Acarbose bioequivalence: Exploration of eligible protocol design

Abstract

What is known and objective Acarbose is a poorly absorbed α‐glucosidase inhibitor that acts locally in the intestinal tract. Therefore, the evaluation of its bioequivalence (BE) should be based on pharmacodynamic (PD) rather than pharmacokinetic (PK) endpoints. Currently, there is no consensus on the best method for acarbose BE evaluation. The optimal protocol design regarding dosing time/dose and PD parameters requires further exploration. The aim of the study was to identify an optimum protocol for establishing acarbose BE in healthy Chinese volunteers using PD endpoints. Methods Three pilot studies were conducted in healthy Chinese subjects. Study 1 was an open, randomized, two‐period crossover study using the reference (R) drug at the dose of 1 × 50 mg. Study 1 aimed to determine appropriate dosing time by comparing the PD effect of acarbose between two administration methods. One method was concomitant administration of sucrose and acarbose, and another method was acarbose administration 10 min before sucrose. Study 2 was an open, randomized, three‐period crossover study. Subjects were given the R drug at the dose of 1 × 50 mg, 2 × 50 mg or 3 × 50 mg in a random sequence. The aim of Study 2 was to identify a reasonable dose of acarbose in the BE study. Study 3 was conducted with an open, randomized, three‐period crossover design using the test (T) or R drug in an R‐T‐R sequence at the dose of 2 × 50 mg. Study 3 aimed to compare the BE between the R and T drug and determine intra‐individual variation. Twelve subjects were recruited in Study 1, Study 2 and Study 3, respectively, with a one‐week washout period. Serum glucose and insulin concentrations were determined after sucrose administration (baseline) and sucrose/acarbose co‐administration. Results and discussion In Study 1, no significant differences in PD parameters were found between the two administration methods. The results of Study 2 revealed that the optimal dose was between 1 × 50 mg and 2 × 50 mg. The comparison of PD parameters indicated that the rectifying method could distinguish between different formulations. Study 3 showed that the geometric mean ratios of Cmax,r, AUC0–2 h,r and AUC0–4 h,r were 90.06%, 84.55% and 84.21%, respectively, using the rectifying method. The 90% CIs of Cmax,r were within acceptance limits (80.00%–125.00%), whereas that of AUC0–2 h,r and AUC0–4 h,r were out of the range. The intra‐individual variation was approximately 21% for R formulation. Based on the variation, the number of subjects needed to identify formulation differences in the pivotal study would be 55 with 90% power at the 5% level of significance. What is new and conclusion The results from our study manifested that a randomized, balanced, two‐way crossover design was eligible to evaluate acarbose BE. The appropriate dosing time was concomitant administration of sucrose and acarbose, and the optimal dose was 2 × 50 mg. The rectifying method exhibited preferable sensitivity and applicability in acarbose BE evaluation. A practical sample size of t...

Evaluation of acarbose bioequivalence in healthy Chinese populations using novel pharmacodynamics endpoints

“…The 90% confidence intervals of the geometric mean ratios of all the secondary endpoints, including baseline-corrected AUC 0-4h , r , the measured value method (C max , AUC 0-2h , AUC 0-4h ) and the measured value method of insulin level (ISLC max and ISLAUC 0-4h ) between the T and R drug were within the range of 80.00%-125.00%. The data in this pivotal study were consistent with that in the pilot study we previously reported [7] . The results in our pivotal study revealed that the new baseline-corrected PD endpoints were practical for discriminating the differences between preparations.…”

“…Eligible subjects were selected from healthy Chinese volunteers (including males and females). Inclusion and exclusion criteria were described as previous studies [7] .…”

“…On the day of sucrose challenge and the day of sucrose/acarbose co-treatment, venous blood samples (4 mL) were collected from an intravenous indwelling catheter before dosing and at 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 150, 180, 210, 240 min after dosing. After at least 30-minute clotting, serum was separated by centrifugation at 1300 g for 10 minutes at 20°C and stored at -20°C within 4 h after sample collecting and transferred to -80°C within 24 h. Serum glucose concentrations were determined by the hexokinase method using Beckman Coulter AU680 with a lower limit of quantitation (LLOQ) of 0.56 mmol/L (calibration range, 0.56 to 44.40 mmol/L) as previously described [7] . The precision on three concentrations has been validated.…”

“…In turn, it has re-aroused the attention on in vivo acarbose BE evaluation. Recently, quite a few articles discussing the rationality of the protocol design and primary PD parameters were reported [5][6][7][8] . The authors proposed new parameters with pre-dose value deduction instead of FDA parameters considering both applicability and sensitivity.…”

A Review of Fibraurea tinctoria and Its Component, Berberine, as an Antidiabetic and Antioxidant

“…Berberine may exert an antihyperglycemic action in the digestive tract prior to absorption because of its poor gut wall absorption and low bioavailability. It is similar to acarbose, an antihyperglycemic drug with low bioavailability due to poor absorption, and its therapeutic activity is within the gastrointestinal tract [ 351 ].…”