Study design and procedures
The study was a randomized, open-label, 3-period, 3-treatment, 2-sequence crossover study in healthy Korean male subjects. It was conducted at Seoul National University Hospital Clinical Trials Center, Seoul, Republic of Korea. The study protocol was reviewed and approved by the Institutional Review Board of Seoul National University Hospital (number, H-1607-042-774) and Korea Ministry of Food and Drug Safety. This study was registered with ClinicalTrials.gov (number, NCT02954822) and conducted in accordance with the major ethical principles of the Declaration of Helsinki and Korean Good Clinical Practice Guidelines.
Subjects were randomly assigned to the sequence A or B. In sequence A, 5 mg of evogliptin (EVO) (evogliptin tartate, Suganon®, Seoul, Korea) was orally administered once daily from day 1-7, 5 mg of evogliptin and 4 mg of glimepiride (EVO+GLI) (glimepiride, Amaryl®, Sanofi-Aventis Co. Ltd., France) were orally co-administered once daily on day 8 and 9, and then 4 mg of glimepiride (GLI) was orally administered once daily on day 21 and 22 followed by a 12-day wash-out period. In sequence B, 4 mg of glimepiride (GLI) was orally administered once daily on day 1 and 2, 5 mg of evogliptin (EVO) was orally administered once daily from day 14-20 followed by a 12-day wash-out period, and then 5 mg of evogliptin and 4 mg of glimepiride (EVO+GLI) were orally co-administered once daily on day 21 and 22 (Figure 1).
For determination of plasma evogliptin, evogliptin M7, and evogliptin M8 concentration, blood samples (10 mL) were collected at the following time points: pre-dose from day 1-9 and 1, 2, 3, 4, 5, 6, 8, and 12 hours post-dose on days 7 and 9 in sequence A; pre-dose from day 14-22 and 1, 2, 3, 4, 5, 6, 8, and 12 hours post-dose on days 20 and 22 in sequence B. For determination of plasma glimepiride and glimepiride M1 concentration, blood samples were collected at pre-dose on days 8, 9, 22, and 23 and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, and 12 hours post-dosing on days 9 and 22 in sequence A; and pre-dose on days 2, 3, 21, and 22 and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, and 12 hours post-dosing on days 2 and 22 in sequence B (Figure 1). The blood samples were centrifuged at 1,900 g at 4℃ for 10 minutes, and the plasma (4 mL) was transferred into 4 Eppendorf tubes. For determination of urine evogliptin concentration, urine samples were collected at the following periods: 0-24 hours on days 7, 9 and 22 in sequence A; and on days 2, 20 and 22 in sequence B. The obtained plasma and urine samples were frozen below -70℃ until the assay.
Oral glucose tolerance test (OGTT) was conducted for PD evaluation. After an overnight fast, each subject ingested a test solution with 75 g of glucose. Blood samples for determination of serum glucose level and insulin level were collected at the following time points: 0, 0.25, 0.5, 1, 1.5, 2, and 3 hours after solution ingestion on days -1, 6, 8, and 21 in sequence A and at the same time points on days -1, 1, 19, and 21 in sequence B.