Use of partial AUC to demonstrate bioequivalence of Zolpidem Tartrate Extended Release formulations

Pharm Res. 2012 Apr;29(4):1110-20. doi: 10.1007/s11095-011-0662-8. Epub 2012 Jan 26.

Abstract

Purpose: FDA's bioequivalence recommendation for Zolpidem Tartrate Extended Release Tablets is the first to use partial AUC (pAUC) metrics for determining bioequivalence of modified-release dosage forms. Modeling and simulation studies were performed to aid in understanding the need for pAUC measures and also the proper pAUC truncation times.

Methods: Deconvolution techniques, In Vitro/In Vivo Correlations, and the CAT (Compartmental Absorption and Transit) model were used to predict the PK profiles for zolpidem. Models were validated using in-house data submitted to the FDA. Using dissolution profiles expressed by the Weibull model as input for the CAT model, dissolution spaces were derived for simulated test formulations.

Results: The AUC(0-1.5) parameter was indicative of IR characteristics of early exposure and effectively distinguished among formulations that produced different pharmacodynamic effects. The AUC(1.5-t) parameter ensured equivalence with respect to the sustained release phase of Ambien CR. The variability of AUC(0-1.5) is higher than other PK parameters, but is reasonable for use in an equivalence test.

Conclusions: In addition to the traditional PK parameters of AUCinf and Cmax, AUC(0-1.5) and AUC(1.5-t) are recommended to provide bioequivalence measures with respect to label indications for Ambien CR: onset of sleep and sleep maintenance.

MeSH terms

  • Absorption
  • Area Under Curve
  • Chemistry, Pharmaceutical
  • Delayed-Action Preparations
  • Humans
  • Hypnotics and Sedatives / pharmacokinetics*
  • Models, Biological
  • Pyridines / pharmacokinetics*
  • Solubility
  • Tablets / pharmacokinetics
  • Therapeutic Equivalency
  • United States
  • United States Food and Drug Administration
  • Zolpidem

Substances

  • Delayed-Action Preparations
  • Hypnotics and Sedatives
  • Pyridines
  • Tablets
  • Zolpidem