Repaglinide (Page 4 of 5)

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

Table 8: Repaglinide in Combination with Metformin: Mean Change from Baseline after 4 to 5 Months of Treatment1
1: based on intent-to-treat analysis: p< 0.05, for pairwise comparisons with repaglinide and metformin monotherapy.#: p< 0.05, for pairwise comparison with metformin.
Repaglinide MonotherapyRepaglinide Combination Therapywith MetforminMetforminMonotherapy
N282727
Median Final Dose (mg/day)126 (Repaglinide)1500 (metformin)1500
HbA1c (%)
Baseline8.68.38.6
Change from baseline-0.38-1.41* -0.33
Fasting Plasma Glucose (mg/dL)
Baseline174184194
Change from baseline8.8-39.2 -4.5
Weight (kg)
Baseline 879391
Change from baseline 3.02.4# -0.90

Repaglinide in Combination With Pioglitazone

A combination therapy regimen of repaglinide and pioglitazone (N=123) was compared to repaglinide 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 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, -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 (see Figure 1 Legend). The improvement in HbA1c and FPG of the combination group was achieved at a lower daily repaglinide dosage than in the repaglinide monotherapy group.

Figure 1: Repaglinide in Combination with Pioglitazone: HbA1c Values

Figure 1: Repaglinide in Combination with Pioglitazone: HbA1c Values
(click image for full-size original)

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 in Combination With Rosiglitazone
A combination therapy regimen of repaglinide 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 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 and rosiglitazone, as compared to the respective monotherapy groups.

Table 9: Repaglinide in Combination with Rosiglitazone: Mean Change from Baseline in a 24-Week Study1
1: based on intent-to-treat analysis: p< 0.001 for comparison to either monotherapy#: p< 0.05 for comparison to repaglinide
Repaglinide Monotherapy Repaglinide Combination Therapy with Rosiglitazone Rosiglitazone Monotherapy
N6312762
Median Final Dose (mg/day) 126 (Repaglinide)4 (Rosiglitazone)8
HbA1c (%)
Baseline9.39.19.0
Change from baseline-0.17-1.43* -0.56
Fasting Plasma Glucose (mg/dL)
Baseline 269257252
Change from baseline -54-94* -67
Change in Weight (kg) +1.3+4.5# +3.3

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