Revising Pharmacokinetics of Oral Drug Absorption: II Bioavailability-Bioequivalence Considerations

Purpose o explore the application of the parameters of the physiologically based finite time pharmacokinetic (PBFTPK) models subdivided in first-order (PBFTPK)(1) and zero-order (PBFTPK)(0) models to bioavailability and bioequivalence. To develop a methodology for the estimation of absolute bioavailability, F, from oral data exclusively. Methods Simulated concentration time data were generated from the Bateman equation and compared with data generated from the (PBFTPK)(1) and (PBFTPK)(0) models. The blood concentration C-b(tau) at the end of the absorption process tau, was compared to C-max; the utility of AUC(0)(tau) and (AUC)(t)(infinity) in bioequivalence assessment was also explored. Equations for the calculation of F from oral data were derived for the (PBFTPK)(1) and (PBFTPK)(0) models. An estimate for F was also derived from an areas proportionality using oral data exclusively. Results The simulated data of the (PBFTPK)(0) models exhibit rich dynamics encountered in complex drug absorption phenomena. Both (PBFTPK)(1) and (PBFTPK)(0) models result either in C-max = C-b(tau) or C-max > C-b(tau) for rapidly- and not rapidly-absorbed drugs, respectively; in the latter case, C-b(tau) and tau are meaningful parameters for drug's rate of exposure. For both (PBFTPK)(1) and (PBFTPK)(0) models, (AUC)(0)(tau) or portions of it cannot be used as early exposure rate indicators. (AUC)(tau)(infinity) is a useful parameter for the assessment of extent of absorption for very rapidly absorbed drugs. An estimate for F for theophylline formulations was found close to unity. Conclusion The (PBFTPK)(1) and (PBFTPK)(0) models are more akin to in vivo conditions. Estimates for F can be derived from oral data exclusively.

Automated summary

The study explores the application of PBFTPK models in assessing bioavailability and bioequivalence, developing a methodology for estimating absolute bioavailability exclusively from oral data. Simulated data showed that PBFTPK models are more similar to in vivo conditions, with useful parameters for assessing drug exposure and absorption extent. Estimates for F can be derived from oral data exclusively, with findings close to unity for theophylline formulations.