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Pharmacokinetics of Repaglinide in Healthy Caucasian and Japanese Subjects

From Clinical Pharmacology (Dr. Thomsen), Pharmacokinetics (Dr. Nielsen), and Biostatistics (Dr. Jørgensen), Novo Nordisk A/S, Bagsvaerd, Denmark, and Aster-Cephac, Paris, France (Dr. Chassard, Dr. Evène).

The objective of this study was to investigate the pharmacokinetics of three different single doses (0.5, 1.0, and 2.0 mg) of repaglinide in healthy Caucasian and Japanese subjects. In this single-center, open-label, randomized, three-period crossover study, 27 healthy male subjects (15 Caucasian and 12 Japanese) each received three different single doses of repaglinide (0.5, 1.0, and 2.0 mg) at consecutive 24-hour intervals. Pharmacokinetic profiles, including area under the curve (AUC_0-t), maximum serum concentration (C_max), time to C_max (t_max), and half-life (t_1/2), were determined for each dose of repaglinide. The relative change in blood glucose level (RC_1h) and area under the blood glucose curve (AUGC_0-1) at 1 hour after dose were also measured. After oral dosing, both C_max and AUC_0-t increased linearly with dose within the 0.5- to 2.0-mg dose range, regardless of ethnic group. Both C_max and AUC_0-t were significantly higher in Japanese subjects than in Caucasian subjects. At each dose of repaglinide, C_max and AUC were statistically significantly higher in Japanese than in Caucasian subjects (p = 0.0038 and 0.023, respectively). Discrepancies in body weight and body mass index (BMI) between Caucasian and Japanese subjects could not explain the between-group differences in C_max or AUC_0-t. Statistically significant differences in pharmacodynamic parameters (RC_1h and AUGC_0-1) were found between ethnic groups (p < 0.0001), the difference being more pronounced for RC_1h than AUGC_0-1. At a dose of 2.0 mg, the mean decrease in RC_1h was 41% for Japanese subjects and 24% for Caucasian subjects. Hypoglycemic reactions were more common at the highest dose (2.0 mg), where they were observed more frequently in Japanese (7 cases) than in Caucasian subjects (4 cases). It was concluded that higher serum levels of repaglinide and greater reductions in blood glucose levels are found in Japanese than in Caucasian subjects following a single oral dose of repaglinide within the 0.5- to 2.0-mg dose range. Repaglinide is well tolerated in both ethnic groups. The results indicate that glycemic control targets may be achieved at lower doses within the recommended range (0.5-4.0 mg/meal) when repaglinide is used to treat Japanese patients in comparison to Caucasian patients.