Nikolaos Alimpertis 1, Athanasios A. Tsekouras 2,3, Panos Macheras 1,3
1 Faculty of Pharmacy, National & Kapodistrian University of Athens (Athens, Greece), 2 Department of Chemistry, National & Kapodistrian University of Athens (Athens, Greece), 3 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] with one or more absorption stages provide meaningful parameter estimates for the duration τ, of absorption stage(s) and the drug input rate(s). Besides, an estimate for the concentration value FD/V of the fraction (F) of dose (D) and the volume of distribution V for each one of the absorption stages 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 ranging from bioavailability (BA) and bioequivalence (BE) assessment, the revamping of the foundations of biopharmaceutics-PK, the in vitro-in vivo correlations and pharmacometrics (PM) were published recently [9-16]. Finite Pharmacokinetics (FTPK) Software based on the PBFTPK models was developed recently [17].
Objectives Use the FTPK software to (A) uncover the true meaning of Cmax used in PK, pharmacodynamics (PD), PM, BA and BE. (B) analyze PBPK studies based on middle-out approach (C) formulate new strategies for i) drug and ii) generics development (D) develop-design prolonged release formulations. (E) formulate a model dependent BE assessment
Methods (A) We used simulations based on a PBFTPK model with one absorption stage, first-order elimination and one-compartment model disposition. (B) Literature bottom up PBPK studies based on middle out approach were analyzed using the FTPK software [18] (C)(i). We analyzed a literature semi-simultaneous pharmacokinetic LiCl study using the FTPK software for the estimation of the drug input rates, the estimation of duration of absorption and the absolute bioavailability with minimum blood sampling data from the intravenous administration. (C)(ii). We analyzed the in vivo data of the carbamazepine formulations using the FTPK software; we also analyzed their in vitro data and correlated the percent dissolved with the percent absorbed following the methods described in [11,12] (D) We analyzed a sustained release formulation of drug X administered every 12h using the FTPK software to get the estimates for the drug input rate and its duration; these data were further utilized for the design of a double dose prolonged release formulation given once per day. (E) We analyzed a digoxin bioavailability study using the FTPK software to get estimates for the extent of absοrption, FD/V and the rate of absorption, (FD/Vτ).
Results (A) We found that Cmax, actually corresponds to the blood drug concentration at the end of the absorption process, Cτ which is proportional to the fraction, F of dose D absorbed minus the quantity of drug eliminated from time zero to time τ, Qel (τ). Τhe estimate for the concentration value FD/V derived from the fitting of the PBFTPK models, where V is the volume of distribution, is proportional to drug’s extent of absorption (FD) [18]. (B) The analysis of nefazodone, furosemide and aprepitant data reported in [19] revealed not only the analytical power of FTPK software leading to reliable estimates for the number of input stages, their duration and their input rates but also the paucity of the PBPK models in capturing the spatiotemporal dynamics of drugs’ absorption [18]. (Ci). FTPK software analysis of a semi-simultaneous study [20] involving intraperitoneal administration of a LiCl dose to rats followed 2 h later by an iv administration of a double dose resulting in an absolute bioavailability of ip administered LiCl almost equal to unity in accord with the results in [20]. (Cii). We analyzed carbamazepine bioequivalence studies and found for all four formulations examined three absorption stages and duration of carbamazepine absorption more than sixteen hours [12]. Based on these results the percent absorbed versus time curves were constructed as described in [11] and found to have three linear segments. (D) Analysis of the digoxin bioavailability study [21] using the FTPK software based on the FD/V estimates for the ratio reference/test fasted state data was found to be 2296/2343=0.98, which is quite similar to 1.01 found with the classical approach based on AUCs [21]; the corresponding rates of absorption based on (FD/Vτ) estimates were found to be 2367, 2391 pg/mLh for the reference and test, respectively (E). Analysis using the FTPK software of immediate formulation of drug X administered every 12h, resulted in the following estimates for the two input phases: F1D/V=11.72 ng/ml, τ1=1.04h , F2D/V=7.34 ng/ml, τ2=3.29h.
Conclusions (A) The uncovered meaning of Cmax will induce revolutionary changes not only in the MIDD approaches applied in the development of drugs and generics but also the interpretation of PK and PD data. Relevant conclusions can be drawn for the use of [AUC]_0^τ and [AUC]_0^∞ (B) The use of FTPK software opens a new era in early oral drug development, which currently is based on PBPK approaches exclusively (Ci) The development of drugs can be reliably based on a semi-simultaneous study with minimum blood sampling after the intravenous dose; development will be accelerated based on both the detailed absorption profile and the estimate for the bioavailable fraction (Cii) Generic development should always start from the analysis of the reference in vivo data using the FTPK software coupled with construction of the % absorbed curve and its correlation with the % dissolved curve of the reference as described in [11,12] (D) The model based assessment of BE using the FTPK software relies on meaningful parameter estimates for the extent (FD/V) and the rate of absorption (FD/Vτ) (E) the input rates estimates (F1D/Vτ1)=11.27ng/mlh (F2D/Vτ2)=2.23ng/mlh allowed the design of pharmacokinetic scenarios including different percentages of burst release resulting in various C,t profiles of the sustained release formulation with frequency of administration 24 h using the double dose; since prolonged release formulations are mostly based on zero-order kinetics, the FTPK software is extremely valuable for this type of simulations.
References:
References
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[17] FTPK software by Enalos Cloud Platform (NovaMechanics Ltd) https://enaloscloud.novamechanics.com/EnalosWebApps/model_fittingsV2/
[18] P. Macheras, et al Finite-Time Pharmacokinetics guides the next Era in Early Oral Drug Development. Submitted
[19] Pepin, X.J.H. et al. (2021) AAPS J. 23, 12 doi: 10.1208/s12248-020-00548-8. PMID: 33398593
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[21] Center for Drug Evaluation and Research, Digoxin Bioequivalency Review 76268. 2002. https://www.accessdata.fda.gov/drugsatfda_docs/anda/2002/76268_Digoxin_Bioeqr.pdf
Reference: PAGE 34 (2026) Abstr 11970 [www.page-meeting.org/?abstract=11970]
Poster: Drug/Disease Modelling - Absorption & PBPK