CLINICAL PHARMACOLOGY

Mechanism of Action

ACTOS is a thiazolidinedione antidiabetic agent that depends on the presence of insulin for its mechanism of action. ACTOS decreases insulin resistance in the periphery and in the liver resulting in increased insulin-dependent glucose disposal and decreased hepatic glucose output. Unlike sulfonylureas, pioglitazone is not an insulin secretagogue. Pioglitazone is a potent and highly selective agonist for peroxisome proliferator-activated receptor-gamma (PPARg). P.A. receptors are found in tissues important for insulin action such as adipose tissue, skeletal muscle, and liver. Activation of PPARg nuclear receptors modulates the transcription of a number of insulin responsive genes involved in the control of glucose and lipid metabolism.

In animal models of diabetes, pioglitazone reduces the hyperglycemia, hyperinsulinemia, and hypertriglyceridemia characteristic of insulin-resistant states such as type 2 diabetes. The metabolic changes produced by pioglitazone result in increased responsiveness of insulin-dependent tissues and are observed in numerous animal models of insulin resistance.

Since pioglitazone 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

Serum concentrations of total pioglitazone (pioglitazone plus active metabolites) remain elevated 24 hours after once daily dosing. Steady-state serum concentrations of both pioglitazone and total pioglitazone are achieved within 7 days. At steady state, two of the pharmacologically active metabolites of pioglitazone, Metabolites III (M-III) and IV (M-IV), reach serum concentrations equal to or greater than pioglitazone. In both healthy volunteers and in patients with type 2 diabetes, pioglitazone comprises approximately 30% to 50% of the peak total pioglitazone serum concentrations and 20% to 25% of the total area under the serum concentration-time curve (AUC).

Maximum serum concentration (Cmax), A.C. and trough serum concentrations (Cmin) for both pioglitazone and total pioglitazone increase proportionally at doses of 15 mg and 30 mg per day. There is a slightly less than proportional increase for pioglitazone and total pioglitazone at a dose of 60 mg per day.

Absorption: Following oral administration, in the fasting state, pioglitazone is first measurable in serum within 30 minutes, with peak concentrations observed within 2 hours. Food slightly delays the time to peak serum concentration to 3 to 4 hours, but does not alter the extent of absorption.

Distribution: The mean apparent volume of distribution (Vd/F) of pioglitazone following single-dose administration is 0.63 ± 0.41 (mean ± SD) L/kg of body weight. Pioglitazone is extensively protein bound (>99%) in human serum, principally to serum albumin. Pioglitazone also binds to other serum proteins, but with lower affinity. Metabolites M-III and M-IV also are extensively bound (>98%) to serum albumin.

Metabolism: Pioglitazone is extensively metabolized by hydroxylation and oxidation; the metabolites also partly convert to glucuronide or sulfate conjugates. Metabolites M-II and M-IV (hydroxy derivatives of pioglitazone) and M-III (keto derivative of pioglitazone) are pharmacologically active in animal models of type 2 diabetes. In addition to pioglitazone, M-III and M-IV are the principal drug-related species found in human serum following multiple dosing. At steady state, in both healthy volunteers and in patients with type 2 diabetes, pioglitazone comprises approximately 30% to 50% of the total peak serum concentrations and 20% to 25% of the total AUC.

Pioglitazone incubated with expressed human P450 or human liver microsomes results in the formation of M-IV and to a much lesser degree, M-II. The major cytochrome P450 isoforms involved in the hepatic metabolism of pioglitazone are CYP2C8 and C.P.A. with contributions from a variety of other isoforms including the mainly extrahepatic CYP1A1. Ketoconazole inhibited up to 85% of hepatic pioglitazone metabolism in vitro at a concentration equal molar to pioglitazone. Pioglitazone did not inhibit P450 activity when incubated with human P450 liver microsomes. In vivo human studies have not been performed to investigate any induction of C.P.A. by pioglitazone.

Excretion and Elimination: Following oral administration, approximately 15% to 30% of the pioglitazone dose is recovered in the urine. Renal elimination of pioglitazone is negligible, and the drug is excreted primarily as metabolites and their conjugates. It is presumed that most of the oral dose is excreted into the bile either unchanged or as metabolites and eliminated in the feces.

The mean serum half-life of pioglitazone and total pioglitazone ranges from 3 to 7 hours and 16 to 24 hours, respectively. Pioglitazone has an apparent clearance, CL/F, calculated to be 5 to 7 L/hr.

Special Populations

Renal Insufficiency: The serum elimination half-life of pioglitazone, M-III, and M-IV remains unchanged in patients with moderate (creatinine clearance 30 to 60 mL/min) to severe (creatinine clearance < 30 mL/min) renal impairment when compared to normal subjects. No dose adjustment in patients with renal dysfunction is recommended (see DOSAGE AND ADMINISTRATION).

Hepatic Insufficiency: Compared with normal controls, subjects with impaired hepatic function (Child-Pugh Grade B/C) have an approximate 45% reduction in pioglitazone and total pioglitazone mean peak concentrations but no change in the mean AUC values.

ACTOS therapy should not be initiated if the patient exhibits clinical evidence of active liver disease or serum transaminase levels (ALT) exceed 2.5 times the upper limit of normal (see PRECAUTIONS, Hepatic Effects).

Elderly: In healthy elderly subjects, peak serum concentrations of pioglitazone and total pioglitazone are not significantly different, but AUC values are slightly higher and the terminal half-life values slightly longer than for younger subjects. These changes were not of a magnitude that would be considered clinically relevant.

Pediatrics: Pharmacokinetic data in the pediatric population are not available.

Gender: The mean Cmax and AUC values were increased 20% to 60% in females. As monotherapy and in combination with sulfonylurea, metformin, or insulin, ACTOS improved glycemic control in both males and females. In controlled clinical trials, hemoglobin A1c (HbA1c ) decreases from baseline were generally greater for females than for males (average mean difference in HbA1c 0.5%). Since therapy should be individualized for each patient to achieve glycemic control, no dose adjustment is recommended based on gender alone.

Ethnicity: Pharmacokinetic data among various ethnic groups are not available.

Pharmacodynamics and Clinical Effects

Clinical studies demonstrate that ACTOS improves insulin sensitivity in insulin-resistant patients. ACTOS enhances cellular responsiveness to insulin, increases insulin-dependent glucose disposal, improves hepatic sensitivity to insulin, and improves dysfunctional glucose homeostasis. In patients with type 2 diabetes, the decreased insulin resistance produced by ACTOS results in lower blood glucose concentrations, lower plasma insulin levels, and lower HbA1c values. Based on results from an open-label extension study, the glucose lowering effects of ACTOS appear to persist for at least one year. In controlled clinical trials, ACTOS in combination with sulfonylurea, metformin, or insulin had an additive effect on glycemic control.

Patients with lipid abnormalities were included in clinical trials with ACTOS. Overall, patients treated with ACTOS had mean decreases in triglycerides, mean increases in HDL cholesterol, and no consistent mean changes in LDL and total cholesterol.

In a 26-week, placebo-controlled, dose-ranging study, mean triglyceride levels decreased in the 15 mg, 30 mg, and 45 mg ACTOS dose groups compared to a mean increase in the placebo group. Mean HDL levels increased to a greater extent in the ACTOS-treated patients than in the placebo-treated patients. There were no consistent differences for LDL and total cholesterol in ACTOS-treated patients compared to placebo (Table 1).

Table1

Lipids in a 26-Week Placebo-Controlled Dose-Ranging Study

In the two other monotherapy studies (24 weeks and 16 weeks) and in combination therapy studies with sulfonylurea (16 weeks) and metformin (16 weeks), the results were generally consistent with the data above. For ACTOS-treated patients, the placebo-corrected mean changes from baseline decreased 5% to 26% for triglycerides and increased 6% to 13% for HDL cholesterol.

In the combination therapy study with insulin (16 weeks), the placebo-corrected mean percent change from baseline in triglyceride values for ACTOS-treated patients was also decreased. A placebo-corrected mean change from baseline in LDL cholesterol of 7% was observed for the 15 mg dose group. Similar results to those noted above for HDL and total cholesterol were observed.

In all clinical trials, a reduction in HbA_1c was accompanied by increased body weight in ACTOS-treated patients in a dose-related manner. The change in average weight in U.S. placebo-controlled monotherapy trials ranged from 0.5 kg to 2.8 kg for ACTOS-treated patients and -1.3 kg to -1.9 kg for placebo-treated patients. In combination with sulfonylurea, the change in average weight was 1.9 kg and 2.9 kg for 15 mg and 30 mg of ACTOS, respectively, and -0.8 kg for placebo. In combination with insulin, the change in average weight was 2.3 kg and 3.7 kg for 15 mg and 30 mg of ACTOS, respectively, and 0 kg for placebo. In combination with metformin, the change in average weight was 1.0 kg for 30 mg of ACTOS and -1.4 kg for placebo.

Clinical Studies

Monotherapy: In the U.S., three randomized, double-blind, placebo-controlled trials with durations from 16 to 26 weeks were conducted to evaluate the use of ACTOS as monotherapy in patients with type 2 diabetes. These studies examined ACTOS at doses up to 45 mg or placebo once daily in 865 patients. In a 26-week dose-ranging study, 408 patients with type 2 diabetes were randomized to receive 7.5 mg, 15 mg, 30 mg, or 45 mg of ACTOS, or placebo once daily. Therapy with any previous antidiabetic agent was discontinued 8 weeks prior to the double-blind period. Treatment with 15 mg, 30 mg, and 45 mg of ACTOS produced statistically significant improvements in HbA1c and fasting blood glucose (FBG) at endpoint compared to placebo (see Table 2).

Table 2 shows HbA_1c and FBG values for the entire study population.

Table 2

Glycemic Parameters in a 26-Week Placebo-Controlled Dose-Ranging Study

+ Adjusted for baseline, pooled center, and pooled center by treatment interaction

* p £0.050 vs. placebo

The study population included patients not previously treated with antidiabetic medication (naïve; 31%) and patients who were receiving antidiabetic medication at the time of study enrollment (previously treated; 69%). The data for the naïve and previously treated patient subsets are shown in Table 3. All patients entered an 8 week washout/run-in period prior to double-blind treatment. This run-in period was associated with little change in HbA1c and FBG values from screening to baseline for the naïve patients; however, for the previously-treated group, washout from previous anti-diabetic medication resulted in deterioration of glycemic control and increases in HbA1c and FBG. Although most patients in the previously-treated group had a decrease from baseline in HbA1c and FBG with ACTOS, in many cases the values did not return to screening levels by the end of the study. The study design did not permit the evaluation of patients who switched directly to ACTOS from another antidiabetic agent.

Table 3

Glycemic Parameters in a 26-Week Placebo-Controlled Dose-Ranging Study

* Adjusted for baseline and pooled center

In a 24-week study, 260 patients with type 2 diabetes were randomized to one of two forced-titration ACTOS treatment groups or a mock titration placebo group. Therapy with any previous antidiabetic agent was discontinued 6 weeks prior to the double-blind period. In one ACTOS treatment group, patients received an initial dose of 7.5 mg once daily. After four weeks, the dose was increased to 15 mg once daily and after another four weeks, the dose was increased to 30 mg once daily for the remainder of the study (16 weeks). In the second ACTOS treatment group, patients received an initial dose of 15 mg once daily and were titrated to 30 mg once daily and 45 mg once daily in a similar manner. Treatment with ACTOS, as described, produced statistically significant improvements in HbA1c and FBG at endpoint compared to placebo (see Table 4).

Table 4

Glycemic Parameters in a 24-Week Placebo-Controlled Forced-Titration Study

+ Final dose in forced titration

++ Adjusted for baseline, pooled center, and pooled center by treatment interaction

* p £0.050 vs. placebo

For patients who had not been previously treated with antidiabetic medication (24%), mean values at screening were 10.1% for HbA1c and 238 mg/dL for FBG. At baseline, mean HbA1c was 10.2% and mean FBG was 243 mg/dL. Compared with placebo, treatment with ACTOS titrated to a final dose of 30 mg and 45 mg resulted in reductions from baseline in mean HbA1c of 2.3% and 2.6% and mean FBG of 63 mg/dL and 95 mg/dL, respectively. For patients who had been previously treated with antidiabetic medication (76%), this medication was discontinued at screening. Mean values at screening were 9.4% for HbA1c and 216 mg/dL for FBG. At baseline, mean HbA1c was 10.7% and mean FBG was 290 mg/dL. Compared with placebo, treatment with ACTOS titrated to a final dose of 30 mg and 45 mg resulted in reductions from baseline in mean HbA 1c o f 1.3% and 1.4% and mean FBG of 55 mg/dL and 60 mg/dL, respectively. For many previously-treated patients, HbA1c and FBG had not returned to screening levels by the end of the study.

In a 16-week study, 197 patients with type 2 diabetes were randomized to treatment with 30 mg of ACTOS or placebo once daily. Therapy with any previous antidiabetic agent was discontinued 6 weeks prior to the double-blind period. Treatment with 30 mg of ACTOS produced statistically significant improvements in HbA1c and FBG at endpoint compared to placebo (see Table 5).

Table 5

Glycemic Parameters in a 16-Week Placebo-Controlled Study

+ Adjusted for baseline, pooled center, and pooled center by treatment interaction

* p £0.050 vs. placebo

For patients who had not been previously treated with antidiabetic medication (40%), mean values at screening were 10.3% for HbA1c and 240 mg/dL for FBG. At baseline, mean HbA1c was 10.4% and mean FBG was 254 mg/dL. Compared with placebo, treatment with ACTOS 30 mg resulted in reductions from baseline in mean HbA1c of 1.0% and mean FBG of 62 mg/dL. For patients who had been previously treated with antidiabetic medication (60%), this medication was discontinued at screening. Mean values at screening were 9.4% for HbA1c and 216 mg/dL for FBG. At baseline, mean HbA1c was 10.6% and mean FBG was 287 mg/dL. Compared with placebo, treatment with ACTOS 30 mg resulted in reductions from baseline in mean HbA1c of 1.3% and mean FBG of 46 mg/dL. For many previously-treated patients, HbA1c and FBG had not returned to screening levels by the end of the study.

Combination Therapy: Three 16-week, randomized, double-blind, placebo-controlled clinical studies were conducted to evaluate the effects of ACTOS on glycemic control in patients with type 2 diabetes who were inadequately controlled (HbA1c ³8%)despite current therapy with a sulfonylurea, metformin, or insulin. Previous diabetes treatment may have been monotherapy or combination therapy.

In one combination study, 560 patients with type 2 diabetes on a sulfonylurea, either alone or combined with another antidiabetic agent, were randomized to receive 15 mg or 30 mg of ACTOS or placebo once daily in addition to their current sulfonylurea regimen. Any other antidiabetic agent was withdrawn. Compared with placebo, the addition of ACTOS to the sulfonylurea significantly reduced the mean HbA1c by 0.9% and 1.3% for the 15 mg and 30 mg doses, respectively. Compared with placebo, mean FBG decreased by 39 mg/dL (15 mg dose) and 58 mg/dL (30 mg dose). The therapeutic effect of ACTOS in combination with sulfonylurea was observed in patients regardless of whether the patients were receiving low, medium, or high doses of sulfonylurea (< 50%, 50%, or > 50% of the recommended maximum daily dose).

In a second combination study, 328 patients with type 2 diabetes on metformin either alone or combined with another antidiabetic agent, were randomized to receive either 30 mg of ACTOS or placebo once daily in addition to their metformin. Any other antidiabetic agent was withdrawn. Compared to placebo, the addition of ACTOS to metformin significantly reduced the mean HbA1c by 0.8% and decreased the mean FBG by 38 mg/dL. The therapeutic effect of ACTOS in combination with metformin was observed in patients regardless of whether the patients were receiving lower or higher doses of metformin (< 2,000 mg per day or ³2,000 mg per day).

In a third combination study, 566 patients with type 2 diabetes receiving a median of 60.5 units per day of insulin, either alone or combined with another antidiabetic agent, were randomized to receive either 15 mg or 30 mg of ACTOS or placebo once daily in addition to their insulin. Any other antidiabetic agent was discontinued. Compared to placebo, treatment with ACTOS in addition to insulin significantly reduced both HbA1c (0.7% for the 15 mg dose and 1.0% for the 30 mg dose) and FBG (35 mg/dL for the 15 mg dose and 49 mg/dL for the 30 mg dose). The therapeutic effect of ACTOS in combination with insulin was observed in patients regardless of whether the patients were receiving lower or higher doses of insulin (< 60.5 units per day or ³60.5 units per day).