A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Rezulin Pharmacology, Pharmacokinetics, Studies, Metabolism - Troglitazone (removed from the US market 3/21/00)
Rezulin Pharmacology, Pharmacokinetics, Studies, Metabolism - Troglitazone (removed from the US market 3/21/00)
CLINICAL PHARMACOLOGY
Mechanism of Action
Troglitazone is a thiazolidinedione
antidiabetic agent
that lowers blood glucose by improving target
cell response
to insulin. It has a unique mechanism of action
that is dependent on the presence of insulin
for activity. Troglitazone decreases hepatic
glucose output
and increases insulindependent glucose disposal in skeletal
muscle. Its mechanism
of action is thought
to involve binding to nuclear
receptors (PPAR) that regulate the transcription
of a number of insulin
responsive genes critical
for the control of glucose
and lipid metabolism. Unlike sulfonylureas, troglitazone
is not an insulin secretagogue.
In animal models of
diabetes, troglitazone
reduces the hyperglycemia. hyperinsulinemia. and hypertriglyceridemia
characteristic
of insulin-resistant states such
as type II diabetes. Plasma
lactate and ketone
body formation are also
decreased. The metabolic changes produced by troglitazone
result from the increased responsiveness of insulin-dependent tissues
and are observed in numerous animal
models of insulin resistance.
Treatment with troglitazone did not affect
pancreatic weight,
islet number
or glucagon content. but did increase regranulation of the pancreatic
beta cells in rodent models
of insulin resistance.
Since troglitazone
enhances the effects of circulating insulin
(by decreasing insulin resistance), it does not lower blood
glucose in animal
models that lack endogenous
insulin.
Pharmacokinetics and Drug Metabolism
Maximum plasma concentration
(Cmax) and the area
under plasma concentration- time
curve (AUC) of troglitazone
increase proportionally with increasing doses over the dose
range of 200 to 600 mg/day
(Table 1). Following daily drug
administration, steady-state plasma
concentrations of troglitazone
are reached within 3 to 5 days.
TABLE 1.
|
Mean(+1 SD) Steady-State Pharmacokinetics of
Troglitazone in 21 Normal Volunteers
|
|
Dose
(mg/day)
|
Cmax
mL
|
AUC (0-24)
(ug.hr/mL)
|
CL/F*
(mL/min)
|
|
200
|
0.90 (0.36)
|
7.4 (2.4)
|
500 (187)
|
|
400
|
1.61 (0.69)
|
13.4 (5.5)
|
601 (324)
|
|
600
|
2.82 (1.03)
|
22.1 (6.8)
|
496 (166)
|
| *CL/F = Apparent oral
clearance. |
Absorption: Troglitazone is absorbed rapidly following
oral administration; the time
for maximum plasma
concentration
(tmax) occurs within 2 to 3 hours. Food increases the
extent of absorption
by 30% to 85%, thus Rezulin should be taken with a meal
to enhance systemic drug availability.
Distribution: Mean apparent
volume of distribution
(V/F) of troglitazone following multiple-dose administration
ranges from 10.5 to 26.5 Ukg of body weight. Troglitazone is extensively
bound ( > 99%) to serum
albumin. [14C] troglitazone
partitions into red blood
cells (- 5% of whole blood
radioactivity).
Metabolism: In
6 healthy male
volunteers given a single 400 mg
dose of [14C]
troglitazone after
14 days of treatment with 400 mg
troglitazone tablets,
the major metabolites found in the plasma were the sulfate
conjugate (Metabolite
1) followed by the quinone
metabolite (Metabolite 3). Only 3.1% of the dose
was detected in the urine; this was primarily in the form
of the glucuronide
conjugate (Metabolite
2), which is present
in negligible amounts in the plasma. In
both normal volunteers
and patients with type
II diabetes, steady-state
levels of Metabolite 1 are 6 to 7 times that of troglitazone
and Metabolite 3.
Troglitazone incubated with expressed human
P450 1A1, 1 A2. 2A6. 2B6, 2D6, 2E1, and 3A4 in the presence and
absence of known inhibitors
of these enzymes showed no
Metabolite 3 formation
above levels in control
samples. Studies in human
microsomes suggest that Metabolite 3 is not subject
to further metabolism
by the major P450 isozymes. Troglitazone did not inhibit any of
the major P450 enzymes at clinically relevant concentrations. The
inhibitory characteristics of Metabolite 3 have not been investigated
directly.
The results of human
in vivo drug interaction
trials suggest that troglitazone induces cytochrome
P450 3A4 at clinically relevant doses (see ).
Excretion: Following oral
administration
of [14 C] troglitazone, approximately 88% of the radioactivity
is recovered in feces
(85%) and urine (3%). Unchanged troglitazone
is not recovered in urine
following oral administration. Mean plasma
elimination half-life
of troglitazone ranges from 16 to 34 hours.
Special Populations
Renal Insufficiency: In
patients with various degrees of renal
function, the apparent
clearance of total
and unbound troglitazone and the plasma
elimination half-life
of troglitazone, Metabolite 1, and Metabolite 3 do not correlate
with creatinine clearance.
Thus, dose adjustment in
patients with renal dysfunction
is not necessary (see DOSAGE
AND ADMINISTRATION).
Hepatic Insufficiency: Troglitazone, Metabolite 1,
and Metabolite 3 plasma
concentrations in patients with chronic
liver disease (Childs-Pugh
Grade B or C) were increased by approximately 30%, 40 % and 100%
respectively, compared to those in healthy
subjects without hepatic dysfunction. There was no
change in plasma protein
binding. No adverse events
were noted in any group
that were attributed to drug. However, Rezulin therapy should not
be initiated if the patient
exhibits clinical or
laboratory evidence of active liver
disease (e.g., ALT>
3 times the upper limit of normal); see WARNINGS.
Geriatrics: Steady-state pharmacokinetics
of troglitazone, Metabolite 1 and Metabolite 3 in healthy
elderly subjects are comparable to those seen in young adults.
Pediatrics: Pharmacokinetic data in the pediatric
population are not available.
Gender: Plasma concentrations of troglitazone
and its metabolites are similar in men and women.
Ethnicity: Pharmacokinetics of troglitazone
and its metabolites are similar among various ethnic
groups.
Pharmacodynamics and Clinical Effects
Clinical studies demonstrate that Rezulin improves insulin
sensitivity in insulin-resistant patients. Rezulin increases insulin-dependent
glucose disposal, reduces hepatic
gluconeogenesis, and enhances cellular
responsiveness to insulin
and thus, improves dysfunctional glucose
homeostasis. In patients
with type II diabetes,
the decreased insulin
resistance produced
by Rezulin causes decreases in serum
glucose, plasma
insulin, and hemoglobin
A1C. Unlike sulfonylureas, Rezulin does not stimulate
insulin secretion. Addition
of Rezulin to a sulfonylurea
has a synergistic
effect since both agents
act to improve glucose
tolerance by different
but complementary mechanisms. These effects occur without weight
loss and persist for 52
weeks of Rezulin treatment.
In clinical trials
of Rezulin as monotherapy
or in combination, an increase in LDL
(up to 1 3%), HDL (up to
16%), and total cholesterol
(total-C) (up to 5%) occurred while total-C/ HDL
and LDUHDL ratios did not change. The increase in total cholesterol
is due to the increase in HDL
and LDL cholesterol. Despite
the observed increase in total and LDL
cholesterol, fraction
levels are not increased.
Patients treated with Rezulin as monotherapy
or in combination with other agents exhibited a reduction
in fasting (-13% to
-26%) and postprandial triglyceride levels. For patients on Rezulin
and insulin, reduction
in insulin doses may occur following Rezulin therapy
and some attenuation of the triglyceride reduction
may occur.
Pharmacokinetic estimators of systemic
troglitazone exposure
do not improve the prediction of pharmacodynamic response
beyond that obtained based upon knowledge of the administered dose.
Rezulin has only been shown to exert its antihyperglycemic effect
in the presence of insulin. Because Rezulin does not stimulate
insulin secretion, hypoglycemia
in patients treated with Rezulin alone is not to be expected. Because
of this insulin-dependent mechanism
of action, Rezulin should not be used in patients with type
l diabetes.
Clinical Studies
Combination With Sulfonylureas: A Q-week, double-blind,
placebo-controlled study of Rezulin and 12 mg
micronized glyburide, alone and in combination, was conducted in
patients with type II diabetes
(N= 552), who had failed to achieve adequate glycemic control
(FSG of 224 mg/dL and HbA1C of 9.6%) while on maximal
doses of a sulfonylurea. Patients randomized to receive micronized
glyburide showed mean
increases in FSG and HbA1C. Similarly, patients who switched
from a sulfonylurea to Rezulin monotherapy
also demons rated increases in FSG and HbA1C.
TABLE 2.
|
Combination Therapy With Glyburide: Mean Difference
From 12 mg
Micronized Glyburide Monotherapy (1 yr)
|
| |
200 mg Rezulin
+ Glyburide
|
400 mg Rezulin
+ Glyburide
|
600 mg Rezulin
+ Glyburide
|
| FSG (mg/dL)
|
| Mean Baseline |
226
|
231
|
220
|
| Adjusted Mean Change
From Baseline |
-31
|
-38
|
-56
|
| Adjusted Mean Difference
|
-54"
|
-61**
|
-79**
|
| From Glyburide |
| HbA 1C ( %)
|
| Mean Baseline |
9.5
|
9.7
|
9.5
|
| Adjusted Mean Change
From Baseline |
-0.7
|
-0.9
|
-1.8
|
| Adjusted Mean Difference
|
-1.6"
|
-1.8**
|
-2.7* ’
|
| From Glyburide |
| Insulin (uU/mL) |
| Mean Baseline |
28.2
|
24.9
|
26.4
|
| Adjusted Mean Change
From Baseline |
-3.8
|
-5.9
|
-6.1
|
| Adjusted Mean Difference
|
-2.4
|
-4.4'
|
-4.6"
|
| From Glyburide |
| * p <0.05 compared to
continuation of glyburide
monotherapy.
** p <0. 0001 compared to continuation of glyburide
monotherapy.
|
TABLE 3.
|
Combination Therapy With Glyburide: Percent of Patients
Achieving Glycemic Control at End of Study (1 yr)
|
| Rezulin (mg) |
0
|
200
|
400
|
600
|
| Glyburide (mg) |
12
|
12
|
12
|
12
|
| HbA, 1C % |
| <7% |
1
|
22
|
21
|
41
|
| <8% |
10
|
33
|
33
|
60
|
A combination of 200, 400, or 600 mg
of Rezulin with micronized glyburide
achieved lower levels of fasting
plasma glucose and HbA
1C C levels than either agent
achieved alone (see Tables 2 and 3). These improvements in glycemic
control were associated
with mean weight gains of 5.8 to 13.1 pounds. To eliminate
weight as a confounding
factor in this study. patients had been instructed to follow a diet
to maintain current
weight.
Combination With Insulin: Two clinical
studies were conducted to evaluate the effects of Rezulin on glycemic
control and insulin
dose in patients with type
II diabetes who were
being treated with insulin.
In one 6-month, double-blind, placebo-controlled study in insulin-treated
type II diabetic patients
receiving a mean of 73
(range 27- l43) units/day of insulin
with a mean baseline
HbA 1C of 9.42 (range 7.04-12.48), Rezulin (200 or 600
mg/day) or placebo was
added to the insulin
therapy. Investigators were instructed to reduce
insulin doses only if
two consecutive FSGs were <100 mg/dL. Rezulin-treated patients
showed a significant (p< 0.000l ) reduction
in HbA1C compared with patients who received placebo
(see Table 4).
Thirty percent of patients
treated with 200 mg Rezulin
and 57% of patients treated with 600 mg
Rezulin had an HbA 1C value
below 8 % at the end of
the study compared with 11% of placebo
treated patients. Accompanying this improvement in glycemic control
was a significant
(p< 0. 0001) decrease in exogenous
Insulin dosage of 15%
in the 200 mg Rezulin treatment
group and 42% in the 600 mg
Rezulin treatment
group compared with 1%
in the placebo group
HbA 1C values and Insulin dose
as a function of duration
of Rezulin treatment.
TABLE 4.
|
Combination Therapy with Insulin:
Mean Change From Baseline at 6 Months
|
| |
Troglitazone
|
| Parameter |
Placebo
|
200 mg
|
600 mg
|
| N |
118
|
116
|
116
|
| HbA 1C (%)
|
| Mean Baseline (SE) |
9.43 (0.10)
|
9.51 (0.10)
|
9.32 (0.11)
|
| Mean Change From Baseline
(SE) 1 |
-0.12 (0.10)
|
-0.84 (0.10)
|
-1.41 (0.10)
|
| Adjusted Mean Difference
From Placebo (SE) |
--
|
-0.72 (0.14)"
|
-1.29 (0.14)*
|
| Percent Mean Change From
Baseline |
-1.3
|
-8.8
|
-15.1
|
| Insulin
daily dosage (units)
|
| Mean Baseline (SE) |
75 (3.3)
|
73 (3.4)
|
71 (2.9)
|
| Mean Change From Baseline
(SE) |
1 (2.1)
|
-11 (2.1)
|
-29 (2.2)
|
| Adjusted Mean Difference
From Placebo (SE) |
--
|
-12 (3.0)*
|
-30 (3.0)*
|
| Percent Mean Change From
Baseline |
1
|
-15
|
-42
|
| * p <0. 0001 |
A second 6- month, double-blind, placebo-controlled study in insulin-treated
type II diabetics who previously
were poorly controlled on oral
agents receiving 30 to 150 units insulin/day assessed the use of
Rezulin in reducing exogenous
insulin dosage
while improving glycemic control as measured by capillary
blood glucose.
Patients treated with 200 mg
(N= 75) and 400 mg (N= 76)
Rezulin had their insulin
doses decreased by 41% and 58%, respectively, compared to a reduction
of insulin dose
in the placebo group
(N’= 71) of 14% while maintaining or improving glycemic control.
Forty-one percent of
the patients in the 400 mg
group decreased their
insulin injection
frequency an average
from 3 to 1 injections per
day; 19% of patients receiving placebo
decreased their injection
frequency an average
from 3 to 2 injections per
day. Insulin therapy was discontinued in 15% of patients in the
400 mg Rezulin group compared
to 7% in the 200 mg group
and 1.5% in the placebo
group.
A greater than 50 % reduction
in insulin dose
was achieved by 51% of patients on 200 mg
and 70% on 400 mg once daily
as compared to 17% on placebo.
Monotherapy: Three clinical
trials, including 2 placebo-controlled studies with durations from
12 to 26 weeks have been conducted to study the use of Rezulin as
monotherapy. These studies have examined Rezulin doses from 100
to 600 mg/day in approximately 1500 patients. The patients studied
have included patients previously treated with a sulfonylurea
who were studied following prior therapy
wash out (N= 1265) and
patients previously treated with diet
only (N= 230). In patients
previously treated with a sulfonylurea, Rezulin treatment
did not result in an improvement in glycemic control beyond that
seen with the patients prior therapy
although glucose lowering was significantly better than that seen
with placebo treatment
for patients previously treated with diet,
Rezulin doses of 200 mg, 400 mg and 600 mg/day were associated with
improved FSG compared to placebo. However, only the 600 mg/day dose
resulted in a difference compared with placebo that was statistically
significant in both
studies (see Table 5). At 600 mg
per day, 58% of patients
previously treated with diet
in the 12-week study and 47% of patients previously treated with
diet in the 26-week study
(versus placebo values
of 28% 280s and 21%, respectively) had a response to Rezulin of
> 30 mg/dL reduction
from baseline in fasting
serum glucose.
TABLE 5.
|
Glycemic Parameters in Diet-Failure Patients
|
| |
12 Week Study
|
| |
Placebo
|
200
|
400
|
600
|
| N |
19
|
23
|
20
|
33
|
| FSG (mg/ dL) |
| Mean Baseline |
168
|
169
|
181
|
196
|
| Adjusted Mean Change
From Baseline |
14
|
-14
|
-20
|
-38
|
| Adjusted Mean Difference
From Placebo |
|
-31
|
-37’
|
-55’
|
| HbA 1C, (%) |
| Mean Baseline |
8
|
8.2
|
86
|
8.6
|
| Adjusted Mean Change
From Baseline |
-0.1
|
-0.6
|
-0.6
|
-0.8
|
| |
26 Week Study
|
| |
Placebo
|
200
|
400
|
600
|
| N |
18
|
18
|
19
|
15
|
| FSG (mg/ dL) |
| Mean Baseline |
202
|
191
|
201
|
201
|
| Adjusted Mean Change
From Baseline |
-6
|
-24
|
-17
|
-48
|
| Adjusted Mean Difference
From Placebo |
|
-18
|
-10
|
-42’
|
| HbA 1C (%) |
| Mean Baseline |
8.7
|
8.3
|
8.5
|
8.6
|
| Adjusted Mean Change
From Baseline |
0.4
|
-0.2
|
0.3
|
-1
|
| Adjusted Mean Difference
From Placebo |
|
-0.6
|
-0.1
|
-1.4’
|
| *p< 0.05 |
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