Repaglinide (Page 4 of 6)

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 — 4 mg dose range, indicating a linear relationship between dose and plasma drug levels.

Table 5: Pharmacokinetic Parameters for Repaglinide in Healthy Subjects


CL (based on i.v.)

38 ± 16 L/hr

Vss (based on i.v.)

31 ± 12 L


56 ± 9%

CL = total body clearance

Vss = volume of distribution at steady state

AbsBio = absolute bioavailability

Table 6: Pharmacokinetic Parameters for Repaglinide in Patients with Type 2 Diabetes*

Pharmacokinetic Parameter


AUC0-24 hr (ng/mL*hr)Mean (SD)

Cmax0-5 hr (ng/mL)Mean (SD)


68.9 (154.4)

9.8 (10.2)


125.8 (129.8)

18.3 (9.1)


152.4 (89.60)

26.0 (13.0)


447.4 (211.3)

65.8 (30.1)

Tmax0-5 hr

Means (SD)


Means (Ind Range)

0.5 — 4

1.0 – 1.4 (0.3 – 0.5) hr

1.0 – 1.4 (0.4 – 8.0) hr

*dosed preprandially with three meals


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 (Cmax ) occur within 1 hour (Tmax ). 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 Tmax was not changed, but the mean Cmax and AUC (area under the time/plasma concentration curve) were decreased 20% and 12.4%, respectively.


After intravenous (IV) dosing in healthy subjects, the volume of distribution at steady state (Vss ) 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


Healthy volunteers were treated with a regimen of 2 mg repaglinide tablets 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)].


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.


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 – 80 mL/min), and severe renal function impairment (CrCl = 20 – 40 mL/min). Both AUC and Cmax 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 Cmax 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 (AUChealthy : 91.6 ng/mL*hr; AUCCLD patients : 368.9 ng/mL*hr; Cmax, healthy : 46.7 ng/mL; Cmax, 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 tablets had no clinically relevant effect on the pharmacokinetic properties of digoxin, theophylline, or warfarin. Co-administration of cimetidine with repaglinide tablets did not significantly alter the absorption and disposition of repaglinide.

Additionally, the following drugs were studied in healthy volunteers with co-administration of repaglinide tablets.

Table 7: Effect of Other Drugs on AUC and Cmax of Repaglinide

Study Drug







250 mg BIDfor 4 days
40% ↑
67% ↑


300 mg
(Day 1)75 mg QD (Day 2-3)

0.25 mg(Day 1

and 3)

(day 1) 5.1 fold ↑(3.9-6.6)(day 3) 3.9 fold ↑(2.9-5.3)
2.5 fold ↑(1.8-3.5)2.0 fold ↑(1.3-3.1)


100 mg(2 doses 12 hours apart)
2.5 fold ↑
1.8 fold ↑


30 mg/kg QDfor 4 days

0.5 mg

2.3 fold ↑
62% ↑


200 mg QDfor 5 days


600 mg BIDfor 3 days
8.1 fold ↑
2.4 fold ↑


100 mg BIDfor 3 days
1.4 fold ↑
1.5 fold ↑

Gemfibrozil + Itraconazole* Co-administration

Gem: 600 mg BIDfor 3 daysItra: 100 mg BIDfor 3 days
19 fold ↑
2.8 fold ↑


200 mg QDfor 4 days

2 mg

15% ↑
16% ↑

Levonorgestrel/ethinyl Estradiol

(0.15 mg/0.03 mg)Combination tablet QDfor 21 days

2 mg

20% ↑


10 mg TIDfor 4 days

2 mg



600 mg QDfor 6-7 days

4 mg

32 — 80% ↓
17 — 79% ↓


20 mg QDfor 4 days

2 mg

26% ↑


160 mg BIDfor 2 days160 mg QDfor 1 day
61% ↑
41% ↑

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

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