Panos Macheras1,2, Athanasios Tsekouras1,2
1National and Kapodistrian University of Athens, 2Athena Research Center
Introduction Clinical pharmacology deals, among other topics, with data analysis which can include modelling and simulation techniques, leading to the so-called model informed drug development (MIDD) techniques [1]. Oral drug absorption, monitored with pharmacokinetics (PK), has been described since 1953 as a first-order kinetics process lasting for ever. Development and regulatory issues [1] have relied on these principles since 1977. The determination of Cmax and [AUC]0-8 have been used as metrics of drug absorption rate and absorption extent to evaluate bioavailability and bioequivalence of new drugs and generics. The recently introduced concept of Finite Absorption Time (F.A.T.) [2-6] necessitated the re-evaluation of these metrics, questioned their appropriateness and provided a means for obtaining better alternatives. Objectives The uncovering of the true meaning of Cmax and [AUC]_0^8 using the physiologically sound finite Absorption Time (F.A.T.) concept. The evaluation of these parameters using the pertinent Physiologically Based Finite Time Pharmacokinetic (PBFTPK) models in the case of semisimultaneous drug administration data. Methods Very often the maximum drug concentration in the blood Cmax corresponds to the end of the absorption process. After that, in a one-compartment drug, the PK data show an exponential decline with the shape determined solely by the elimination rate constant. Since elimination has started from the start of the absorption process, the amount eliminated can be added to the existing drug concentration to generate an adjusted concentration which is proportional to the amount of drug absorbed. So, the amount of drug absorbed is deduced from PK data by adding to the drug concentration in the blood the equivalent concentration of the amount eliminated from the body. This calculation at the end of the absorption process allows the determination of the total drug absorbed. After that time PK data are identical to bolus intravenous administration. If the volume of distribution, Vd, were known, the extend of drug absorption, F, could be determined. Hence, Cmax is the blood concentration at the end of the absorption process and is an indication of the amount absorbed rather than a metric of absorption rate. Results Simulations show pictorially the meaning of Cmax and of the area under the curve both from time 0 to infinity [AUC]0-8 or from the end of the absorption process, i.e, after tmax, to infinity [AUC]t-8. The adjusted drug concentration is shown to have the latter area under the curve equal to the former for an orally administered drug. Analysis of PK data from a semisimultaneous administration of LiCl intraperitoneally (ip) and then intravenously (iv) or in the opposite order [7] was based on the PBFTPK models. The stages of drug administration were treated each as a zero-order absorption stage with another two elimination stages. The concentration parameters for each absorption stage allowed the determination of the fraction of dose absorbed in the ip administration, hence the absolute bioavailability. This methodology can be also extended to sparingly soluble drugs and lead to the abolishment of microdosing studies involving labeled compounds in early drug development [8]. Conclusions A realization, which remained buried for more than seventy years under the wrong first-order absorption hypothesis, coupled with the analytical power of PBFTPK models providing real and meaningful parameters for oral drug absorption, leads to the emergence of a new world for MIDD techniques relevant to pharmacokinetics, pharmacodynamics and pharmacometrics. Overall, a great number of the F.A.T. concept and the PBFTPK models applications to pharmacokinetics, pharmacodynamics, pharmacometrics, bioavailability and bioequivalence assessment is anticipated. A new era for the MIDD techniques will emerge in all phases of drug and generics development.
[1] Guideline on the Investigation of Bioequivalence https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-investigation-bioequivalence-rev1_en.pdf [2] Macheras P (2019) On an Unphysical Hypothesis of Bateman Equation and its Implications for Pharmacokinetics. Pharm Res 36:94 https://doi.org/10.1007/s11095-019-2633-4 [3] Macheras P, Chryssafidis P (2020) Revising Pharmacokinetics of Oral Drug Absorption: I Models Based on Biopharmaceutical/Physiological and Finite Absorption Time Concepts. Pharm Res 37:187. https://doi.org/10.1007/s11095-020-02894-w. Erratum Pharm Res. 37:206. https://doi.org/10.1007/s11095-020-02935-4 [3] Chryssafidis P, Tsekouras AA, Macheras P (2022) Re-writing Oral Pharmacokinetics Using Physiologically Based Finite Time Pharmacokinetic (PBFTPK) Models. Pharm Res 39:691-701 https://doi.org/10.1007/s11095-022-03230-0 [4] Chryssafidis P, Tsekouras AA, Macheras P (2021), Revising Pharmacokinetics of Oral Drug Absorption: II Bioavailability-Bioequivalence Considerations, Pharm Res 38:1345-1356 10.1007/s11095-021-03078-w, Erratum Pharm Res 38:1633 https://doi.org/10.1007/s11095-021-03101-0 [5] Alimpertis N, Tsekouras AA, Macheras P (2023) Revamping Biopharmaceutics-Pharmacokinetics with Scientific and Regulatory Implications for Oral Drug Absorption, Pharm Res 40:2167-2175 https://doi.org/0.1007/s11095-023-03578-x [6] Macheras P, Tsekouras AA (2023) Revising Oral Pharmacokinetics, Bioavailability and Bioequivalence based on the Finite Absorption Time (FAT) Concept. Springer. p. 150, 2023 https://doi.org/10.1007/978-3-031-20025-0 [7] Lappin G, Noveck R, Burt T (2013) Microdosing and drug development: past, present and future. Expert Opin Drug Metab Toxicol 9:817 https://doi.org/10.1517/17425255.2013.786042 [8] Karlsson MO, Bredberg U (1989) Estimation of bioavailability on a single occasion after semisimultaneous drug administration. Pharm Res. 1989 Sep;6(9):817-21. https://doi.org/10.1023/a:1015939917646.
Reference: PAGE 33 (2025) Abstr 11557 [www.page-meeting.org/?abstract=11557]
Poster: Methodology - Other topics