Nikoalos Alimpertis1, Antreas Tsoumanis3, Antreas Afantitis3, Athanasios Tsekouras1,2, Panos Macheras1,2
1National and Kapodistrian University of Athens, 2Athena Recearch Center, 3NovaMechanics Ltd & Entelos Institute
Introduction: The concept of finite absorption time (F.A.T.) has led to the development of physiologically based finite time pharmacokinetic (PBFTPK) models, which have been successfully applied to the analysis of pharmacokinetic data following a variety of administration routes [1-5]. The PBFTPK models provide meaningful estimates for the number of absorption stages, the duration of each absorption stage and the input rates. Building upon this framework, we developed Software FTPK, a novel tool based on PBFTPK models for the analysis of pharmacokinetic data. Objectives: The primary objective was to develop a user-friendly software application employing PBFTPK models to analyze pharmacokinetic data. More specifically, to estimate the absorption parameters, number of absorption stages, the duration of each absorption stage and the input rates for drugs exhibiting one- and two-compartment model disposition kinetics. Although the PBFTPK models have been tested extensively on experimental software platforms, they were not available for the general user. Methods: Software FTPK estimates absorption parameters by fitting PBFTPK model equations to pharmacokinetic data. It utilizes non-linear regression techniques to determine the number of absorption stages, their respective durations, and drug input rates. All parameters are given with associated uncertainties as well as overall fitting criteria such as chi squared (sum of squares of deviations), correlation coefficient of the fit, and parameter correlation coefficients. The software was tested using simulated and published blood concentration-time data, implementing statistical analyses to compare FTPK-derived estimates with those reported in the literature. Parameters reported include the concentration values FD/Vd or FD/Vc for each absorption stage, where F is the fraction of dose D absorbed and Vd the volume of drug distribution and Vc the volume of the central compartment, the duration t of each stage, the drug absorption rate for each stage, the elimination rate constant for one-compartment models or all three rate microconstants k12, k21, k10 and equivalent a and ß hybrid rate constants for two-compartment models. Results: Errorless simulated data and realistic simulated data were analyzed with Software FTPK and model parameters were recovered as expected. Furthermore, the new software was put to the test by using published blood concentration-time data from multiple sources. For one- and two-compartment drugs, such as ibuprofen, paracetamol, almotriptan, theophylline, cyclosporine, carbamazepine, niraparib, have been analyzed before and the pharmacokinetic parameters determined with the new software aligned well with values found in the experimental version of the PBFTPK software. The ease of use and user friendliness along with quality of calculations and presentation of the results can vouch for the usefulness of this software to the practicing pharmacometrician. Conclusion: Software FTPK offers a robust and efficient approach for estimating absorption parameters, leveraging the physiological concept of F.A.T. to enhance the accuracy of pharmacokinetic analyses. Its use improves the detailed understanding of the absorption process which is currently based on the erroneous first-order absorption kinetics. Its integration into early drug development workflows could eliminate the need for costly and time-consuming studies used to determine drug properties in pharmaceutical research.
1. Macheras P. On an unphysical hypothesis of Bateman equation and its implications for pharmacokinetics. Pharm Res. 2019;36:94. https://doi.org/10.1007/s11095-019-2633-4 2. Macheras P, Chryssafidis P. Revising Pharmacokinetics of Oral Drug Absorption: I Models Based on Biopharmaceutical/ Physiological and Finite Absorption Time Concepts. Pharm Res. 2020;37:187. https://doi.org/10.1007/s11095-020-02894-w, Erratum. Pharm Res 2020;37:206. https://doi.org/10.1007/s11095-020-02935-4 3. Chryssafidis P, Tsekouras AA, Macheras P. Revising Pharmacokinetics of Oral Drug Absorption: II Bioavailability-Bioequivalence Considerations. Pharm Res. 2021;38:1345–1356. https://doi.org/10.1007/s11095-021-03078-w 4. Chryssafidis P, Tsekouras AA, Macheras P. Re-writing Oral Pharmacokinetics Using Physiologically Based Finite Time Pharmacokinetic (PBFTPK) Models. Pharm Res. 2022;39:691-701. https://doi.org/10.1007/s11095-022-03230-0 5. Tsekouras AA, Macheras P. Re-examining Naloxone Pharmacokinetics After Intranasal and Intramuscular Administration Using the Finite Absorption Time Concept. Eur J Drug Metab Pharmacokinet. 2023;48:455–462. https://doi.org/10.1007/s13318-023-00831-x
Reference: PAGE 33 (2025) Abstr 11708 [www.page-meeting.org/?abstract=11708]
Poster: Drug/Disease Modelling - Absorption & PBPK