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

Abstract

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. 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. 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. These results place an end to the routinely reported exponential %absorbed versus time curves prevailing in biopharmaceutics-pharmacokinetics since their inception in the'60s. 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.