Actos (Page 5 of 7)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

A two-year carcinogenicity study was conducted in male and female rats at oral doses up to 63 mg/kg (approximately 14 times the maximum recommended human oral dose of 45 mg based on mg/m2). Drug-induced tumors were not observed in any organ except for the urinary bladder. Benign and/or malignant transitional cell neoplasms were observed in male rats at 4 mg/kg/day and above (approximately equal to the maximum recommended human oral dose based on mg/m2). A two-year carcinogenicity study was conducted in male and female mice at oral doses up to 100 mg/kg/day (approximately 11 times the maximum recommended human oral dose based on mg/m2). No drug-induced tumors were observed in any organ.

Pioglitazone hydrochloride was not mutagenic in a battery of genetic toxicology studies, including the Ames bacterial assay, a mammalian cell forward gene mutation assay (CHO/HPRT and AS52/XPRT), an in vitro cytogenetics assay using CHL cells, an unscheduled DNA synthesis assay, and an in vivo micronucleus assay.

No adverse effects upon fertility were observed in male and female rats at oral doses up to 40 mg/kg pioglitazone hydrochloride daily prior to and throughout mating and gestation (approximately 9 times the maximum recommended human oral dose based on mg/m2).

13.2 Animal Toxicology and/or Pharmacology

Heart enlargement has been observed in mice (100 mg/kg), rats (4 mg/kg and above) and dogs (3 mg/kg) treated orally with pioglitazone hydrochloride (approximately 11, 1, and 2 times the maximum recommended human oral dose for mice, rats, and dogs, respectively, based on mg/m2). In a one-year rat study, drug-related early death due to apparent heart dysfunction occurred at an oral dose of 160 mg/kg/day (approximately 35 times the maximum recommended human oral dose based on mg/m2). Heart enlargement was seen in a 13-week study in monkeys at oral doses of 8.9 mg/kg and above (approximately 4 times the maximum recommended human oral dose based on mg/m2), but not in a 52-week study at oral doses up to 32 mg/kg (approximately 13 times the maximum recommended human oral dose based on mg/m2).

13.3 Reproductive and Developmental Toxicology

Pioglitazone was not teratogenic in rats at oral doses up to 80 mg/kg or in rabbits given up to 160 mg/kg during organogenesis (approximately 17 and 40 times the maximum recommended human oral dose based on mg/m2 , respectively). Delayed parturition and embryotoxicity (as evidenced by increased postimplantation losses, delayed development and reduced fetal weights) were observed in rats at oral doses of 40 mg/kg/day and above (approximately 10 times the maximum recommended human oral dose based on mg/m2). No functional or behavioral toxicity was observed in offspring of rats. In rabbits, embryotoxicity was observed at an oral dose of 160 mg/kg (approximately 40 times the maximum recommended human oral dose based on mg/m2). Delayed postnatal development, attributed to decreased body weight, was observed in offspring of rats at oral doses of 10 mg/kg and above during late gestation and lactation periods (approximately 2 times the maximum recommended human oral dose based on mg/m2).

14 CLINICAL STUDIES

14.1 Monotherapy

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 trials examined ACTOS at doses up to 45 mg or placebo once daily in a total of 865 patients.

In a 26-week dose-ranging monotherapy trial, 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 plasma glucose (FPG) at endpoint compared to placebo (see Figure 1, Table 17).

Figure 1 shows the time course for changes in HbA1c in this 26-week study.

Figure 1 Mean Change from Baseline for HbA1c in a 26-Week Placebo-Controlled Dose-Ranging Study (Observed Values)
Figure 1
(click image for full-size original)
Table 17: Glycemic Parameters in a 26-Week Placebo-Controlled Dose-Ranging Monotherapy Trial
Placebo ACTOS15 mgOnceDaily ACTOS30 mgOnceDaily ACTOS45 mgOnceDaily
*
Adjusted for baseline, pooled center, and pooled center by treatment interaction
p ≤ 0.05 vs. placebo
Total Population
HbA1c (%) N=79 N=79 N=85 N=76
Baseline (mean) 10.4 10.2 10.2 10.3
Change from baseline (adjusted mean *) 0.7 -0.3 -0.3 -0.9
Difference from placebo (adjusted mean *)95% Confidence Interval -1.0(-1.6, -0.4) -1.0(-1.6, -0.4) -1.6(-2.2, -1.0)
Fasting Plasma Glucose (mg/dL) N=79 N=79 N=84 N=77
Baseline (mean) 268 267 269 276
Change from baseline (adjusted mean *) 9 -30 -32 -56
Difference from placebo (adjusted mean *)95% Confidence Interval -39(-63, -16) -41(-64, -18) -65(-89, -42)

In a 24-week placebo-controlled monotherapy trial, 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 trial (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 FPG at endpoint compared to placebo (Table 18).

Table 18: Glycemic Parameters in a 24-Week Placebo-Controlled Forced-Titration Monotherapy Trial
Placebo ACTOS30 mg *OnceDaily ACTOS45 mg *OnceDaily
*
Final dose in forced titration
Adjusted for baseline, pooled center, and pooled center by treatment interaction
p ≤ 0.05 vs. placebo
Total Population
HbA1c (%) N=83 N=85 N=85
Baseline (mean) 10.8 10.3 10.8
Change from baseline (adjusted mean ) 0.9 -0.6 -0.6
Difference from placebo (adjusted mean )95% Confidence Interval -1.5(-2.0, -1.0) -1.5(-2.0, -1.0)
Fasting Plasma Glucose (mg/dL) N=78 N=82 N=85
Baseline (mean) 279 268 281
Change from baseline (adjusted mean ) 18 -44 -50
Difference from placebo (adjusted mean )95% Confidence Interval -62(-82, -0.41) -68(-88, -0.48)

In a 16-week monotherapy trial, 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 FPG at endpoint compared to placebo (Table 19).

Table 19: Glycemic Parameters in a 16-Week Placebo-Controlled Monotherapy Trial
Placebo ACTOS 30 mgOnce Daily
*
Adjusted for baseline, pooled center, and pooled center by treatment interaction
p ≤ 0.050 vs. placebo
Total Population
HbA1c (%) N=93 N=100
Baseline (mean) 10.3 10.5
Change from baseline (adjusted mean *) 0.8 -0.6
Difference from placebo (adjusted mean *)95% Confidence Interval -1.4(-1.8, -0.9)
Fasting Plasma Glucose (mg/dL) N=91 N=99
Baseline (mean) 270 273
Change from baseline (adjusted mean *) 8 -50
Difference from placebo (adjusted mean *)95% Confidence Interval -58(-77, -38)

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