Partial-area method in bioequivalence assessment: naproxen

Regulatory authorities require demonstration of bioequivalence through comparisons of different pharmacokinetic parameters, the area under the plasma concentration-time curve (AUC), the maximum plasma concentration (Cmax), and the time to reach peak concentration (Tmax). The applicability and validity of regulatory requirements have been widely criticized on statistical and clinical relevance grounds. For most noncomplicated absorption models, the AUC correlates well with the extent of absorption. However, in nonlinear models of absorption, in mechanisms involving recycling of drugs, and for drugs with long half-life, the use of total AUC (from zero to infinity) can give erroneous and clinically irrelevant results since the area is mostly determined by elimination phase or by recycling. The calculation of total AUC also involves prolonged sampling, adding to the cost and risks associated with bioequivalence studies. The use of Cmax or Tmax as a measure of rate of absorption, to correlate with clinical relevance, is widely criticized on logical, technical, and statistical grounds. For drugs used on a multiple-dose basis, Cmax and Tmax evaluations become redundant since the average plateau concentration is not affected by these parameters. To resolve the drawbacks in the traditional methodology of bioequivalence evaluation, the use of partial areas in lieu of total AUC, Tmax, and Cmax is suggested. This study investigates the logic and robustness of the partial-area method in establishing bioequivalence. We conclude that the 5h AUC is a more relevant parameter to establish naproxen bioequivalence than AUCinf. We recommend against using symmetrical confidence intervals and report excellent agreement among several methods of calculating confidence intervals, probability values, and nonparametric tests. We suggest that a single-point short-term AUC is a better indicator of the bioequivalence of generic products than the total AUC, Cmax, and Tmax as required currently by the regulatory authorities.