SPEAKER: Panos Macheras, Emeritus Professor, National and Kapodistrian University of Athens, Athens, Greece
DATE: NOVEMBER 6, 3.00 pm ECT
TITLE: ENTERING THE NEW WORLD OF THE FINITE ABSORPTION TIME (F.A.T.) CONCEPT WITHIN THE PHARMACEUTICAL INDUSTRY
PROGRAMME
3.00-3.30pm:
The false assumption that breaks oral drug absorption: The development of Finite Absorption Time (F.A.T) concept and the rise of Physiologically Based Finite Time Pharmacokinetic (PBFTPK) models
The talk starts with the first applications of first-order kinetics in Physics. It introduces the Bateman equation based on a model with three radioactive species, namely, mother, daughter and granddaughter. This equation was adopted by Dost in 1953 to describe the concentration-time curve of drug absorption after oral administration assuming one-compartment model disposition. The extensive use of first-order kinetics in oral drug absorption phenomena along with the governing role of the absorption rate constant will be described. Emphasis will be given to the unphysical assumption of infinite time of absorption associated with the use of Bateman equation in pharmacokinetics. A minimal model of gastrointestinal drug absorption based on the F.A.T. concept will be described. The model relies on the following observation: "The high blood flow rate in the portal vein (20-40 cm/s) [Iranpour P, et al (2016) Altered Doppler flow patterns in cirrhosis patients: an overview Ultrasonography 35:3-12. https://doi.org/10.14366/usg.15020] causes the rapid removal of the absorbed drug molecules towards the liver maintaining sink conditions in the first-order drug transfer; thus, oral drug absorption obeys zero-order kinetics." Physiological time limits were applied for drug absorption in the small intestines or colon considering BCS classification of the drug. The talk ends with the development of Physiologically Based Finite Time Pharmacokinetic (PBFTPK) Models and their applications for the analysis of concentration-time data.
3.30-3.35pm: Q/A
3.35-4.05pm: The F.A.T. concept guides the development of drugs
Early phases and Phase I studies. Currently, upon completion of the preclinical phase physiologically based pharmacokinetic (PBPK) models, are applied, which are followed by Phase I studies to find the optimal dose and assess safety. For PBPK models focusing on gastrointestinal absorption, the preclinical data of the biopharmaceutical properties solubility, permeability and factors such as dose and drug particle size associated with drug dissolution are routinely used. In the PBPK studies, first-order kinetics is being used since the absorption rate constant ka is linked with the effective permeability Peff and radius R of the gastrointestinal lumen, namely, ka = 2 Peff/R. The validity of this relationship will be questioned. Instead, we propose an oral pharmacokinetic study with a small number of subjects; the data are analysed with the top-down PBFTPK models to estimate for the first time absolute bioavalability from oral data exclusively.This speeds up and validates the development process since both the absolute bioavailability and the characteristics of drug absorption are estimated, namely, i) the number of absorption stages, ii) the corresponding drug input rates and iii) the duration of each stage τi, as well as the total duration of absorption, τ.
Phase II and III studies. The vast majority of published pharmacokinetic, pharmacodynamic and pharmacometrics studies of Phases II and III dealing with oral drug absorption rely on first-order absorption models. In all these studies the fallacious first-order absorption rate constant governs and quantifies the rate of drug absorption. The first-order kinetic concept is also being used arbitrarily in many drugs kinetic processes in the body. Also, in the field of interspecies scaling and paediatric scaling, the inverse time units of the absorption rate constant do not allow a scaling exercise. In contrast, the physiologically based meaningful input parameters of the PBFTPK models allow the scaling between adult and children or species oral data. The analytical power of PBFTK models will be presented with examples which are currently analyzed with flip-flop kinetics and stochastic approaches. Finally, another important area of the PBFTPK models’ application is their use as structural models in population analyses, which are an integral part of Phases II and III studies. Results of a population PBFTPK model of abacavir in infants, toddlers and children will be presented.
4.05-4.10pm: Q/A
4.10-4.40: The F.A.T. concept guides the development of generics
The Wagner-Nelson and Loo-Riegelman methods developed in the 1960s used as such or embedded in deconvolution software for the construction of percent of drug absorbed as a function of time curves were revamped in terms of the physiologically sound F.A.T. concept; the modified %absorbed versus time curves are of bilinear or multilinear type with the final ascending limb intersecting the horizontal line of 100% drug absorbed at F.A.T. ( doi: 10.1007/s11095-023-03578-x.) . The Finite Dissolution Time (F.D.T.) was developed considering the in vivo drug dissolution in terms of the physiological time constraints. Intuitively, for BCS Class II & IV drugs F.A.T.=F.D.T, while for Class I and III drugs F.D.T.< F.A.T. In this context the methodology for IVIVC was revised (doi: 10.1007/s11095-024-03653-x). The two-time limits based on the dissolution criteria 15 and 30 minutes for very rapidly and rapidly dissolved drugs (biowaivers) are also considered in terms of F.A.T and F.D.T. The development of generics starts from the IVIVC plot of the reference product derived from the analysis of reference in vivo data using the PBFTPK models in conjunction with the in vitro dissolution data of the reference product.
4.40-4.45: Q/A
4.45-5.15 Bioequivalence in the light of the F.A.T. concept
Initially, the true meaning of Cmax and will be uncovered using the physiologically sound Finite Absorption Time (F.A.T.) concept. The amount eliminated from the body at the time corresponding to Cmax was calculated and correlated with the amount of drug remaining in the body at the same time. It is shown that Cmax is proportional to the bioavailable fraction of the dose minus the eliminated quantity of drug at the time corresponding to Cmax. This clearly shows the Cmax is a metric for the extent of absorption and not the rate of absorption being used since 1977. Therefore, the use of Cmax as rate metric in bioequivalence guidelines should be discontinued. This realization remained buried for nearly half a century under the wrong first-order absorption hypothesis. The analysis of five bioequivalence studies revealed that the assessment of extent of absorption using AUC can be accomplished sooner, practically by blood sampling up to F.A.T. (τ). Two approaches are proposed for the assessment of bioequivalence studies. The first is a model dependent approach relying on the fitting of the PBFTPK models to the experimental data of reference and test formulations. The assessment of the extent of absorption can be based on the FD/Vd estimates, while the assessment of the rate of absorption can be based on FD/τVd estimates. The second model independent approach relies on the (AUC)test, (AUC)ref, and (AUC)test/(AUC)ref versus time plots for the assessment of the extent of absorption based on the intersection of the horizontal limb of the curve with the y-axis representing (AUC)test/(AUC)ref. The assessment of the rate of absorption can be based on the slope of the cumulative amount of drug absorbed (expressed in terms of concentration) versus time plot. Caution should be exercised in the estimation of slope for rapidly absorbed drugs. For very rapidly absorbed drugs, e.g., inhalers the use of is recommended.
5.15-5.20 pm Q/A
5.20-5.50: The first priorities of “F.A.T. Laboratories”
1. Drugs. Estimation of absolute bioavailability from oral data exclusively in Phase I: Replacing PBPK studies with a small pharmacokinetic study and analysis of data based on the top-down PBFTPK models.
2. Generics:
i. The development starts with the analysis of the reference in vivo data using PBFTPK models followed by the establishment, if any, of IVIVC based on the F.A.T. principles for the reference product. The development of generics relies on these findings and follows the same principles.
ii. Development of a universal dissolution-uptake device based on the F.A.T. principles for successful IVIVC.
3. Super-generics: Fast track development speeding up the solubilization/dissolution of sparingly soluble drugs applying an in situ preparation of formulation
4. Failed Biowaiver reports: An oral study with less than five subjects for drugs without first-pass effect analyzed with top-down PBFTPK models can prove 100% extent of absorption.
5. Bioequivalence studies:
i. Prior to the execution of the study, reference and test products are analyzed as delineated above (See Generics (i)). The IVIVC based on the F.A.T. concept for reference and test, provides a solid basis for bioequivalence prediction.
ii. Upon completion of the BE study and analysis of data in accord with the regulatory Guidelines, the client will additionally receive a) a report with the analysis of data based on our physiologically sound novel BE metrics published in the literature and b) estimates for the bioavailable fraction for the reference and test.
6. Clinical studies: We are eager to start the clinical studies in Athens and Thessaloniki hospitals in collaboration with Coronis CORONIS Research - Contract Research Organization | Clinical Trials | Pharmaceutical Consulting
7. Software:
Release of four software is scheduled for June 2026 and first presentation in the 34th PAGE meeting, Dubrovnik, Croatia, 2-6 June 2026 (Welcome to the Population Approach Group in Europe), namely,
i. FTPK Software. Suitable for both modelers and pharmaceutical scientists working in academia or big pharma and generic companies to perform the fitting of PBFTPK models to the concentration-time data.
ii. FTPK+BA Software. Suitable for both modelers and pharmaceutical scientists working in academia or big pharma to perform the PBFTPK fittings as well as the estimation of absolute bioavailability from oral data exclusively in in early drug development.
iii. FTPK+BE+IVIVC Software. Suitable for both modelers and pharmaceutical scientists working in academia or big pharma and generic companies to perform the fitting of PBFTPK models to the concentration-time data, develop IVIVC based on the F.A.T. concept and analyze bioequivalence data using model dependent and model independent approaches.
iv. FTPK-Population Software. Suitable for modelers in academia and industry to apply nonlinear mixed effect modeling based on PBFTPK structural models.
5.50-6.20 pm Q/A
Registration fees
1. Industry, CROs 300 Euros
2. Academics, Public institutions 150 Euros
3. Students (post and undergraduate) 50 Euros
4. Greek students ((post and undergraduate) 2
Complete list of published work related to the F.A.T. concept.
Book
P. Macheras and A. A. Tsekouras, Revising Oral Pharmacokinetics, Bioavailability and Bioequivalence Based on the Finite Absorption Time Concept, Springer, Cham, 2023 10.1007/978-3-031-20025-0
Book Chapters
1. A. A. Tsekouras, P. Macheras, Physiologically Based Finite Time Pharmacokinetic (PBFTPK) Models: Inception and Development, in Advances in Pharmacokinetics and Pharmacodynamics, P. Macheras, Ed., Springer, Cham, 2023, pp. 57-81, 10.1007/978-3-031-29541-6_3
2. A. A. Tsekouras, N. Alimpertis, P. Macheras, Physiologically Based Finite Time Pharmacokinetic (PBFTPK) Models: Applications, in Advances in Pharmacokinetics and Pharmacodynamics, P. Macheras, Ed., Springer, Cham, 2023, pp. 83-105, 10.1007/978-3-031-29541-6_4
Posters, Invited talks, Webinars on F.A.T.