Marina Kotsiopoulou1, Dr Kosmas Kosmidis2, Athanasios A. Tsekouras1,3, Dr Panas Macheras1,3
1National and Kapodistrian University of Athens, 2Aristotle University of Thessaloniki, 3ATHENA Research Center
Introduction/ Objectives. Flip flop kinetics is being used in pharmacokinetics and pharmacometrics when following oral dosing the absorption half-life is larger than the elimination half-life [1-3] assuming first-order kinetics for drug absorption and elimination. According to the finite absorption time (F.A.T.) concept developed recently (4- 6), the gastrointestinal absorption of drugs follows zero-order (single or multiple) kinetics because of the passive drug absorption under sink conditions caused by the high blood flow rate 20-40 cm/s in the portal vein; therefore, flip flop kinetics cannot be substantiated in the gastrointestinal absorption. In this work, we re-analyze pharmacokinetic data which have been reported to follow flip flop kinetics in gastrointestinal absorption or after intramuscular administration of long acting formulations [7,8]. Methods. The concentration (C) and time (t) data of the plots in [7,8] were digitized by transferring the published figures to the Windows utility MS Paint, reading off the coordinates of axis ranges and data points, and performing linear interpolation to recover the data shown in the published papers. They were then analyzed using physiologically based finite time pharmacokinetic (PBFTPK) models. The least-squares method was implemented within the programming environment of Igor Pro 9 by WaveMetrics for the PBFTPK model fittings. We also fitted the fractal kinetics [9,10] model, dC/dt =kt^(-?) -kelC, where k is a rate coefficient with concentration.(time)^(?-1) units and kel is the elimination rate constant, to the data. The analytical solution of the differential equation was used in the fitting exercise. The program used was custom code written in Wolfram Language (Mathematica version 14.2). Results. The doxycycline [7] data were nicely described with a PBFTPK model with one input stage, absorption duration 0.44±0.06 h, input rate 3.5±0.07 (µg/mL)/h, elimination rate constant 0.073±0.09 h^-1, correlation coefficient R²=0.985 and one compartment model disposition. Since the input rate for the doxycycline data is described by zero-order kinetics (input rate 3.5±0.07 (µg/mL), the comparison with the elimination rate constant (0.073±0.09 h^-1) cannot be made; thus, flip flop kinetics cannot be justified. The two sets of data in [8] were best described with a model having input rate driven by a time-dependent coefficient and one compartment model disposition. For the data set of methylprednisolone sodium succinate (MPS) which is a hydrosoluble pro-drug of methylprednisolone (MP), administered intravenously and transformed to MP, the time dependent coefficient was equal to 229.1 (ng/mL)(min)^-0.52 , ?=0.48, the elimination rate constant was found 0.041min^-1 and R²=0.964; for methylprednisolone acetate, a non-hydrosoluble pro-drug of MP administered intramuscularly at the same dose rate of 4 mg/kg (as MP), the time dependent coefficient was equal to14.36 (ng.mL)h^-0.56 , ?=0.44 , the elimination rate constant was found 0.179 h^-1 and R²=0.958. The time-dependent character of the absorption process of MP in both data sets examined does not allow a comparison with the elimination characteristics of MP; this is so since a half-life for MP’s absorption, which follows fractal kinetics, cannot be defined [11]. Conclusions. In all three examples studied using PBFTPK and fractal models, flip flop kinetics cannot be justified.
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Reference: PAGE 33 (2025) Abstr 11514 [www.page-meeting.org/?abstract=11514]
Poster: Drug/Disease Modelling - Absorption & PBPK