Acarbose Bioequivalence: Exploration of New Pharmacodynamic Parameters

Abstract

Abstract. To investigate bioequivalence (BE) testing of an acarbose formulation in healthy Chinese volunteers through the use of recommended and innovative pharmacodynamic (PD) parameters. Following the Food and Drug Administration (FDA) guidance, a randomized, cross-over study of acarbose test (T) and reference (R) (Glucobay®) formulations was performed with a 1-week wash-out period. Preliminary pilot studies showed that the appropriate dose of acarbose was 2×50 mg, and the required number of subjects was 40. Serum glucose concentrations after sucrose administration (baseline) and co-administration of sucrose/acarbose on the following day were both determined. Three newly defined PD measures of glucose fluctuation (glucose excursion (GE), GE′ (glucose excursion without the effect of the homeostatic glucose control), and fAUC (degree of fluctuation of serum glucose based on AUC)), the plateau glucose concentration (C ss ), and time of maximum reduction in glucose concentration (T max ) were tested in the evaluation. The adequacy of the two parameters recommended by the FDA, ΔC SG,max (maximum reduction in serum glucose concentration) and AUEC (0-4h) (reduction in the AUC (0-4h) of glucose between baseline and acarbose formulation) was also evaluated. The T max values were comparable, and the 90% confidence intervals of the geometric test/reference ratios (T/R) for ΔC SG,max , C ss , GE, and fAUC were all within 80-125%. The parameter GE′ was slightly outside the limits, and the parameter AUEC (0-4h) could not be computed due to the presence of negative values. In acarbose BE evaluation, while the recommended parameter ΔC SG,max is valuable, the combination of C ss and one of the newly defined glucose fluctuation parameters, GE, GE', and fAUC is preferable than AUEC (0-4h) . The acarbose test formulation can be initially considered to be bioequivalent to Glucobay®.KEY WORDS: acarbose; bioequivalence (BE); degree of fluctuation of serum glucose based on AUC (fAUC); glucose excursion (GE); pharmacodynamic.

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

“…In fact, the findings of several recent acarbose BE studies [7][8][9][10][11] performed in different countries indicated challenges in applying the current FDA-recommended BE evaluation method, and some researchers attempted to explore and propose new PD metrics, such as PD metrics reflecting the fluctuation of blood glucose. 7 However, all the PD metric exploration was based on the assumption that the reference and test formulations were bioequivalent, while in fact the premise was uncertain, so the applicability, sensitivity and scientificity of these new PD metrics still need further confirmation. Considering these limitations, our research was the first to determine the appropriateness of the FDA's guidance for assessing acarbose BE using branded drugs and to apply a more systematic assessment method to explore optimal indicating insufficient sensitivity of these PD metrics (Tables S1 and S2, Figure S3).…”

“…Thus far, owing to the importance of the FDA's guidance in drug research and development, multiple countries have carried out acarbose BE studies with reference to these guidelines. [7][8][9][10][11] However, both of these parameters are unsuitable for BE testing mainly because of the negative values of ΔAUC 0-4h and ΔC max0-4h during data processing, and the proportion of negative values can reach up to 30%. To guide BE studies, several new PD metrics have been proposed by different groups, [7][8][9][10][11] but the applicability, sensitivity and scientificity of these new PD metrics still need further confirmation because the effects of the formulation on acarbose BE cannot be ruled out.…”

“…• The guidance issued by the Food and Drug Administration (FDA) helps the development of new drugs in many countries. Unfortunately, previous studies [7][8][9][10][11] found that the FDA guidance for evaluating the bioequivalence (BE) of acarbose tablets appeared to be inappropriate in practice.…”

Modified Regulatory Pathways to Approve Generic Drugs in the US and a Systematic Review of Their Outcomes

“…In addition, two studies of generic acarbose in Asian countries compared locally available generic versions with the brand name. Both were bioequivalence studies, although one found irregularities within the limits allowed by the Korean drug regulatory authority [38,39].…”

Pharmacodynamic Endpoint Bioequivalence Studies

“…Recently, a set of new bioequivalence criteria have been investigated in healthy Chinese volunteers by following the FDA recommended study design (Zhang et al 2012). In this study, consistent with the FDA guidance, serum glucose concentration was used as PD endpoint.…”