Sensitivity of empirical metrics of rate of absorption in bioequivalence studies.
OBJECTIVE
The sensitivity and effectiveness of indirect metrics proposed for the assessment of comparative absorption rates in bioequivalence studies [Cmax, Tmax, partial AUC (AUCp), feathered slope (SLf), intercept metric (I)] were originally tested by assuming first-order absorption. The present study re-evaluates their sensitivity performances using the more realistic inverse Gaussian (IG) model characterizing the input process for oral drug administration.


METHODS
Simulations were performed for both the first-order or exponential model (EX) which is determined by only one parameter, the mean absorption time (MAT = 1/k(a)), and the IG model, which additionally contains a shape parameter, the relative dispersion of absorption time distribution (CV2A). Kinetic sensitivities (KS) of the indirect metrics were evaluated from bioequivalence trials (error free data) generated with various ratios of the true parameters (MAT and CV2A) of the two formulations.


RESULTS
The behavior of the metrics was similar with respect to changes in MAT ratios with both models: KS was low with Cmax, moderate with SLf and AUCp, and high with I and Tmax following correction for apparent lag time (Tlag). Changes of the shape parameter CV2A, however, were not detectable by Cmax, Tmax, SLf, and AUCp. Changes in both MAT and CV2A were well reflected by I with CV2A - ratio > 1. I exhibited approximately full KS also with CV2A - ratio < 1 when a correction was first applied for the apparent lag time.


CONCLUSIONS
The time profile of absorption rates is insufficiently characterized by only one parameter (MAT). Indirect metrics which are sensitive enough to detect changes in the scale and shape of the input profile could be useful for bioequivalence testing. Among the tested measures, I is particularly promising when a correction is applied for Tlag.
Ring
A
A
Department of Pharmacology, Martin Luther University Halle-Wittenberg, Halle, Germany.
Tothfalusi
L
L
Endrenyi
L
L
Weiss
M
M
D014150:Antipsychotic Agents / Q000493:pharmacokinetics; D019540:Area Under Curve; D002749:Chlorprothixene / Q000493:pharmacokinetics; D007408:Intestinal Absorption; D019999:Pharmaceutical Solutions; D010599:Pharmacokinetics; D013535:Suspensions; D013607:Tablets; D013810:Therapeutic Equivalency
D014150:Antipsychotic Agents; D019999:Pharmaceutical Solutions; D013535:Suspensions; D013607:Tablets; D002749:Chlorprothixene