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 C 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, ΔC and ΔAUC , 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 (C and AUC ) were 1.035 (94.23-112.68) and 0.982 (89.28-107.17), respectively. Further, C and AUC 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 (C and AUC ) are more sensitive than the FDA-recommended PD metrics for acarbose BE evaluation from 0-4 hours (ΔC and ΔAUC ). 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.