Exploration of suitable pharmacodynamic parameters for acarbose bioequivalence evaluation: A series of clinical trials with branded acarbose.

Aims: To determine deficiencies in the Food and Drug Administration (FDA)'s guidance for assessing acarbose bioequivalence (BE) and to explore optimal pharmacodynamic (PD) metrics for better evaluation of acarbose BE. Methods: Three clinical trials with branded acarbose were conducted in healthy subjects, including a pilot study (Study I, n = 11, 50 and 100 mg), a 2×2 crossover BE study (Study II, n = 36, 100 mg) and a 4×4 Williams study (Study III, n = 16, 50/100/150 mg). Serum glucose concentrations were measured by the glucose oxidase method. Results: In Study I, compared with 50 mg acarbose, only 100 mg acarbose had a significantly lower Cmax0–4h than that of sucrose administration alone (7.96 ± 0.83 mmol/L vs 6.78 ± 1.02 mmol/L, P <.05). In Study II, the geometric mean ratios of the test formulation to the reference formulation (both formulations were the branded drug) for FDA PD metrics, ΔCmax0–4h and ΔAUC0–4h, were 0.903 and 0.776, respectively, and the 90% confidence intervals were 67.44–120.90 and 53.65–112.13, respectively. The geometric mean ratios (confidence interval) for possible optimal evaluation PD metrics (Cmax0–2h and AUC0–2h) were 1.035 (94.23–112.68) and 0.982 (89.28–107.17), respectively. Further, Cmax0–2h and AUC0–2h also met the sensitivity requirements for BE evaluation in Study III. Conclusion: Considering the mechanisms of action of acarbose, the PD effect was shown to be dose independent during the 2–4 hours postadministration of acarbose. Hence PD metrics based on the serum glucose concentration from 0 to 2 hours (Cmax0–2h and AUC0–2h) are more sensitive than the FDA‐recommended PD metrics for acarbose BE evaluation from 0–4 hours (ΔCmax0–4h and ΔAUC0–4h). The trial has been registered at the Chinese Clinical Trial Registry (http://www.chictr.org.cn, ChiCTR1800015795, ChiCTR‐IIR‐17013918, ChiCTR‐IIR‐17011903). All subjects provided written informed consent before screening. [ABSTRACT FROM AUTHOR]