Chenodal (Chenodiol) - Description and Clinical Pharmacology

DESCRIPTION

Chenodiol is the non-proprietary name for chenodeoxycholic acid,
a naturally occurring human bile acid. It is a bitter-tasting white powder
consisting of crystalline and amorphous particles freely soluble in methanol,
acetone and acetic acid and practically insoluble in water. Its chemical name is
3alpha, 7alpha-dihydroxy-5beta-cholan-24-oic acid (C24H40O4), it has a molecular weight of
392.58, and its structure is shown below;

CLINICAL PHARMACOLOGY

At therapeutic doses, chenodiol suppresses hepatic synthesis of
both cholesterol and cholic acid, gradually replacing the latter and its
metabolite, deoxycholic acid in an expanded bile acid pool. These actions
contribute to biliary cholesterol desaturation and gradual dissolution of
radiolucent cholesterol gallstones in the presence of a gall-bladder visualized
by oral cholecystography. Chenodiol has no effect on radiopaque (calcified)
gallstones or on radiolucent bile pigment stones.

Chenodiol is well absorbed from the small intestine and taken up by the liver
where it is converted to its taurine and glycine conjugates and secreted in
bile. Owing to 60 % to 80% first-pass hepatic clearance, the body pool of
chenodiol resides mainly in the enterohepatic circulation; serum and urinary
bile acid levels are not significantly affected during chenodiol therapy.

At steady-state, an amount of chenodiol near the daily dose escapes to the
colon and is converted by bacterial action to lithocholic acid. About 80% of the
lithocholate is excreted in the feces; the remainder is absorbed and converted
in the liver to its poorly absorbed sulfolithocholyl conjugates. During
chenodiol therapy there is only a minor increase in biliary lithocholate, while
fecal bile acids are increased three- to fourfold.

Chenodiol is unequivocally hepatotoxic in many animal species, including
sub-human primates at doses close to the human dose. Although the theoretical
cause is the metabolite, lithocholic acid, an established hepatotoxin, and man
has an efficient mechanism for sulfating and eliminating this substance, there
is some evidence that the demonstrated hepatotoxicity is partly due to chenodiol
per se. The hepatotoxicity of
lithocholic acid is characterized biochemically and morphologically as
cholestatic.

Man has the capacity to form sulfate conjugates of lithocholic acid.
Variation in this capacity among individuals has not been well established and a
recent published report suggests that patients who develop chenodiol-induced
serum aminotransferase elevations are poor sulfators of lithocholic acid (see   ADVERSE
REACTIONS and    WARNINGS).

General Clinical Results

 Both the desaturation of bile and the clinical dissolution of cholesterol gallstones are dose-related. In
the National Cooperative Gallstone Study (NCGS) involving 305 patients in each
treatment group, placebo and chenodiol dosages of 375 mg and 750 mg per day were
associated with complete stone dissolution in 0.8%, 5.2% and 13.5%,
respectively, of enrolled subjects over 24 months of treatment. Uncontrolled
clinical trials using higher doses than those used in the NCGS have shown
complete dissolution rates of 28 to 38% of enrolled patients receiving body
weight doses of from 13 to 16 mg/kg/day for up to 24 months. In a prospective
trial using 15 mg/kg/day, 31% enrolled surgical-risk patients treated more than
six months (n = 86) achieved complete confirmed dissolutions.

Observed stone dissolution rates achieved with chenodiol treatment are higher
in subgroups having certain pretreatment characteristics. In the NCGS, patients
with small {less than 15 mm in diameter} radiolucent stones, the observed rate
of complete dissolution was approximately 20% on 750 mg/day. In the uncontrolled
trails using 13 to 16 mg/kg/day doses of chenodiol, the rates of complete
dissolution for small radiolucent stones ranged from 42% to 60%. Even higher
dissolution rates have been observed in patients with small floatable stones.
(See Floatable versus Nonfloatable Stones, below). Some
obese patients and occasional normal weight patients fail to achieve bile
desaturation even with doses of chenodiol up to 19 mg/kg/day for unknown
reasons. Although dissolution is generally higher with increased dosage of
chenodiol, doses that are too low are associated with increased cholecystectomy
rates (see    ADVERSE REACTIONS).

Stones have recurred within five years in about 50% of patients following
complete confirmed dissolutions. Although retreatment with chenodiol has proven
successful in dissolving some newly formed stones, the indications for and
safety of retreatment are not well defined. Serum aminotransferase elevations
and diarrhea have been notable in all clinical trials and are dose-related
(refer to    ADVERSE REACTIONS and WARNINGSsections
for full information).

Floatable versus Nonfloatable Stones

A major finding in clinical trials was a difference between floatable and nonfloatable stones,
with respect to both natural history and response to chenodiol. Over the
two-year course of the National Cooperative Gallstone Study (NCGS), placebo –
treated patients with floatable stones (n = 47) had significantly higher rates
of biliary pain and cholecystectomy than patients with nonfloatable stones (n =
258) (47% versus 27% and 19%versus 4%, respectively). Chenodiol treatment (750
mg/day) compared to placebo was associated with a significant reduction in both
biliary pain and the cholecystectomy rates in the group with floatable stones
(27% versus 47% and 1.5% versus 19%, respectively). In an uncontrolled clinical
trial using 15 mg/kg/day, 70% of the patients with small (less than 15 mm)
floatable stones (n = 10) had complete confirmed dissolution.

In the NCGS in patients with nonfloatable stones, chenodiol produced no
reduction in biliary pain and showed a tendency to increase the cholecystectomy
rate (8% versus 4%). This finding was more pronounced with doses of chenodiol
below 10 mg/kg. The subgroup of patients with nonfloatable stones and a history
of biliary pain had the highest rates of cholecystectomy and aminotransferase
elevations during chenodiol treatment. Except for the NCGS subgroup with
pretreatment biliary pain, dose-related aminotransferase elevations and diarrhea
have occurred with equal frequency in patients with floatable or nonfloatable
stones. In the uncontrolled clinical trial mentioned above, 27% of the patients
with nonfloatable stones (n = 59) had complete confirmed dissolutions, including
35% with small (less than 15 mm)(n= 40) and only 11% with large, nonfloatable
stones (n= 19).

Of 916 patients enrolled NCGS, 17.6% had stones seen in upright form
(horizontal X-ray beam) to float in the dye-laden bile during oral
cholecystography using iopanoic acid. Other investigators report similar
findings. Floatable stones are not detected by ultrasonography in the absence
for dye. Chemical analysis has shown floatable stones to be essentially pure
cholesterol).

Other Radiographic and Laboratory Features

Radiolucent stones may have rims or centers of opacity representing
calcification. Pigment stones and partially calcified radiolucent stones do not
respond to chenodiol. Subtle calcification can sometimes be detected in flat
film X-rays, if not obvious in the oral cholecystogram. Among nonfloatable
stones, cholesterol stones are more apt than pigment stones to be smooth
surfaced, less than 0.5 cm in diameter, and to occur in numbers less than 10. As
stone size number and volume increase, the probability of dissolution within 24
months decreases. Hemolytic disorders, chronic alcoholism, biliary cirrhosis and
bacterial invasion of the biliary system predispose to pigment gallstone
formation. Pigment stones of primary biliary cirrhosis should be suspected in
patients with elevated alkaline phosphates, especially if positive
anti-mitochondrial antibodies are present. The presence of microscopic
cholesterol crystals in aspirated gallbladder bile, and demonstration of
cholesterol super saturation by bile lipid analysis increase the likelihood that
the stones are cholesterol stones.

PATIENT SELECTION