Repaglinide (Page 5 of 6)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 104-week carcinogenicity study in rats at doses up to 120 mg/kg/day, which is approximately 90 times clinical exposure on a mg/m2 basis, the incidences of benign adenomas of the thyroid and liver were increased in male rats. No evidence of carcinogenicity was found in female rats. The higher incidences of thyroid and liver tumors in male rats were not seen at lower dose of 30 mg/kg/day and 60 mg/kg/day respectively (which are over 20 and 45 times, respectively, clinical exposures on a mg/m2 basis). In a 104-week carcinogenicity study in mice at doses up to 500 mg/kg/day, no evidence of carcinogenicity was found in mice (which is approximately 187 times clinical exposure on a mg/m2 basis).

Repaglinide was non-genotoxic in a battery of in vivo and in vitro studies: Bacterial mutagenesis (Ames test), in vitro forward cell mutation assay in V79 cells (HGPRT), in vitro chromosomal aberration assay in human lymphocytes, unscheduled and replicating DNA synthesis in rat liver, and in vivo mouse and rat micronucleus tests.

In a rat fertility study, repaglinide was administered to male and female rats at doses up to 300 and 80 mg/kg/day, respectively. No adverse effects on fertility were observed (which are over 60 times clinical exposure on a mg/m2 basis).

14 CLINICAL STUDIES

14.1 Monotherapy Trials

A double-blind, placebo-controlled trial was carried out in 362 patients treated for 24 weeks. HbA1c for the repaglinide- treated groups (1 and 4 mg groups combined) at the end of the study was decreased compared to the placebo-treated group in treatment naïve patients and in patients previously treated with oral hypoglycemic agents by 2.1% and 1.7%, respectively. In this fixed-dose trial, patients who were treatment naïve to oral hypoglycemic agent therapy and patients with a HbA1c below 8% at baseline showed greater blood glucose-lowering.

14.2 Combination Trials

Repaglinide Tablets in Combination With Metformin

Repaglinide tablets were studied in combination with metformin in 83 patients not satisfactorily controlled on exercise, diet, and metformin alone. Repaglinide tablet dosage was titrated for 4 to 8 weeks, followed by a 3-month maintenance period. Combination therapy with repaglinide tablets and metformin resulted in statistically significant improvement in HbA1c and fasting plasma glucose (FPG) compared to repaglinide tablets or metformin monotherapy (Table 8). In this study where metformin dosage was kept constant, the combination therapy of repaglinide tablets and metformin showed dose-sparing effects with respect to repaglinide tablets. The improvement in HbA1c and FPG of the combination group was achieved at a lower daily repaglinide tablet dosage than in the repaglinide tablets monotherapy group (Table 8).

Table 8: Repaglinide Tablets in Combination with Metformin:Mean Change from Baseline after 4 to 5 Months of Treatment1

Repaglinide TabletMonotherapy
Repaglinide TabletCombination Therapywith Metformin
MetforminMonotherapy

N

28
27
27

Median Final Dose (mg/day)

12
6 (Repaglinide Tablets)1500 (metformin)
1500

HbA1c (%)

Baseline
8.6
8.3
8.6
Change from baseline
-0.38
-1.41*
-0.33

Fasting Plasma Glucose (mg/dL)

Baseline
174
184
194
Change from baseline
8.8
-39.2*
-4.5

Weight (kg)

Baseline
87
93
91
Change from baseline
3.0
2.4#
-0.90

1: based on intent-to-treat analysis

*: p< 0.05, for pairwise comparisons with repaglinide tablets and metformin monotherapy.

#: p< 0.05, for pairwise comparison with metformin.

Repaglinide Tablets in Combination With Pioglitazone

A combination therapy regimen of repaglinide tablets and pioglitazone (N=123) was compared to repaglinide tablets alone (N=61) and pioglitazone alone (N=62) in a 24-week trial that enrolled 246 patients previously treated with sulfonylurea or metformin monotherapy (HbA1c > 7.0%). Repaglinide tablets dosage was titrated during the first 12 weeks, followed by a 12-week maintenance period. Combination therapy resulted in statistically significant improvement in HbA1c and FPG compared to monotherapy (Figure 1). The changes from baseline for completers in FPG (mg/dL) and HbA1c (%), respectively were: -39.8 mg/dL and -0.1% for repaglinide tablets, -35.3 mg/dL and -0.1% for pioglitazone and -92.4 mg/dL and -1.9% for the combination. In this study where pioglitazone dosage was kept constant, the combination therapy group showed dose-sparing effects with respect to repaglinide tablets (see Figure 1 Legend). The improvement in HbA1c and FPG of the combination group was achieved at a lower daily repaglinide tablet dosage than in the repaglinide tablet monotherapy group.

Figure 1: Repaglinide Tablets in Combination with Pioglitazone: HbA1c Values

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LEGEND: HbA1c values by study week for patients who completed study (combination, N = 101; Repaglinide, N = 35, pioglitazone, N = 26).

Subjects with FPG above 270 mg/dL were withdrawn from the study.

Pioglitazone dose: fixed at 30 mg/day; repaglinide median final dose: 6 mg/day for combination and 10 mg/day for monotherapy.

Repaglinide Tablets in Combination With Rosiglitazone

A combination therapy regimen of repaglinide tablets and rosiglitazone was compared to monotherapy with either agent alone in a 24-week trial that enrolled 252 patients previously treated with sulfonylurea or metformin (HbA1c > 7.0%). Combination therapy resulted in statistically significant improvement in HbA1c and FPG compared to monotherapy (Table 9 below). The glycemic effects of the combination therapy were dose-sparing with respect to both total daily repaglinide tablet dosage and total daily rosiglitazone dosage (see Table 9 Legend). The improvement in HbA1c and FPG of the combination therapy group was achieved with lower daily dose of repaglinide tablets and rosiglitazone, as compared to the respective monotherapy groups.

Table 9: Repaglinide Tablets in Combination with Rosiglitazone:Mean Change from Baseline in a 24-Week Study1

Repaglinide TabletMonotherapy
Repaglinide TabletCombination Therapywith Rosiglitazone
RosiglitazoneMonotherapy

N

63
127
62

Median Final Dose (mg/day)

12
6 (Repaglinide Tablets)4 (Rosiglitazone)
8

HbA1c (%)

Baseline
9.3
9.1
9.0
Change from baseline
-0.17
-1.43*
-0.56

Fasting Plasma Glucose (mg/dL)

Baseline
269
257
252
Change from baseline
-54
-94*
-67

Change in Weight (kg)

+1.3
+4.5#
+3.3

1: based on intent-to-treat analysis

*: p ≤ 0.001 for comparison to either monotherapy

#: p < 0.05 for comparison to repaglinide tablets

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