IVIVC Revised.

PURPOSE: To revise the IVIVC considering the physiologically sound Finite Absorption Time (F.A.T.) and Finite Dissolution Time (F.D.T.) concepts. METHODS: The estimates τ and τd for F.A.T. and F.D.T., respectively are constrained by the inequality τd ≤ τ; their relative magnitude is dependent on drug's BCS classification. A modified Levy plot, which includes the time estimates for τ and τd was developed. IVIVC were also considered in the light of τ and τd estimates. The modified Levy plot of theophylline, a class I drug, coupled with the rapid (30 min) and very rapid (15 min) dissolution time limits showed that drug dissolution/absorption of Class I drugs takes place in less than an hour. We reanalyzed a carbamazepine (Tegretol) bioequivalence study using PBFTPK models to reveal its complex absorption kinetics with two or three stages. RESULTS: The modified Levy plot unveiled the short time span (~ 2 h) of the in vitro dissolution data in comparison with the duration of in vivo dissolution/absorption processes (~ 17 h). Similar results were observed with the modified IVIVC plots. Analysis of another set of carbamazepine data, using PBFTPK models, confirmed a three stages absorption process. Analysis of steady-state (Tegretol) data from a paediatric study using PBFTPK models, revealed a single input stage of duration 3.3 h. The corresponding modified Levy and IVIVC plots were found to be nonlinear. CONCLUSIONS: The consideration of Levy plots and IVIVC in the light of the F.A.T. and F.D.T. concepts allows a better physiological insight of the in vitro and in vivo drug dissolution/absorption processes.

Revamping Biopharmaceutics-Pharmacokinetics with Scientific and Regulatory Implications for Oral Drug Absorption.

PURPOSE: The Wagner-Nelson and Loo-Riegelman methods developed in the 1960s and used since for the construction of percent of drug absorbed as a function of time as well as in in vitro in vivo correlations are re-considered in the light of the physiologically sound Finite Absorption Time (F.A.T.) concept developed recently. METHODS: The classical equations for the percentage of drug absorption as a function of time were modified by taking into account the termination of drug absorption at F.A.T., replacing the parameters associated with the assumption of infinite drug absorption. RESULTS: Mathematical analysis using the relevant Physiologically Based Pharmacokinetic Finite Time (PBFTK) models assuming one- or two-compartment drug disposition, revealed that the modified %absorbed versus time curves are of bilinear type with an ascending limb intersecting the horizontal line at F.A.T. A computer-based methodology is described for the estimation of F.A.T. from experimental data. More than one linear ascending limb is found when more than one absorption phase is operating. Experimental data were analyzed and the estimates for F.A.T were found to be similar to those derived from nonlinear regression analysis using PBFTPK models. CONCLUSION: These results place an end to the routinely reported exponential %absorbed versus time curves prevailing in biopharmaceutics-pharmacokinetics since their inception in the'60 s. These findings point to the use of the F.A.T. concept in drug absorption research and regulatory guidelines such as deconvolution techniques for the assessment of drug input rate, stochastic mean absorption time calculations, population analyses, in vitro in vivo correlations and bioequivalence guidelines.