow-up analysis of 95 liver-biopsy specimens, only the group receiving ursodiol showed a significant improvement in the mean histologic score (p<0.002) and in all the characteristic histologic features except fibrosis.
At the end of this trial, all patients received ursodiol (13-15 mg/kg/day) and were monitored for an additional two years, using the same criteria.
After four years, the overall treatment failure rate was 12% in the ursodiol group and 26% in the original placebo group (p<0.001). Two patients in the ursodiol group had undergone a liver transplantation, compared to 12 in the original placebo group (p<0.001). Survival was similar in the two groups: 5 deaths (various causes) occurred in the ursodiol group and 7 in the original placebo group.
Combined Analysis: The raw data from the three previously mentioned studies have been combined in order to estimate, at four years, the magnitude of the effect of ursodiol treatment on survival free of transplant, defined as time to transplant, or death without transplant.
In these studies, all patients had histologically confirmed, antimitochondrial antibody positive, primary biliary cirrhosis. They were randomized to receive ursodiol (13-15 mg/kg/day) or identical placebo. In one study, blinded randomization continued for four years. In two studies, open label ursodiol was offered to all patients after two years. The endpoint of survival free of liver transplant was compared between the ursodiol and placebo groups using standard life table analyses. Analyses were done on an "intent-to-treat" basis. The risk reduction was calculated in order to define the magnitude of the benefit from ursodiol treatment.
A total of 548 patients were randomized in these studies: 273 received ursodiol and 275, the placebo. Baseline characteristics were comparable at entry in both groups. Median length of follow-up was four years in the ursodiol group, and 3.8 years in the original placebo group. Placebo patients who received ursodiol did so for a mean of one year. There were 47 patients in the ursodiol group and 68 in the placebo group who did not survive nor needed a liver transplant. Survival free of transplantation was extended in patients originally randomized to ursodiol when compared to those on placebo (mean of 3.66 versus 3.45 years, p=0.014). In the ursodiol group the risk of dying or being transplanted was reduced by 32% (± 11%) of that observed in the original placebo group.
Unapproved High-Dose Ursodeoxycholic Acid for the Treatment of Primary Sclerosing Cholangitis: In a recent Clinical Trial (Lindor et al.
, 2009), one hundred fifty adult patients with PSC were enrolled in a long-term, randomized, double-blind controlled trial of high-dose (28-30 mg/kg/day - 1.5 to 2.0 fold the recommended dose) versus placebo. Liver biopsy and cholangiography were performed before randomization and after 5 years. The primary outcome measures were development of cirrhosis, varices, cholangiocarcinoma, liver transplantation, or death. The study was terminated after 6 years due to futility. During therapy, aspartate aminotransferase and alkaline phosphatase levels decreased more in the ursodeoxycholic acid group than the placebo group (P
<0.01), but improvements in liver function tests were not associated with decreased endpoints. By the end of the study, 30 patients in the ursodeoxycholic acid group (39%) versus 19 patients in the placebo group (26%) had reached one of the pre-established clinical endpoints. The risk was 2.1 times greater for death and transplantation in the ursodeoxycholic acid group versus the placebo group (P
=0.038). Serious adverse events were more common in the ursodeoxycholic acid group than the placebo group (63% versus 37% [P
<0.01]). Long-term, high-dose ursodeoxycholic acid therapy was associated with improvement in serum liver function tests in PSC but did not improve survival and was associated with higher rates of serious adverse events.
Administration of ursodiol to rats, rabbits, hamsters and dogs produced modification of bile composition. Bile flow increased as did total bile acid output. In the liver, ursodiol decreased HMG-CoA reductase activity and cholesterol 7-hydroxylase activity. Triglyceride, phospholipid and cholesterol synthesis were decreased.
Studies have demonstrated that ursodiol acts on the hepatic cells and plays a role in the bile acid dependent mechanism of bile formation. Its choleretic activity results from its osmotic activity as well as its stimulating effect on organic ion transport (probably HCO3
studies showed that tauroursodeoxycholic acid (i.e. in the liver ursodiol is conjugated with taurine or glycine) decreased cholesterol uptake in rat jejunal membranes by an unknown mechanism. When ursodiol was perfused into the liver of rats or baboons, bile flow either remained unchanged or increased, bile acid and phospholipid outputs were increased, while cholesterol specific activity was decreased. Tauroursodeoxycholic acid caused only little output of plasma membrane enzyme concentration (5-nucleotidase and alkaline phosphatase), which may represent a characteristic difference between the effects of chenodiol and ursodiol on the hepatobiliary system.
Ursodiol produced minimal or no effect on water and sodium excretion from the GI tract of rats and rabbits. It induced less damage to the GI tract mucosa than chenodiol. These observations correlate well with the clinical findings that diarrhea is infrequent with ursodiol.
Ursodiol lowered blood sugar levels in mice, and increased the volume of pancreatic secretion in rabbits, thus suggesting a stimulatory effect of ursodiol on the pancreas.
At therapeutic doses, ursodiol uncouples the normal relationship between cholesterol, phospholipids and bile acid secretion. Ursodiol inhibits cholesterol absorption in the gut, thereby, reducing cholesterol output into the bile. It further reduces cholesterol secretion into bile. These actions contribute to biliary cholesterol desaturation.
Ursodiol (UDCA) is normally present as a minor fraction of the total bile acids in humans (about 5%). Following oral administration, the majority of ursodiol is absorbed by passive diffusion and its absorption is incomplete.
In healthy subjects, at least 70% of ursodiol (unconjugated) is bound to plasma protein. No information is available on the binding of conjugated ursodiol to plasma protein in healthy subjects or primary biliary cirrhosis (PBC) patients. However, since the efficacy of ursodiol is related to its concentration in bile rather than in plasma, serum levels are not indicative of bioavailability in clinical settings. Its volume of distribution has not been determined, but is expected to be small since the drug is mostly distributed in the bile and small intestine. In bile, UDCA concentration reaches a peak in 1-3 hours.
Once absorbed, ursodiol undergoes hepatic extraction to the extent of about 70% in the absence of liver disease. This leads to low blood levels in the systemic circulation. As the severity of liver disease increases, the extent of extraction decreases. In the liver, ursodiol is conjugated with glycine or taurine, then secreted into bile. These conjugates of ursodiol are absorbed in the small intestine by passive and active mechanisms. The conjugates can also be deconjugated in the ileum by intestinal enzymes, leading to the formation of free ursodiol that can be reabsorbed and reconjugated in the liver. Nonabsorbed ursodiol passes into the colon where it is mostly 7-dehydroxylated to lithocholic acid. Some ursodiol is epimerized to chenodiol (CDCA) via a 7-oxo intermediate. Chenodiol also undergoes 7-dehydroxylation to form lithocholic acid. These metabolites are poorly soluble and excreted in the feces. A small portion of lithocholic acid is reabsorbed, conjugated in the liver with glycine or taurine, and sulfated at the 3 position. The resulting sulfated lithocholic acid conjugates are excreted in bile and then lost in feces.
Lithocholic acid, when administered chronically to animals, causes cholestatic liver injury that may lead to death from liver failure in certain species unable to form sulfate conjugates. Ursodiol is 7-dehydroxylated more slowly than chenodiol. For equimolar doses of ursodiol and chenodiol, steady state levels of lithocholic acid in biliary bile acids are lower during ursodiol administration than with chenodiol administration. Humans and chimpanzees can sulfate lithocholic acid. Although liver injury has not been associated with ursodiol therapy, a reduced capacity to sulfate may exist in some individuals. Nonetheless, such a deficiency has not yet been clearly demonstrated and must be extremely rare, given the several thousand patient-years of clinical experience with ursodiol.
Ursodiol is excreted primarily in the feces. With treatment, urinary excretion increases, but remains less than 1%, except in severe cholestatic liver disease.
Toxicology: Acute Toxicity:
Results from various studies indicated that oral, subcutaneous, intraperitoneal and intravenous administration of ursodiol in mice, rats, hamsters, and dogs at single doses of 1.21 to 10 g/kg over a seven-day observation period, did not cause any deaths in any of the species used. For mice and dogs, the LD50
was >10 g/kg, and rats had an LD50
over >5 g/kg. Hamsters were found to be more sensitive than rats and dogs as the LD50
for this species was calculated to be >3.16 g/kg.
No significant sex difference was seen. Toxic signs observed included: inhibition of motility, CNS toxicity such as ataxia and sedation, GI tract disturbances such as vomiting, salivation, decreased body weight and appetite.
Two short-term toxicological studies were conducted in rats. Ursodiol was administered orally at a daily dose of 0.5 to 4.0 g/kg/day for five weeks or alternatively at doses of 0.0625 to 0.5 g/kg daily for five weeks by the intraperitoneal route.
No deaths occurred in the study with oral administration of ursodiol, whereas, one male and one female rat died in the 0.25 g/kg group, and six males and four females died in the 0.5 g/kg group of the study in which ursodiol was administered by the intraperitoneal route. The most marked autopsy findings were dilation and adhesion of intraperitoneal organs. As these became gradually more severe, retention of ascites and renal abscesses appeared. It was concluded that 0.0625 g/kg was the safe dose and 0.125 g/kg was near the maximum tolerable dose.
Ursodiol orally administered to rats did not cause any clinical symptoms or any changes in laboratory parameters.
Four long-term toxicity studies were performed in rats and monkeys. The results of these studies are summarized as follows.
Rat Study: In one study, ursodiol was administered orally to Sprague-Dawley rats for 26 weeks. The dosage varied between 0.1 and 2.5 g/kg/day and various observations were performed daily.
No deaths occurred during the experimental period. Lower doses (0.1 and 0.5 g/kg) were well tolerated. However, a 2.5 g/kg dose of ursodiol resulted in significant reduction of body weight gain and food intake. No significant changes were seen in laboratory findings and clinical observations.
In the second study, male Wistar rats were given 0.5 to 4.0 g/kg of ursodiol orally for 26 consecutive weeks and a variety of observations were made.
The results indicated a decrease in body weight gain and an increase in water intake in the 4.0 g/kg dosage group. Eight rats (four at the high dose level) died during the experiment. The cause of death was attributed to pathological changes in the lung and intestine. Laboratory findings revealed no abnormal changes that might be ascribed to drug administration.
Monkey study: A 26-week study was performed in Rhesus monkeys. Ursodiol at doses of 0.04 and 0.10 g/kg/day were given orally.
No deaths occurred during the treatment period. There were no abnormalities in the laboratory parameters.
In a 52-week study, ursodiol at a dose of 0.05 to 0.9 g/kg was administered to Rhesus monkeys. The animals were observed daily for various clinical signs and symptoms. They were weighed weekly, blood and urine was collected and examined every three months. After 52 weeks, the animals were sacrificed and an autopsy was performed.
Three animals belonging to the 0.90 g/kg group, two in the 0.30 g/kg group and one in the 0.10 g/kg died during the study. These deaths were considered to be related to ursodiol. Liver toxicity (small round-cell infiltration, vacuolar degeneration, necrosis of hepatic cells, phagocytosis and hepatic abscess) and thickening of the alveolar wall of the lungs was observed in deceased animals from all groups. Necrosis of the stomach wall was observed in deceased animals from the 0.90 g/kg group. A regression of body weight gain was seen in the 0.30 and 0.90 g/kg groups. Episodes of diarrhea were observed in all groups including the control group. No remarkable changes were noted in hematological, urinary, electrographic, blood pressure and ocular fundi examinations. However, serum SGPT, AST and ALP increased significantly.
From the previously mentioned findings, it was concluded that ursodiol, when administered at daily doses exceeding 0.10 g/kg, caused hepatotoxicity in Rhesus monkeys.
In two 24-month oral carcinogenicity studies in mice, ursodiol at doses up to 1000 mg/kg/day (3000 mg/m2
/day) was not tumorigenic. Based on body surface area, for a 50 kg person of average height (1.46 m2
body surface area), this dose represents 5.4 times the recommended maximum clinical dose of 15 mg/kg/day (555 mg/m2
In a two-year oral carcinogenicity study in Fischer 344 rats, ursodiol at doses up to 300 mg/kg/day (1800 mg/m2
/day, 3.2 times the recommended maximum human dose based on body surface area) was not tumorigenic.
In a life-span (126-138 weeks) oral carcinogenicity study, Sprague-Dawley rats were treated with doses of 33 to 300 mg/kg/day, 0.4 to 3.2 times the recommended maximum human dose based on body surface area. Ursodiol produced a significantly (p <0.5, Fisher's exact test) increased incidence of pheochromocytomas of the adrenal medulla in females of the highest dose group.
In 103-week oral carcinogenicity studies of lithocholic acid, a metabolite of ursodiol, doses up to 250 mg/kg/day in mice and 500 mg/kg/day in rats did not produce any tumors. In a 78-week rat study, intrarectal instillation of lithocholic acid (1 mg/kg/day) for 13 months did not produce colorectal tumors. A tumor-promoting effect was observed when it was administered after a single intrarectal dose of a known carcinogen N-methyl-N'-nitro-N-nitrosoguanidine. On the other hand, in a 32-week rat study, ursodiol at a daily dose of 240 mg/kg (1,440 mg/m2
, 2.6 times the maximum recommended human dose based on body surface area) suppressed the colonic carcinogenic effect of another known carcinogen, azoxymethane.
Ursodiol was not genotoxic in the Ames test, the mouse lymphoma cell (L5178Y, TK+/-
) forward mutation test, the human lymphocyte sister chromatid exchange test, the mouse spermatogonia chromosome aberration test, the Chinese hamster micronucleus test and the Chinese hamster bone marrow cell chromosome aberration test.
Reproduction and Teratology:
Ursodiol did not show any teratogenic effect in mice, rats and rabbits at oral dose levels up to 1.5, 4.0 and 0.3 g/kg, respectively, and in mice and rats at intraperitoneal dose levels up to 0.2 g/kg. Furthermore, it did not influence mating performance and fertility, except in one study where these parameters were slightly reduced in female rats receiving 2.0 g/kg. Breeding capacity was not altered by the administration of ursodiol.
Oral administration of 1.5 g/kg in mice and 2.0 g/kg in rats induced a decrease in maternal weight gain and lower mean weights of live fetuses. In addition, the number of resorption sites was increased in rats at a dose of 2.0 g/kg. Rabbits were much more sensitive than mice and rats to the toxic action of ursodiol. The administration of doses of 0.1 g/kg and greater caused a decrease in food consumption, maternal body weight gain and motor activity as well as an increase in resorption sites, and absorption death.
Intraperitoneal administration of 0.2 g/kg ursodiol to mice and rats induced a decrease in maternal body weight gain, low fetal weight and an increase of resorption sites.