Nikos Alimpertis 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: Pharmacokinetic (PK) analyses, data evaluation, and simulations assume that absorption of drugs administered orally or otherwise lasts forever since an empirical first-order absorption rate constant is always applied. This erroneous practice has been pointed out in several recent publications [1-5]. The Finite Absorption Time (F.A.T.) concept [2] applied in the Physiologically Based Finite Time Pharmacokinetic (PBFTPK) models [3-7] provide meaningful parameter estimates for the duration τ, of absorption stage(s) and the drug input rate(s). Besides, an estimate for the concentration maximum value FD/V of the bioavailable fraction (F) of dose (D) and the volume of distribution V is derived; this parameter is a metric of the drug’s extent of absorption. Zero-order absorption kinetics are applied given the rapid blood flow [8] in the portal vein. Various applications of the F.A.T. concept were published recently [9-17]. In this work we couple the Finite Pharmacokinetics (FTPK) Software [17] with the semi-simultaneous method [18], which is used nowadays in pharmacokinetic and pharmacometrics studies in absolute bioavailability and clearance [19, 20].
Objectives: For the early drug development, we propose a semi-simultaneous study involving one single measurement after the intravenous administration of drug coupled with FTPK software analysis to get the number of drug input stages, their duration and input rates as well as an estimate of drug’s absolute bioavailability.
Methods: The study involves a per os administered dose followed by i) an intravenous bolus (iv) administration of a dose at the end of the sampling period and ii) a blood drug measurement right after. If the drug is insoluble and a microdose intravenous bolus dose must be used (21-23), the administration scheme in reverse order is applied. The concentration-time data of the per os administration are analyzed by PBFTPK models using the FTPK software. The estimation of the absolute bioavailability of the per os formulation is estimated from the ratio of the “concentration maximum” FD/V, derived from the per os data fitting, over the drug concentration measured after the intravenous bolus dose administered applying dose correction if needed. We analyzed literature data using the (FTPK) software to demonstrate the validity of these approaches.
Results: Th semi-simultaneous study [18] involved intraperitoneal (ip) administration of a LiCl dose to rats followed by an iv administration of a double dose and another set in reverse order. We dealt with each iv dose as a finite time administration of very short absorption time (0.01 h = 36 s). Assuming finite absorption time for the ip dose, we set a scheme of three absorption stages, the 1st and the 3rd one for the actual administration and the 2nd one with 0 dose. The results for the absolute bioavailability of LiCl formulation given intraperitoneally, Fip, for the two sets of data, ip-iv: Fip = 2 F1D/F3D = 1.1 and iv –ip: Fip = F3D/2F1D = 0.92, show that the absolute bioavailability of ip LiCl was found almost equal to unity in accord with [19].
We also analyzed the microdosing absolute bioavailability study of Venetoclax (21). The single point measurement at t=0, C(0)= (Dose/V)iv was set equal to 0.0198 μg/mL which corresponds to the first measurement at 8min found upon digitization. The best fitting results were obtained using a two compartment model with one input stage; the following parameters were estimated, (FD/V)= 0.166±0.057μg/mL, τ=3.8±0.34h, k10=0.011±0.034h-1, k12=0.066±0.47h-1, k21=0.016± 18.11h-1, α=0.20h-1, β=0.02h-1, R2=0.995, χ2=0.00025. The estimation of the bioavailable fraction F was based on the concentration maxima of the i.v. and oral administration applying dose correction; the amount eliminated from the oral dose from time zero up to time τ, Qel(τ) was also taken into account i.e. F=(Dose)iv[(FD/V)estimate+ Qel(τ)/V]oral/(Dose/V)iv(Dose)oral where Qel(τ)= (FD/V)estimate-C(τ). We found F(%)=1.1 while the reported value (21) is F(%)=5.4. The difference of 4.3% can be considered logical and is attributed to the vast difference of the two methodologies.
Conclusions. This work represents a paradigm shift in oral drug development. It demonstrates that applying the FTPK software to a simple pharmacokinetic study conducted in a small number of volunteers can accurately determine the complete drug absorption profile, including the number of input stages, their duration, and their respective input rates. In parallel, the absolute bioavailability can be estimated using the proposed protocol.
References:
References
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Reference: PAGE 34 (2026) Abstr 11857 [www.page-meeting.org/?abstract=11857]
Poster: Drug/Disease Modelling - Absorption & PBPK