CLINICAL PHARMACOLOGY
Mechanism of Action
Rosiglitazone, a member of the thiazolidinedione
class of antidiabetic agents, improves glycemic control
by improving insulin sensitivity. Rosiglitazone is a highly
selective and potent agonist for the peroxisome proliferator-activated
receptor-gamma (PPARg). In humans, P.A. receptors are found
in key target tissues for insulin action such as adipose
tissue, skeletal muscle, and liver. Activation of PPARg
nuclear receptors regulates the transcription of insulinresponsive
genes involved in the control of glucose production, transport,
and utilization. In addition, PPARg-responsive genes also
participate in the regulation of fatty acid metabolism.
Insulin resistance is a common feature characterizing the
pathogenesis of type 2 diabetes. The antidiabetic activity
of rosiglitazone has been demonstrated in animal models
of type 2 diabetes in which hyperglycemia and/or impaired
glucose tolerance is a consequence of insulin resistance
in target tissues. Rosiglitazone reduces blood glucose concentrations
and reduces hyperinsulinemia in the ob/ob obese mouse, db/db
diabetic mouse, and fa/fa fatty Zucker rat. Rosiglitazone
also prevents the development of overt diabetes in both
the db/db mouse and Zucker fa/fa Diabetic Fatty rat models.
In animal models, rosiglitazone’s antidiabetic activity
was shown to be mediated by increased sensitivity to insulin’s
action in the liver, muscle, and adipose tissues. The expression
of the insulin-regulated glucose transporter GLUT-4 was
increased in adipose tissue. Rosiglitazone did not induce
hypoglycemia in animal models of type 2 diabetes and/or
impaired glucose tolerance.
Pharmacokinetics and Drug Metabolism
Maximum plasma concentration (Cmax) and the area
under the curve (AUC) of rosiglitazone increase in a dose-proportional
manner over the therapeutic dose range (Table 1). The elimination
half-life is 3 to 4 hours and is independent of dose.
Table 1. Mean (SD) Pharmacokinetic Parameters for
Rosiglitazone Following Single Oral Doses (N= 32)
| Parameter |
1 mg Fasting
|
2 mg Fasting
|
8 mg Fasting
|
8 mg Fed
|
| AUC 0-¥
[ng.hr./mL]
|
358
(112)
|
733
(184)
|
2971
(730)
|
2890
(795)
|
| Cmax
[ng/mL]
|
76
(13)
|
156
(42)
|
598
(117)
|
432
(92)
|
| Half-life
[hr.] |
3.16
(0.72)
|
3.15
(0.39)
|
3.37
(0.63)
|
3.59
(0.70)
|
| CL/F* [L/hr] |
3.03
(0.87)
|
2.89
(0.71)
|
2.85
(0.69)
|
2.97
(0.81)
|
* CL/F = Oral Clearance
Absorption
The absolute bioavailability of rosiglitazone is
99%. Peak plasma concentrations are observed about 1 hour
after dosing. Administration of rosiglitazone with food
resulted in no change in overall exposure (AUC), but there
was an approximately 28% decrease in Cmax and a delay in
Tmax (1.75 hours). These changes are not likely to be clinically
significant; therefore, Avandia may be administered with
or without food.
Distribution
The mean (CV%) oral volume of distribution (Vss/
F) of rosiglitazone is approximately 17.6 (30%) liters,
based on a population pharmacokinetic analysis. Rosiglitazone
is approximately 99.8% bound to plasma proteins, primarily
albumin.
Metabolism
Rosiglitazone is extensively metabolized with no
unchanged drug excreted in the urine. The major routes of
metabolism were N-demethylation and hydroxylation, followed
by conjugation with sulfate and glucuronic acid. All the
circulating metabolites are considerably less potent than
parent and therefore, are not expected to contribute to
the insulin-sensitizing activity of rosiglitazone.
In vitro data demonstrate that rosiglitazone is predominantly
metabolized by Cytochrome P450 (CYP) isoenzyme 2C8, with
CYP2C9 contributing as a minor pathway.
Excretion
Following oral or intravenous administration of
[14C] rosiglitazone maleate, approximately 64% and 23% of
the dose was eliminated in the urine and in the feces, respectively.
The plasma half-life of [14C] related material ranged from
103 to 158 hours.
Population Pharmacokinetics in Patients with Type
2 Diabetes
Population pharmacokinetic analyses from three
large clinical trials including 642 men and 405 women with
type 2 diabetes (aged 35 to 80 years) showed that the pharmacokinetics
of rosiglitazone are not influenced by age, race, smoking,
or alcohol consumption. Both oral clearance (CL/F) and oral
steady-state volume of distribution (Vss/F) were shown to
increase with increases in body weight. Over the weight
range observed in these analyses (50 to 150 kg), the range
of predicted CL/F and Vss/F values varied by <1.7-fold
and <2.3-fold, respectively. Additionally, rosiglitazone
CL/F was shown to be influenced by both weight and 124 gender,
being lower (about 15%) in female patients.
Special Populations
Age: Results of the population pharmacokinetic
analysis (n= 716 <65 years; n= 331 ³65 years) showed
that age does not significantly affect the pharmacokinetics
of rosiglitazone.
Gender: Results of the population pharmacokinetics
analysis showed that the 132 mean oral clearance of rosiglitazone
in female patients (n= 405) was approximately 6% lower compared
to male patients of the same body weight (n= 642).
As monotherapy and in combination with metformin, Avandia
improved glycemic control in both males and females. In
metformin combination studies, efficacy was demonstrated
with no gender differences in glycemic response.
In monotherapy studies, a greater therapeutic response was
observed in females; however, in more obese patients, gender
differences were less evident. For a given body mass index
(BMI), females tend to have a greater fat mass than males.
Since the molecular target PPARg is expressed in adipose
tissues, this differentiating characteristic may account,
at least in part, for the greater response to Avandia in
females. Since therapy should be individualized, no dose
adjustments are necessary based on gender alone.
Hepatic Impairment: Unbound oral clearance
of rosiglitazone was significantly lower in patients with
moderate to severe liver disease (Child-Pugh Class B/ C)
compared to healthy subjects. As a result, unbound Cmax
and AUC0-¥ were increased 2- and 3- fold, respectively.
Elimination half-life for rosiglitazone was about 2 hours
longer in patients with liver disease, compared to healthy
subjects.
Therapy with Avandia should not be initiated if the patient
exhibits clinical evidence of active liver disease or increased
serum transaminase levels (ALT >2.5X upper limit of normal)
at baseline (see PRECAUTIONS, Hepatic Effects).
Renal Impairment: There are no clinically
relevant differences in the pharmacokinetics of rosiglitazone
in patients with mild to severe renal impairment or in hemodialysis-dependent
patients compared to subjects with normal renal function.
No dosage adjustment is therefore required in such patients
receiving Avandia. Since metformin is contraindicated in
patients with renal impairment, co-administration of metformin
with Avandia is contraindicated in these patients.
Race: Results of a population pharmacokinetic
analysis including subjects of Caucasian, black, and other
ethnic origins indicate that race has no influence on the
pharmacokinetics of rosiglitazone.
Pediatric Use: The safety and effectiveness
of Avandia in pediatric patients have not been established.
Pharmacodynamics and Clinical Effects
In clinical studies, treatment with Avandia resulted
in an improvement in glycemic control, as measured by fasting
plasma glucose (FPG) and hemoglobin A1c (HbA1c), with a
concurrent reduction in insulin and C-peptide. Postprandial
glucose and insulin were also reduced. This is consistent
with the mechanism of action of Avandia as an insulin sensitizer.
The improvement in glycemic control was durable, with maintenance
of effect for 52 weeks. The maximum recommended daily dose
is 8 mg. Dose-ranging studies suggested that no additional
benefit was obtained with a total daily dose of 12 mg.
The addition of Avandia to metformin resulted in significant
reductions in hyperglycemia compared to either of the agents
alone. These results are consistent with a synergistic effect
of Avandia plus metformin combination therapy on glycemic
control.
Reduction in hyperglycemia was associated with increases
in weight. In the 26-week clinical trials, the mean weight
gain in patients treated with Avandia was 1.2 kg (4 mg daily)
and 3.5 kg (8 mg daily) when administered as monotherapy
and 0.7 kg (4 mg daily) and 2.3 kg (8 mg daily) when administered
in combination with metformin. A mean weight loss of about
1 kg was seen for both placebo and metformin alone in these
studies. In the 52-week glyburidecontrolled study, there
was a mean weight gain of 1.75 kg and 2.95 kg for patients
treated with 4 mg and 8 mg of Avandia daily, respectively,
versus 1.9 kg in glyburide-treated patients.
Patients with lipid abnormalities were not excluded from
clinical trials of Avandia. In all 26-week controlled trials,
across the recommended dose range, Avandia as monotherapy
was associated with increases in total cholesterol, LDL,
and HDL and decreases in free fatty acids. These changes
were statistically significantly different from placebo
or glyburide controls (Table 2).
Increases in LDL occurred primarily during the first 1 to
2 months of therapy with Avandia and LDL levels remained
elevated above baseline throughout the trials. In contrast,
HDL continued to rise over time. As a result, the LDL/ HDL
ratio peaked after 2 months of therapy and then appeared
to decrease over time. Because of the temporal nature of
lipid changes, the 52-week glyburide-controlled study is
most pertinent to assess long-term effects on lipids. At
baseline, week 26, and week 52, mean LDL/HDL ratios were
3.1, 3.2, and 3.0, respectively for Avandia 4 mg twice daily.
The corresponding values for glyburide were 3.2, 3.1, and
2.9. The differences in change from baseline between Avandia
and glyburide at week 52 were statistically significant.
The pattern of LDL and HDL changes following therapy with
Avandia in combination with metformin were generally similar
to those seen with Avandia in monotherapy.
The changes in triglycerides during therapy with Avandia
were variable and were generally not statistically different
from placebo or glyburide controls.
Table 2. Summary of Mean Lipid Changes in 26-Week
Placebo-Controlled and 52-Week Glyburide-Controlled Monotherapy
Studies
| |
Placebo-controlled StudiesWeek 26
|
Glyburide-controlled Study Week 26 and Week 52
|
|
Placebo
|
Avandia
|
Glyburide titration
|
Avandia 8 mg
|
|
4 mg daily*
|
8 mg daily*
|
Wk 26
|
Wk 52
|
Wk26
|
Wk 52
|
| Free Fatty
Acids
N
Baseline (mean) % Change from baseline
(mean)
|
207
18.1
+0.2%
|
428
17.5
-7.8%
|
436
17.9
-14.7%
|
181
26.4
-2.4%
|
168
26.4
-4.7%
|
166
26.9
-20.8%
|
145
26.6
-21.5%
|
| LDL
N
Baseline (mean) % Change from baseline
(mean)
|
190
123.7
+4.8%
|
400
126.8
+14.1%
|
374
125.3
+18.6
|
175
142.7
-0.9%
|
160
141.9
-0.5%
|
161
142.1
+11.9%
|
133
142.1
+12.1%
|
| HDL
N
Baseline (mean) % Change from baseline
(mean)
|
208
44.1
+8.0%
|
429
44.4
+11.4%
|
436
43.0
+14.2%
|
184
47.2
+47.2
|
170
47.7
+8.7%
|
170
48.4
+14.0%
|
145
48.3
+18.5%
|
* once daily and twice daily dosing groups were combined.
Clinical Studies
Monotherapy:
A total of 2315 patients with type 2 diabetes, previously
treated with diet alone or antidiabetic medication(s), were
treated with Avandia as monotherapy in six double-blind
studies, which included two 26-week placebo-controlled studies,
one 52-week glyburide-controlled study, and three placebo-controlled
doseranging studies of 8 to 12 weeks duration. Previous
antidiabetic medication(s) were withdrawn and patients entered
a 2 to 4 week placebo run-in period prior to randomization.
Two 26-week, double-blind, placebo-controlled trials, in
patients with type 2 238 diabetes with inadequate glycemic
control (mean baseline FPG approximately 228 mg/dL and mean
baseline HbA1c 8.9%), were conducted. Treatment with Avandia
produced statistically significant improvements in FPG and
HbA1c compared to baseline and relative to placebo (Table
3).
Table 3. Glycemic Parameters in Two 26-Week Placebo-Controlled
Trials Placebo
| |
Placebo
|
Avandia
2 mg twice
daily
|
Avandia
4 mg twice
daily
|
| Study A |
| N |
158
|
166
|
169
|
| FPG (mg/dL) |
| Baseline
(mean) |
229
|
227
|
220
|
| Change
from baseline (mean) |
19
|
-38
|
-54
|
| Difference
from placebo (adjusted mean) |
|
-58*
|
-76*
|
| Responders
(³ 30 mg/dL
decrease from baseline) |
16%
|
54%
|
64%
|
| HbA1c (%) |
| Baseline
(mean) |
9.0
|
9.0
|
8.8
|
| Change
from baseline (mean) |
0.9
|
-0.3
|
-0.6
|
| Difference
from placebo (adjusted mean) |
|
-1.2*
|
-1.5*
|
| Responders
(³0.7% decrease
from baseline) |
6%
|
40%
|
42%
|
| |
| |
Placebo
|
Avandia
4 mg once daily
|
Avandia
2 mg twice
daily
|
Avandia
8 mg once daily
|
Avandia
4 mg twice
daily
|
| Study B |
| N |
173
|
180
|
186
|
181
|
187
|
| FPG (mg/dL) |
| Baseline
(mean) |
225
|
229
|
225
|
228
|
228
|
| Change from
baseline (mean) |
8
|
-25
|
-35
|
-42
|
-55
|
| Difference
from placebo (adjusted mean) |
-
|
-31*
|
-43*
|
-49*
|
-62*
|
| Responders
(³ 30 mg/dL
decreases from baseline) |
19%
|
45%
|
54%
|
58%
|
70%
|
| HbA1c (%) |
| Baseline
(mean) |
8.9
|
8.9
|
8.9
|
8.9
|
9.0
|
| Change
from baseline (mean) |
0.8
|
0.0
|
-0.1
|
-0.3
|
-0.7
|
| Difference
from placebo (adjusted mean) |
-
|
-0.8*
|
-0.9*
|
-1.1*
|
-1.5*
|
| Responders
(³ 0.7% decrease
from baseline) |
9%
|
28%
|
29%
|
39%
|
54%
|
*< 0.0001 compared to placebo.
When administered at the same total daily dose, Avandia
was generally more effective in reducing FPG and HbA1c when
administered in divided doses twice daily compared to once
daily doses. However, for HbA1c, the difference between
the 4 mg once daily and 2 mg twice daily doses was not statistically
significant.
Long-term maintenance of effect was evaluated in a 52-week,
double-blind, glyburide-controlled trial in patients with
type 2 diabetes. Patients were randomized to treatment with
Avandia 2 mg twice daily (N= 195) or Avandia 4 mg twice
daily (N= 189) or glyburide (N= 202) for 52 weeks. Patients
receiving glyburide were given an initial dosage of either
2.5 mg/day or 5.0 mg/day. The dosage was then titrated in
2.5 mg/day increments over the next 12 weeks, to a maximum
dosage of 15.0 mg/day in order to optimize glycemic control.
Thereafter the glyburide dose was kept constant.
The median titrated dose of glyburide was 7.5 mg. All treatments
resulted in a statistically significant improvement in glycemic
control from baseline (Figures 1 and 2). At the end of week
52, the reduction from baseline in FPG and HbA1c was -40.8
mg/dL and -0.53% with Avandia 4 mg twice daily; -25.4 mg/dL
and - 264 0.27% with Avandia 2 mg twice daily; and -30.0
mg/dL and -0.72% with glyburide. For HbA1c, the difference
between Avandia 4 mg twice daily and glyburide was not statistically
significant at week 52. The initial fall in FPG with glyburide
was greater than with Avandia; however, this effect was
less durable over time. The improvement in glycemic control
seen with Avandia 4 mg twice daily at week 26 was maintained
through week 52 of the study.
Hypoglycemia was reported in 12.1% of glyburide-treated
patients versus 0.5% (2 mg twice daily) and 1.6% (4 mg twice
daily) of patients treated with Avandia. The improvements
in glycemic control were associated with a mean weight gain
of 1.75 kg and 2.95 kg for patients treated with 2 mg and
4 mg twice daily of Avandia, respectively versus 1.9 kg
in glyburide-treated patients. In patients treated with
Avandia, C-peptide, insulin, pro-insulin, and pro-insulin
split products were significantly reduced in a dose-ordered
fashion, compared to an increase in the glyburide-treated
patients.
Combination with Metformin:
A total of 670 patients with type 2 diabetes participated
in two 26-week, randomized, double-blind, placebo/active-controlled
studies designed to assess the efficacy of Avandia in combination
with metformin. Avandia, administered in either once daily
or twice daily dosing regimens, was added to the therapy
of patients who were inadequately controlled on a maximum
dose (2.5 grams/day) of metformin.
In one study, patients inadequately controlled on 2.5 grams/day
of metformin (mean baseline FPG 216 mg/dL and mean baseline
HbA1c 8.8%) were randomized to receive Avandia 4 mg once
daily, Avandia 8 mg once daily, or placebo in addition to
metformin. A statistically significant improvement in FPG
and HbA1c was observed in patients treated with the combinations
of metformin and Avandia 4 mg once daily and Avandia 8 mg
once daily, versus patients continued on metformin alone
(Table 4).
Table 4. Glycemic Parameters in a 26-Week Combination
Study Metformin
| |
Metformin
|
Avandia
4 mg once daily
+ metformin
|
Avandia
8 mg once daily
+ metformin
|
| N |
113
|
116
|
110
|
| FPG (mg/dL) |
| Baseline
(mean) |
214
|
215
|
220
|
| Change from
baseline (mean) |
6
|
-33
|
-48
|
| Difference
from placebo (adjusted mean) |
|
-40*
|
-53*
|
| Responders
(³ 30 mg/dL
decreases from baseline) |
20%
|
45%
|
61%
|
| HbA1c (%) |
| Baseline
(mean) |
8.6
|
8.9
|
8.9
|
| Change
from baseline (mean) |
0.5
|
-0.6
|
-0.8
|
| Difference
from placebo (adjusted mean) |
|
-1.0*
|
-1.2*
|
| Responders
(³ 0.7% decrease
from baseline) |
11%
|
45%
|
52%
|
*< 0.0001 compared to metformin.
In a second 26-week study, patients with type 2 diabetes
inadequately controlled on 2.5 grams/day of metformin who
were randomized to receive the combination of Avandia 4
mg twice daily and metformin (N= 105) showed a statistically
significant improvement in glycemic control with a mean
treatment effect for FPG of -56 mg/dL and a mean treatment
effect for HbA1c of -0.8% over metformin alone. The combination
of metformin and Avandia resulted in lower levels of FPG
and HbA1c than either agent alone.
Patients who were inadequately controlled on a maximum dose
(2.5 grams/day) of metformin and who were switched to monotherapy
with Avandia demonstrated loss of glycemic control, as evidenced
by increases in FPG and HbA1c. In this group, increases
in LDL and VLDL were also seen.
|
|
