Center of gravity of drug level curves: a model-independent parameter useful in bioavailability studies

The center of gravity (CG) of a drug level curve [c(t)] has the time coordinate AUMC/AUC and the concentration coordinate AUCC/2AUC, where AUC, AUMC, and AUCC are the integrals from time t = zero to t = infinity of c(t), tc(t), and c(t).c(t), respectively. An algorithm and computer program for determining CG when c(t) is given by a sum of exponentials is presented and its use is demonstrated with oral cimetidine data. Simulations indicate that the CG appears more suitable for comparison of absorption rates than mean absorption time (MAT) parameters. The limitation of the MAT parameter is due to the fact that this parameter is scale independent in that it only considers the shape and not the magnitude of the drug level or absorption rate curve. The MAT is therefore independent of the extent (F) of absorption. This limitation is not shared by the CG. When dealing with first-order absorption, the absorption rate of drug from product A will consistently (all t greater than 0) be larger than the absorption rate from product B (tested in the same subject) if MATA greater than MATB and AUCA/AUCB greater than MATA/MATB (assuming a time-invariant linear disposition). The above inequality relationships strongly contrast the common thinking about the "nonproblematic" use of MAT in absorption rate comparisons. Since both CG and MAT suffer some fundamental limitations, it is recommended that whenever problems arise, one should compare absorption rates by nonparametric system analysis methods (e.g., deconvolution) if possible.