Repaglinide - How It Works

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Repaglinide lowers blood glucose levels by stimulating the release of insulin from the pancreas.

This action is dependent upon functioning beta (ß) cells in the pancreatic islets.

Insulin release is glucose-dependent and diminishes at low glucose concentrations.

Repaglinide closes ATP-dependent potassium channels in the ß-cell membrane by binding at characterizable sites.

This potassium channel blockade depolarizes the ß-cell, which leads to an opening of calcium channels.

The resulting increased calcium influx induces insulin secretion.

The ion channel mechanism is highly tissue selective with low affinity for heart and skeletal muscle.

12.2 Pharmacodynamics A four-week, double-blind, placebo-controlled dose-response trial was conducted in 138 patients with type 2 diabetes using doses ranging from 0.25 (not an approved dose) to 4 mg taken with each of three meals.

Repaglinide therapy resulted in dose-proportional glucose lowering over the full dose range.

Plasma insulin levels increased after meals and reverted toward baseline before the next meal.

Most of the fasting blood glucose-lowering effect was demonstrated within 1 to 2 weeks.

In a double-blind, placebo-controlled, 3-month dose titration study, repaglinide or placebo doses for each patient were increased weekly from 0.25 mg (not an approved dose) through 0.5, 1, and 2 mg, to a maximum of 4 mg, until a fasting plasma glucose (FPG) level <160 mg/dL was achieved or the maximum dose reached.

The dose that achieved the targeted control or the maximum dose was continued to end of study.

FPG and 2-hour post-prandial glucose (PPG) increased in patients receiving placebo and decreased in patients treated with repaglinide.

Differences between the repaglinide- and placebo-treated groups were -61 mg/dL (FPG) and -104 mg/dL (PPG) (Table 4).

Table 4: Repaglinide vs Placebo Mean Change from Baseline after 3 Months of Treatment *:p< 0.05 for between group difference Repaglinide Placebo N 66 33 Fasting Plasma Glucose (mg/dL) Baseline Change from baseline (at last visit) Post Prandial Glucose (mg/dL) Baseline Change from baseline (at last visit) 220.2 -31.0 * 261.7 -47.6 * 215.3 30.3 245.2 56.5 The dosing of repaglinide relative to meal-related insulin release was studied in three trials including 58 patients.

Glycemic control was maintained during a period in which the meal and dosing pattern was varied (2, 3 or 4 meals per day; before meals x 2, 3, or 4) compared with a period of 3 regular meals and 3 doses per day (before meals x 3).

Blood glucose-lowering effect did not differ when repaglinide was administered at the start of a meal, 15 minutes before, or 30 minutes before the meal.

12.3 Pharmacokinetics The pharmacokinetic parameters of repaglinide obtained from a single-dose, crossover study in healthy subjects and from a multiple-dose, parallel, dose-proportionality (0.5, 1, 2 and 4 mg) study in patients with type 2 diabetes are summarized in Tables 5 and 6.

These data indicate that repaglinide did not accumulate in serum.