![[ Visit Client Website ]](images/banner.gif)
Purpose: To demonstrate bioequivalence of linagliptin-metformin fixed-dose combination (FDC) tablets and the corresponding combination of individual tablets taken together, i.e. combination with free pills (FP).
Methods: These studies used a prospective, open-label, randomized, 2-way crossover design. After an overnight fast, healthy volunteers received an FDC tablet once, and on a separate visit received the corresponding FP once. The two possible treatment sequences (FDC/FP and FP/FDC) were randomly allocated to the subjects. A washout period of 35 days separated the two study treatments. Three dosing combinations were evaluated: linagliptin 2.5 mg with 500, 850, or 1000 mg metformin. The primary endpoints were maximum plasma concentration (Cmax), area under the plasma concentration-time curve from 0–72 hours (AUC0–72) for linagliptin, and from 0-infinity (AUC0-¥) for metformin.
Results: The 90% confidence intervals of the geometric mean ratios (GMR) of Cmax and AUC (calculated as FDC/FP) were within the bioequivalence acceptance limits of 0.80–1.25 (table). The number of subjects reporting at least one adverse event (AE) in the FDC group was comparable to or less than that in the FP group. Evaluation of vital signs and clinical laboratory tests revealed no safety issues.
Conclusion: Fixed-dose combination tablets of linagliptin and metformin are bioequivalent to individual tablets of respective dose strengths taken together. Both treatments were well tolerated.
2.5/500 mg* FDC N=94 FP N=95 | 2.5/850 mg* FDC N=95 FP (linagliptin) N=94 FP (metformin) N=93 | 2.5/1000 mg* FDC N=96 FP N=93 | |
| Linagliptin |
|
|
|
| AUC0–72 (nmol×h/L) | 1.00 (0.97–1.03) | 1.04 (1.00–1.08) | 1.07 (1.03–1.10) |
| Cmax (nmol/L) | 0.98 (0.94–1.02) | 1.06 (1.03–1.09) | 1.03 (1.00–1.07) |
| Metformin |
|
|
|
| AUC0-¥ (ng×h/mL) | 0.99 (0.96–1.02) | 1.01 (0.98–1.04) | 1.04 (1.00–1.07) |
| Cmax (ng/mL) | 0.98 (0.94–1.02) | 1.00 (0.96–1.04) | 1.05 (1.00–1.09) |