Food and tablet dissolution characteristics do not affect the bioavailability of linagliptin fixed-dose combination with metformin

Purpose: To investigate the effect of food and tablet-dissolution characteristics on relative bioavailability of a 2.5-mg linagliptin +1000-mg metformin fixed-dose combination (FDC) tablet.

Methods: Two open-label, randomized, 2-way crossover studies enrolled healthy volunteers, who received the FDC tablet once after overnight fast, and once after a high-fat/high-calorie meal (Study-1, N=32), or who received two FDC tablets with either normal-dissolution or prolonged-dissolution behavior after overnight fast (Study-2, N=40). A 35-day washout period separated the two study conditions in each trial. Primary endpoints were C_max and AUC_0–72 for linagliptin, and for metformin C_max and AUC_0-¥ (Study-1), and C_max and AUC_0-tz (Study-2).

Results: The 90% confidence intervals of the geometric mean ratios (GMR) of C_max and AUC_0–72 for FDC taken with/without food and FDC with normal dissolution/slow dissolution were generally within bioequivalence acceptance limits of 0.80–1.25 (Table). 11/32 subjects in Study-1 and 17/40 in Study-2 reported at least 1 adverse event (AE) during the two treatments (none serious); no subject was discontinued due to AE. Vital signs, electrocardiography, and clinical laboratory tests revealed no safety issues.

Conclusion: A high-fat/high-calorie meal does not significantly affect bioavailability of linagliptin or metformin when taken in fixed-dose combination. Food intake reduced the rate of metformin absorption but had no influence on extent of absorption. Differences in FDC dissolution behavior are not relevant for either linagliptin or metformin. All treatments were well tolerated.

Study-1	Without Food	With Food	Adjusted GMR (95% CI)
Linagliptin
AUC0–72(nmol×h/L)	163.8	161.6	0.99 (0.95–1.03)
Cmax(nmol/L)	4.99	4.56	0.91 (0.86–0.97)
Metformin
AUC0-¥ (ng×h/mL)	12,000	11,500	0.96 (0.89–1.03)
Cmax(ng/mL)	1,820	1,490	0.82 (0.77–0.87)
Study-2	Normal Dissolution	Slow Dissolution	Adjusted GMR (90% CI)
Linagliptin
AUC0–72(nmol×h/L)	179	179	1.00 (0.96–1.04)
Cmax(nmol/L)	5.36	5.39	0.99 (0.94–1.05)
Metformin
AUC0-tz(ng×h/mL)	12,100	12,100	1.00 (0.96–1.05)
Cmax(ng/mL)	1,790	1,820	0.98 (0.93–1.04)