Repaglinide

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. Clearance of oral repaglinide did not change over the 0.5 to 4 mg dose range, indicating a linear relationship between dose and plasma drug levels. Table 5: Pharmacokinetic Parameters for Repaglinide in Healthy Subjects CL = total body clearance Vss = volume of distribution at steady state AbsBio = absolute bioavailability Parameter CL (based on i.v.) 38 ± 16 L/hr Vss (based on i.v.) 31 ± 12 L AbsBio 56 ± 9% Table 6: Pharmacokinetic Parameters for Repaglinide in Patients with Type 2 Diabetes* *dosed preprandially with three meals Pharmacokinetic Parameter Dose (mg) AUC 0-24 hr (ng/mL*hr) Mean (SD) C max0-5 hr (ng/mL) Mean (SD) 0.5 68.9 (154.4) 9.8 (10.2) 1 125.8 (129.8) 18.3 (9.1) 2 152.4 (89.60) 26.0 (13.0) 4 447.4 (211.3) 65.8 (30.1) T max0-5 hr Means (SD) T½ Means (Ind Range) 0.5 to 4 1.0 to 1.4 (0.3 to 0.5) hr 1.0 to 1.4 (0.4 to 8.0) hr Absorption After oral administration, repaglinide is completely absorbed from the gastrointestinal tract. After single and multiple oral doses in healthy subjects or in patients, peak plasma drug levels (C max ) occur within 1 hour (T max ). Repaglinide is eliminated from the blood stream with a half-life of approximately 1 hour. The mean absolute bioavailability is 56%. When repaglinide was given with food, the mean T max was not changed, but the mean C max and AUC (area under the time/plasma concentration curve) were decreased 20% and 12.4%, respectively. Distribution After intravenous (IV) dosing in healthy subjects, the volume of distribution at steady state (V ss ) was 31 L, and the total body clearance (CL) was 38 L/h. Protein binding and binding to human serum albumin was greater than 98%. Metabolism and Elimination Repaglinide is completely metabolized by oxidative biotransformation and direct conjugation with glucuronic acid after either an IV or oral dose. The major metabolites are an oxidized dicarboxylic acid (M2), the aromatic amine (M1), and the acyl glucuronide (M7). The cytochrome P-450 enzyme system, specifically 2C8 and 3A4, have been shown to be involved in the N-dealkylation of repaglinide to M2 and the further oxidation to M1. Metabolites do not contribute to the glucose-lowering effect of repaglinide. Within 96 hours after dosing with 14 C-repaglinide as a single, oral dose, approximately 90% of the radiolabel was recovered in the feces and approximately 8% in the urine. Only 0.1% of the dose is cleared in the urine as parent compound. The major metabolite (M2) accounted for 60% of the administered dose. Less than 2% of parent drug was recovered in feces. Repaglinide appears to be a substrate for active hepatic uptake transporter (organic anion transporting protein OATP1B1). Variability of Exposure Repaglinide AUC after multiple doses of 0.25 to 4 mg with each meal varies over a wide range. The intra-individual and inter- individual coefficients of variation were 36% and 69%, respectively. AUC over the therapeutic dose range included 69 to 1005 ng/mL*hr, but AUC exposure up to 5417 ng/mL*hr was reached in dose escalation studies without apparent adverse consequences. Specific Populations Geriatric Healthy volunteers were treated with a regimen of 2 mg repaglinide taken before each of 3 meals. There were no significant differences in repaglinide pharmacokinetics between the group of patients <65 years of age and a comparably sized group of patients ≥65 years of age [see Use in Specific Populations (8.5) ] . Gender A comparison of pharmacokinetics in males and females showed the AUC over the 0.5 mg to 4 mg dose range to be 15% to 70% higher in females with type 2 diabetes. This difference was not reflected in the frequency of hypoglycemic episodes (male: 16%; female: 17%) or other adverse events. Race No pharmacokinetic studies to assess the effects of race have been performed, but in a U.S. 1-year study in patients with type 2 diabetes, the blood glucose-lowering effect was comparable between Caucasians (n=297) and African-Americans (n=33). In a U.S. dose-response study, there was no apparent difference in exposure (AUC) between Caucasians (n=74) and Hispanics (n=33). Renal Impairment Single-dose and steady-state pharmacokinetics of repaglinide were compared between patients with type 2 diabetes and normal renal function (CrCl > 80 mL/min), mild to moderate renal function impairment (CrCl = 40 to 80 mL/min), and severe renal function impairment (CrCl = 20 to 40 mL/min). Both AUC and C max of repaglinide were similar in patients with normal and mild to moderately impaired renal function (mean values 56.7 ng/mL*hr vs 57.2 ng/mL*hr and 37.5 ng/mL vs 37.7 ng/mL, respectively.) Patients with severely reduced renal function had elevated mean AUC and C max values (98.0 ng/mL*hr and 50.7 ng/mL, respectively), but this study showed only a weak correlation between repaglinide levels and creatinine clearance. Hepatic Impairment A single-dose, open-label study was conducted in 12 healthy subjects and 12 patients with chronic liver disease (CLD) classified by Child-Pugh scale and caffeine clearance. Patients with moderate to severe impairment of liver function had higher and more prolonged serum concentrations of both total and unbound repaglinide than healthy subjects (AUC healthy : 91.6 ng/mL*hr; AUC CLD patients : 368.9 ng/mL*hr; C max , healthy : 46.7 ng/mL; C max , CLD patients : 105.4 ng/mL). AUC was statistically correlated with caffeine clearance. No difference in glucose profiles was observed across patient groups. Drug-Drug Interactions Drug interaction studies performed in healthy volunteers show that repaglinide had no clinically relevant effect on the pharmacokinetic properties of digoxin, theophylline, or warfarin. Co-administration of cimetidine with repaglinide did not significantly alter the absorption and disposition of repaglinide. Additionally, the following drugs were studied in healthy volunteers with co-administration of repaglinide. Table 7: Effect of Other Drugs on AUC and C max of Repaglinide 1 Unless indicated all drug interactions were observed with single dose of 0.25 mg repaglinide ↑ indicates increase ↓ indicates decrease * Indicates data are from published literature Study Drug Dosing Repaglinide Dosing 1 Repaglinide AUC C max Clarithromycin* 250 mg BID for 4 days 40% ↑ 67% ↑ Clopidogrel* 300 mg (Day 1) 75 mg QD (Day 2 to 3) 0.25 mg (Day 1 and 3) (day 1) 5.1 fold ↑ (3.9 to 6.6) (day 3) 3.9 fold ↑ (2.9 to 5.3) 2.5 fold ↑ (1.8 to 3.5) 2.0 fold ↑ (1.3 to 3.1) Cyclosporine 100 mg (2 doses 12 hours apart) 2.5 fold ↑ 1.8 fold ↑ Deferasirox* 30 mg/kg QD for 4 days 0.5 mg 2.3 fold ↑ 62% ↑ Fenofibrate 200 mg QD for 5 days 0% 0% Gemfibrozil* 600 mg BID for 3 days 8.1 fold ↑ 2.4 fold ↑ Itraconazole* 100 mg BID for 3 days 1.4 fold ↑ 1.5 fold ↑ Gemfibrozil + Itraconazole* Co-administration Gem: 600 mg BID for 3 days Itra: 100 mg BID for 3 days 19 fold ↑ 2.8 fold ↑ Ketoconazole 200 mg QD for 4 days 2 mg 15% ↑ 16% ↑ Levonorgestrel/ethinyl Estradiol (0.15 mg/0.03 mg) Combination tablet QD for 21 days 2 mg 0% 20% ↑ Nifedipine* 10 mg TID for 4 days 2 mg 0% 0% Rifampin* 600 mg QD for 6 to 7 days 4 mg 32 to 80% ↓ 17 to 79% ↓ Simvastatin 20 mg QD for 4 days 2 mg 0% 26% ↑ Trimethoprim* 160 mg BID for 2 days 160 mg QD for 1 day 61% ↑ 41% ↑