Elias Toulitsis1, Marina Kotsiopoulou1, Athanasios Tsekouras2,3, Panos Macheras1,3
1Faculty of Pharmacy, National and Kapodistrian University of Athens, 2Department of Chemistry, National and Kapodistrian University of Athens, 3PharmaInformatics Unit, ATHENA Research Center
Introduction: The introduction of the Finite Absorption Time (F.A.T.) [1,2] concept led to the development of PBFTPK models [3-6]. These models provided meaningful parameter estimates for the number and the duration of 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] and ii) applied the PBFTPK models in studies dealing with PBPK modeling [4,11]. Objectives: a. To analyze published concentration, time data use PBFTPK models to find out the drug absorption characteristics and generate modified in terms of F.A.T., fraction absorbed versus time plots [10] b. To compare these findings with the results derived from the classical analysis [7-9]. c. To demonstrate the need to incorporate F.A.T features (zero-order kinetics and duration of absorption) in the current PBPK modeling work Methods: The concentration (C) and time (t) observed data of eight drugs, aprepitant (AP) (two formulations), fenofibrate (FE) (two formulations), danazol (DA), ketoconazole (KE) (two formulations) and carbamazepine (CA) reported in [12] were digitized using the Windows utility MS Paint. They analyzed using PBFTPK models as well as classical models with first-order absorption. The least-squares method was implemented within the programming environment of Igor Pro 9 by WaveMetrics for the PBFTPK model fittings. Percent absorbed versus time plots were also constructed using the Wagner Nelson and Loo Riegelman plots [7-9] and their modified versions based on F.A.T. [10]. Results: All data sets were described nicely by the PBFTPK models in contrast to the fitting results using the Bateman equation which were inferior. In all cases, meaningful estimates for (i) the number of the absorption stages (ii) the duration in hours of each absorption stage and the corresponding drug input rate, were obtained using the PBFTPK models. Both AP formulations 80mg and 125mg exhibit a single input with 2.8 ± 0.6 h and 4.5 ± 0.2 h, 223.03 ± 101.6 ng/(ml*h) and 321.1 ± 88.23 ng/(ml*h), respectively; KE (800mg) also exhibits a single input with 2.7 ± 0.09 h and 8450.3 ± 371.2 ng/(ml*h). FE (145 mg 0.2µm), DA and KE (200mg) formulation exhibit 2 input stages, FE (145 mg 0.2µm): 2.7 ± 0.3 h 3433.8 ± 907.2 ng/(ml*h) for 1st stage and 5.8 h ± 5.5 h and 136.4 ± 590.3 ng/(ml*h) for the 2nd stage; DA: 1.1 ± 0.03 h and 58.96 ± 2.9 ng/(ml*h) for the 1st stage and 1.6 ± 0.2 h and 8.54 ± 3.14 ng/(ml*h) for the 2nd stage; KE: 0.37 ± 0.03 h and 600.8 ± 74.03 ng/(ml*h) for the 1st stage and 1.9 ± 0.07 h and 1809.5 ± 130.8 ng/(ml*h). FE (160mg 1.1µm) formulation exhibited 3 input stages with 4.4 ± 0.58 h and 988.8 ± 227.6 ng/(ml*h) for the 1st stage, 6.4 ± 1.4 h and 385.9 ± 88.7 ng/(ml*h) for the 2nd stage and 12 ± 2.6 h and 161.8 ± 118.24 ng/(ml*h). CA formulation was also. exhibited 3 input stages with, 2.8 ± 0.2 h and 1290.9 ± 104.2 ng/(ml*h) for the 1st stage, 10.7 ± 5.6 h and 125.6 ± 90.6 ng/(ml*h) for the 2nd stage and 26.2 ± 7.8h and 41.5 ± 32.37 ng/(ml*h) for the 3rd stage. The absorption rate constant, ka estimates were as follows, AP (two formulations 80mg , 125mg): 1.2 ± 12.8 h^(-1) and 2.8 ± 5404.4 h^(-1) , respectively; FE (two formulations 145mg, 160mg): 1.05 ± 2.5*106 h^(-1) and 0.2 ± 2.2 h^(-1), respectively; DA 2.8 ± 59.3 h^(-1); KE (two formulations 200mg, 800mg) 0.5 ± 1.6 h^(-1) and 0.2 ± 1.5 h^(-1) , respectively; CA: 0.01 ± 0.002 h^(-1). ?hese results show the analytical power of the PBFTPK models. In contrast, the estimates of the single absorption rate constant were in all cases not reliable (SD values were higher than the estimate) except for CA; however, the PBFTPK model for CA had better statistical metrics, ?²=3.5*105, R²= 0.996 versus ?²=7.5*105, R²= 0.986. The % absorbed versus time plots for the eight formulations were mono-exponential when the classical methodologies [7-9] were applied while the methodology based on F.A.T. [7] resulted in bilinear or multilinear plots. The significance of these results for the PBPK modeling work is, drug absorption should be always considered under sink conditions and dissolution functions with finite time duration [13] should replace the classical exponential functions. Conclusions: This study provides insights into the detailed characteristics of oral drug absorption of eight formulations. The results indicate the changes required in the PBPK modeling work.
[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. Re-writing Oral Pharmacokinetics Using Physiologically Based Finite Time Pharmacokinetic (PBFTPK) Models. Pharm Res. 2022 Apr;39(4):691-701. doi: 10.1007/s11095-022-03230-0. Epub 2022 Apr 4. PMID: 35378697. [4] Macheras P, Tsekouras AA. The Finite Absorption Time (FAT) concept en route to PBPK modeling and pharmacometrics. J Pharmacokinet Pharmacodyn. 2023 Feb;50(1):5-10. doi: 10.1007/s10928-022-09832-w. Epub 2022 Nov 11. PMID: 36369406. [5] Chryssafidis, P., Tsekouras, A.A. & Macheras, P. Revising Pharmacokinetics of Oral Drug Absorption: II Bioavailability-Bioequivalence Considerations. Pharm Res 38, 1345–1356 (2021). https://doi.org/10.1007/s11095-021-03078-w [6] Tsekouras, A.A., Macheras, P. Re-examining Naloxone Pharmacokinetics After Intranasal and Intramuscular Administration Using the Finite Absorption Time Concept. Eur J Drug Metab Pharmacokinet 48, 455–462(2023).https://doi.org/10.1007/s13318-023-00831-x [7].Wagner JG, Nelson E. Percent absorbed time plots derived from blood level and/or urinary excretion data. J Pharm Sci. 1963;52:610–1. https://doi.org/10.1002/jps.2600520629. [8]. Wagner JG, Nelson E. The kinetic analysis of blood levels and urinary excretion in the absorptive phase after single doses of drug. J Pharm Sci. 1964;53:1392–403. https:// doi. org/ 10. 1002/ jps.2600531126. [9]. Loo JCK, Riegelman S. New method for calculating the intrinsic absorption rate of drugs. J Pharm Sci. 1968;57:918–28. https:// doi.org/10.1002/jps.2600570602. [10] Alimpertis N, Tsekouras AA, Macheras P. Revamping Biopharmaceutics-Pharmacokinetics with Scientific and Regulatory Implications for Oral Drug Absorption. Pharm Res. 2023 Sep;40(9):2167-2175. doi: 10.1007/s11095-023-03578-x. Epub 2023 Aug 3. PMID: 37537424. [11] D. Wu, A. A. Tsekouras, P. Macheras, F. Kesisoglou, Physiologically based pharmacokinetic models under the prism of the finite absorption time concept, Pharm. Res. 40, 419-429 (2023), 10.1007/s11095-022-03357-0 [12] Sjögren, E., Westergren, J., Grant, I., Hanisch, G., Lindfors, L., Lennernäs, H., … & Tannergren, C. (2013). In silico predictions of gastrointestinal drug absorption in pharmaceutical product development: application of the mechanistic absorption model GI-Sim. European journal of pharmaceutical sciences, 49(4), 679-698. [13] Dokoumetzidis A, Papadopoulou V, Macheras P. Analysis of dissolution data using modified versions of Noyes-Whitney equation and the Weibull function. Pharm Res. 2006;23:256-61. https://doi.org/10.1007/s11095-006-9093-3 [14] Toulitsis, E., Tsekouras, A. A., & Macheras, P. (2024). FDA and EMA Oversight of Disruptive Science on Application of Finite Absorption Time (FAT) Concept in Oral Drug Absorption: Time for Scientific and Regulatory Changes. Pharmaceutics, 16(11), 1435.
Reference: PAGE 33 (2025) Abstr 11706 [www.page-meeting.org/?abstract=11706]
Poster: Drug/Disease Modelling - Absorption & PBPK