Nikos Alimpertis 1, Nefeli Maria Magaliou 1, Athanasios Tsekouras 2,3, Panos Macheras 1,3
1 Faculty of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece (, ), 2 Department of Chemistry, National and Kapodistrian University of Athens, Athens, Greece (, ), 3 PharmaInformatics Unit, ATHENA Research Center, Athens, Greece (, )
Introduction: The introduction of Finite Absorption Time (F.A.T.) [1,2] concept led to the development of Physiologically Based Finite Time Pharmacokinetic (PBFTPK) models [3-6]. These models provided meaningful parameter estimates for the number and the duration of drug absorption stage(s) as well as the input rate(s). Based on PBFTPK models we recently i) revamped the classical % absorbed vs time plots [7-9] developing modified, in terms of F.A.T., approaches [10] ii) applied the PBFTPK models in studies dealing with PBPK modeling [4,11] and iii) suggested a change in the strategy of early drug development [12, 13].
Objectives: To re-define the Absorption number, An of drugs. To explore the use of top-down Physiologically Based Finite Time Pharmacokinetic (PBFTPK) models in early drug development. To analyze PBPK absorption studies based on so-called middle-out approach [14] for nefazodone, furosemide and aprepitant applying PBFTPK models fitting.
Methods: The An of drugs was re-defined as the ratio of residence time of drug in the gastrointestinal tract and the half duration of its absorption, Ï„. The PBFTPK models fitting was based on the Finite Time Pharmacokinetic (FTPK) software developed recently [15].
Results: Using estimates for Ï„ of several drugs derived from the fittings of PBFTPK models to literature experimental data and the mean intestinal transit time, 199 min, we calculated the corresponding An values and discussed them in terms of their BCS classification. Overall, low Ï„ values result in high An estimates. All fasted and fed data sets reported in [14] were described nicely by the PBFTPK models; the best fit models provided meaningful estimates for (i) the number of the absorption stages (ii) the duration in hours of each absorption stage and iii) the concentration at the end of the absorption process (FD/V), where F is the bioavailable fraction, D is the dose and V is the volume of distribution). Best fit results for nefazodone: one compartment PBFTPK model with one input stage under fasted conditions and two-input stages under fed conditions. Best fit results for furosemide: one compartment PBFTPK model with three input stages under fasted and fed conditions. Best fit results for aprepitant: one compartment PBFTPK model with one-input stage for all formulations studied under fasted and fed conditions. The double peak hypothesis applied to interpret the fasted state data of nefazodone in [14] was not justified in the analysis based on the FTPK software. The complex absorption profile found for furosemide could not be predicted using the PBPK approaches. The effect of food on the micronized formulation of aprepitant was found to be very significant in terms of the extent of absorption since the ratio fed/fasted is 2.5 for FD/V estimates. The latter parameter derived from the PBFTPK model fitting is a metric of the extent of absorption.
Conclusions. This work demonstrates the paucity even of PBPK middle out approaches to capture the spatiotemporal dynamics of drug uptake from the different regions of the GI tract. Overall, this work shows that a simple pharmacokinetic study analyzed with the PBFTPK models reliably expedites Phase I drug development and reduces costs. The use of FTPK software opens a new era in early oral drug development, which currently is based on PBPK approaches exclusively.
References:
References
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[15]FTPK software by Enalos Cloud Platform (NovaMechanics Ltd) https://enaloscloud.novamechanics.com/EnalosWebApps/model_fittingsV2/
Reference: PAGE 34 (2026) Abstr 12183 [www.page-meeting.org/?abstract=12183]
Poster: Methodology - New Modelling Approaches