Abstract:

Bioequivalence assessment of extended release (ER) dosage forms is usually carried out at steady-state, using area under the curve (AUG) to evaluate extent of absorption and maximum concentration (C-max) and % peak trough fluctuation ratio (%PTF) to evaluate rate of absorption. Other metrics such as C-max/AUC and partial AUCs have recently been proposed as alternatives for assessing the absorption rate of drugs from immediate release (IR) dosage forms under single dose conditions. The performances of these metrics were assessed using the results of two sets of simulated experiments of ER dosage forms at steady-state and 2 actual pharmacokinetic studies involving ER dosage forms of a Glaxo drug. In the first set of simulations there was no difference in bioavailability between the two formulations; in the second set of simulations the test formulation had a 50% greater absorption rate-constant (ka) than the reference formulation. The following conclusions were reached: 1. For ER dosage forms at steady-state, all the metrics, with the exception of %PTF, resulted in much smaller increases than the underlying 50% increase in ka. Although, %PTF gave the largest effect it was also the most imprecisely estimated. 2. In our studies, none of the metrics tested provided reliable information about changes in the underlying rate of absorption from ER dosage forms under steady-state conditions. 3. The current practice of comparing rate of absorption from ER dosage forms using steady-state C-max is inappropriate due to lack of sensitivity. The use of %PTF may require a widening in the currently accepted 80-125% permissible range set for C-max and AUC.