Glaxo's Experience of Different Absorption Rate Metrics of Immediate Release and Extended Release Dosage Forms

Abstract

As indirect measures (metrics) of rate of drug absorption, C_max is confounded by extent of drug absorption and t_max is a discrete variable, dependent on blood sampling frequency; therefore, there is a need for improved metrics of rate. Building upon the work of Endrenyi et al. (1) and Chen (2), different metrics have been compared using simulated single dose bioequivalence studies of immediate release (IR) dosage forms. Those investigated included: C_max/AUC_∞, partial AUC from zero to t_max of the reference formulation (AUC_r), partial AUC from zero to t_max of the test or reference formulation, whichever occurs earliest (AUC_e), and the normalized partial AUCs (AUC_r/AUC_∞, and AUC_c/AUC_∞, which like C_max/AUC_∞, are not confounded by extent of absorption) (3,4). Importantly, the performance of these metrics was further assessed using the results of several actual pharmacokinetic studies involving IR dosage forms of Glaxo drugs.

For extended release (ER) dosage forms, bioequivalence assessments are carried out at steady-state, using metrics such as C_max and percentage peak trough fluctuation ratio (%PTF) to evaluate rate of absorption. The performance of the different metrics has been compared using simulated experiments of ER dosage forms at steady-state and also using the results of two actual pharmacokinetic studies involving an ER dosage form of a Glaxo drug.

The results obtained from the sets of simulated and actual experiments, using IR or ER dosage forms, allowed the following provisional conclusions to be reached:

1. 1.

For IR dosage forms, there was considerable difference between the metrics in the magnitudes of effect produced (ie, in their sensitivities), for a given change in the underlying rate of absorption. This would suggest that the same 80-125% bioequivalence guideline may be inappropriate for all the metrics,

2.

For IR dosage forms, C_max/AUC_∞ is a more powerful metric than C_max in establishing bioequivalence when the formulations are truly bioequivalent. Also, C_max/AUC_∞ is more statistically powerful than C_max at detecting differences in rate of absorption when they exist. The normalized partial AUCs are more powerful than C_max and the nonnormalized AUCs at detecting true differences in rate of absorption. The performance of AUC_e/AUC_∞ when used with real data was poor, which may imply that it has little practical value; on the other hand the performance of AUC_T/AUC_∞ was good,

3.

For ER dosage forms at steady-state, all the metrics, with the exception of %PTF, produced very small magnitudes of effect, for a given change in rate of absorption. Although %PTF gave the largest effect it was also the most imprecisely estimated, making it difficult to comply with the 80-125% guideline, and

4.

None of the metrics tested can be considered to provide reliable information about changes in rate of absorption from ER dosage forms under steady-state conditions. More reliable information using these metrics would be expected from single dose studies.