Use of Partial AUC to Demonstrate Bioequivalence of Zolpidem Tartrate Extended Release Formulations

• Published in: Pharmaceutical research 2012-04, Vol.29 (4), p.1110-1120
• Main Authors: Lionberger, Robert A., Raw, Andre S., Kim, Stephanie H., Zhang, Xinyuan, Yu, Lawrence X.
• Format: Article
• Language: English
• Subjects: Absorption; Area Under Curve; Biochemistry; Biological and medical sciences; Biomedical and Life Sciences; Biomedical Engineering and Bioengineering; Biomedicine; Chemistry, Pharmaceutical; Delayed-Action Preparations; Drug therapy; General pharmacology; Humans; Hypnotics and Sedatives - pharmacokinetics; Medical Law; Medical sciences; Models, Biological; Parameter estimation; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Pharmacology/Toxicology; Pharmacy; Pyridines - pharmacokinetics; Research Paper; Solubility; Tablets - pharmacokinetics; Therapeutic Equivalency; United States; United States Food and Drug Administration
• ISSN: 0724-8741; 1573-904X
• DOI: 10.1007/s11095-011-0662-8

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.