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.

Coupling Drug Dissolution with BCS.

PURPOSE: The purpose of this study is to develop a Temporal Biopharmaceutic Classification System (T-BCS), linking Finite Dissolution Time (F.D.T.) and Mean Dissolution Time (M.D.T.) for Class I/III drugs and Mean Dissolution Time for saturation (M.D.T.s.) for Class II/IV drugs. METHODS: These parameters are estimated graphically or by fitting dissolution models to experimental data and coupled with the dose-to-solubility ratio (q) for each drug normalized in terms of the actual volume of dissolution medium (900 mL). RESULTS: Class I/III drugs consistently exhibited q values less than 1, aligning with expectations based on their solubility, while some Class II/IV drugs presented a deviation from anticipated q values, with observations of q < 1. This irregularity was rendered to the dissolution volume of 250 mL used for biopharmaceutical classification purposes instead of 900 mL applied as well as the dual classification of some sparingly soluble drugs. Biowaivers were also analyzed in terms of M.D.T., F.D.T. estimates and the regulatory dissolution time limits for rapidly and very-rapidly dissolved drugs. CONCLUSIONS: The T-BCS is useful for establishing correlations and assessing the magnitude of M.D.T., F.D.T., or M.D.T.s. for inter- and intra-class comparisons of different drugs and provide relationships between these parameters across all the models that were utilized.