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Rezulin

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Rezulin

Discontinued Warning IconPlease Note: This Brand Name drug is no longer available in the US.
(Generic versions may still be available.)

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 (troglitazone (removed from the us market 3/21/00)) 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 DRUG INTERACTIONS).

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 (troglitazone (removed from the us market 3/21/00)) 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 (troglitazone (removed from the us market 3/21/00)) improves insulin sensitivity in insulin-resistant patients. Rezulin (troglitazone (removed from the us market 3/21/00)) 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 (troglitazone (removed from the us market 3/21/00)) causes decreases in serum glucose, plasma insulin, and hemoglobin A1C. Unlike sulfonylureas, Rezulin (troglitazone (removed from the us market 3/21/00)) does not stimulate insulin secretion. Addition of Rezulin (troglitazone (removed from the us market 3/21/00)) 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 (troglitazone (removed from the us market 3/21/00)) treatment.

In clinical trials of Rezulin (troglitazone (removed from the us market 3/21/00)) 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 (troglitazone (removed from the us market 3/21/00)) as monotherapy or in combination with other agents exhibited a reduction in fasting (-13% to -26%) and postprandial triglyceride levels. For patients on Rezulin (troglitazone (removed from the us market 3/21/00)) and insulin, reduction in insulin doses may occur following Rezulin (troglitazone (removed from the us market 3/21/00)) 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 (troglitazone (removed from the us market 3/21/00)) has only been shown to exert its antihyperglycemic effect in the presence of insulin. Because Rezulin (troglitazone (removed from the us market 3/21/00)) does not stimulate insulin secretion, hypoglycemia in patients treated with Rezulin (troglitazone (removed from the us market 3/21/00)) alone is not to be expected. Because of this insulin-dependent mechanism of action, Rezulin (troglitazone (removed from the us market 3/21/00)) 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 (troglitazone (removed from the us market 3/21/00)) 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 (troglitazone (removed from the us market 3/21/00)) 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 (troglitazone (removed from the us market 3/21/00)) + Glyburide

400 mg Rezulin (troglitazone (removed from the us market 3/21/00)) + Glyburide

600 mg Rezulin (troglitazone (removed from the us market 3/21/00)) + 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 (troglitazone (removed from the us market 3/21/00)) 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 (troglitazone (removed from the us market 3/21/00)) 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 (troglitazone (removed from the us market 3/21/00)) (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 (troglitazone (removed from the us market 3/21/00)) -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 (troglitazone (removed from the us market 3/21/00)) and 57% of patients treated with 600 mg Rezulin (troglitazone (removed from the us market 3/21/00)) 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 (troglitazone (removed from the us market 3/21/00)) treatment group and 42% in the 600 mg Rezulin (troglitazone (removed from the us market 3/21/00)) treatment group compared with 1% in the placebo group HbA 1C values and Insulin dose as a function of duration of Rezulin (troglitazone (removed from the us market 3/21/00)) 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 (troglitazone (removed from the us market 3/21/00)) 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 (troglitazone (removed from the us market 3/21/00)) 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 (troglitazone (removed from the us market 3/21/00)) 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 (troglitazone (removed from the us market 3/21/00)) as monotherapy. These studies have examined Rezulin (troglitazone (removed from the us market 3/21/00)) 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 (troglitazone (removed from the us market 3/21/00)) 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 (troglitazone (removed from the us market 3/21/00)) 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 (troglitazone (removed from the us market 3/21/00)) 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

Last reviewed on RxList: 12/8/2004
This monograph has been modified to include the generic and brand name in many instances.

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