Skip to main content
SpringerLink
Log in

Revamping Biopharmaceutics-Pharmacokinetics with Scientific and Regulatory Implications for Oral Drug Absorption

  • Original Research Article
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Purpose

The Wagner-Nelson and Loo-Riegelman methods developed in the 1960s and used since for the construction of percent of drug absorbed as a function of time as well as in in vitro in vivo correlations are re-considered in the light of the physiologically sound Finite Absorption Time (F.A.T.) concept developed recently.

Methods

The classical equations for the percentage of drug absorption as a function of time were modified by taking into account the termination of drug absorption at F.A.T., replacing the parameters associated with the assumption of infinite drug absorption.

Results

Mathematical analysis using the relevant Physiologically Based Pharmacokinetic Finite Time (PBFTK) models assuming one- or two-compartment drug disposition, revealed that the modified %absorbed versus time curves are of bilinear type with an ascending limb intersecting the horizontal line at F.A.T. A computer-based methodology is described for the estimation of F.A.T. from experimental data. More than one linear ascending limb is found when more than one absorption phase is operating. Experimental data were analyzed and the estimates for F.A.T were found to be similar to those derived from nonlinear regression analysis using PBFTPK models.

Conclusion

These results place an end to the routinely reported exponential %absorbed versus time curves prevailing in biopharmaceutics-pharmacokinetics since their inception in the’60 s. These findings point to the use of the F.A.T. concept in drug absorption research and regulatory guidelines such as deconvolution techniques for the assessment of drug input rate, stochastic mean absorption time calculations, population analyses, in vitro in vivo correlations and bioequivalence guidelines.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Data Availability

All data used in this study have been published previously as indicated for each data set analyzed.

References

  1. Wagner JG, Nelson E. Percent absorbed time plots derived from blood level and/or urinary excretion data. J Pharm Sci. 1963;52:610–1. https://doi.org/10.1002/jps.2600520629.

    Article  CAS  PubMed  Google Scholar 

  2. Wagner JG, Nelson E. The kinetic analysis of blood levels and urinary excretion in the absorptive phase after single doses of drug. J Pharm Sci. 1964;53:1392–403. https://doi.org/10.1002/jps.2600531126.

    Article  CAS  PubMed  Google Scholar 

  3. Loo JCK, Riegelman S. New method for calculating the intrinsic absorption rate of drugs. J Pharm Sci. 1968;57:918–28. https://doi.org/10.1002/jps.2600570602.

    Article  CAS  PubMed  Google Scholar 

  4. Wagner JG. Application of the Loo-Riegelman absorption method. J Pharmacokinet Biopharm. 1975Feb;3(1):51–67. https://doi.org/10.1007/BF01066595.

    Article  CAS  PubMed  Google Scholar 

  5. Macheras P. On an unphysical hypothesis of Bateman equation and its implications for pharmacokinetics. Pharm Res. 2019;36:94. https://doi.org/10.1007/s11095-019-2633-4.

    Article  CAS  PubMed  Google Scholar 

  6. Cutler DJ. Numerical deconvolution by least squares: use of prescribed input functions. J Pharmacokinet Biopharm. 1978;6(3):227–41. https://doi.org/10.1007/BF01312264.

    Article  CAS  PubMed  Google Scholar 

  7. Margolskee A, Darwich AS, Galetin A, Rostami-Hodjegan A, Aarons L. Deconvolution and IVIVC: Exploring the Role of Rate-Limiting Conditions. AAPS J. 2016Mar;18(2):321–32. https://doi.org/10.1208/s12248-015-9849-y.

    Article  PubMed  Google Scholar 

  8. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER). Guidance for Industry: SUPAC-MR: Modified Release Solid Oral Dosage Forms. 1997. http://www.fda.gov/downloads/Drugs/Guidances/UCM070640.pdf. Accessed Feb 20 2023

  9. Uppoor VR, et al. FDA Guidance to Industry Extended Release Oral Dosage Forms: Development, Evaluation, And Application Of In Vitro/In Vivo Correlations. Dissolution Technol. 1997;4(4):23–32. https://doi.org/10.14227/DT040497P23.

    Article  Google Scholar 

  10. Macheras P, Chryssafidis P. Revising pharmacokinetics of oral drug absorption: I models based on biopharmaceutical/physiological and finite absorption time concepts. Pharm Res. 2020;37:187. https://doi.org/10.1007/s11095-020-02894-w.ErratumPharmRes2020;37:206.

    Article  CAS  PubMed  Google Scholar 

  11. Macheras P, Tsekouras AA. The Finite Absorption Time (FAT) concept en route to PBPK modeling and pharmacometrics. J Pharmacokinet Pharmacodyn. 2023;50:5–10. https://doi.org/10.1007/s10928-022-09832-w.

    Article  PubMed  Google Scholar 

  12. Chryssafidis P, Tsekouras AA, Macheras P. Revising pharmacokinetics of oral drug absorption: II bioavailability bioequivalence considerations. Pharm Res. 2021;38:1345–56. https://doi.org/10.1007/s11095-021-03078-w.

    Article  CAS  PubMed  Google Scholar 

  13. Chryssafidis P, Tsekouras AA, Macheras P. Re-writing oral pharmacokinetics using physiologically based finite time pharmacokinetic (PBFTPK) models. Pharm Res. 2022;39:691–701. https://doi.org/10.1007/s11095-022-03230-0.

    Article  CAS  PubMed  Google Scholar 

  14. Tsekouras AA, Macheras P. Columbus’ egg: Oral drugs are absorbed in finite time. Eur J Pharm Sci. 2022;176:106265. https://doi.org/10.1016/j.ejps.2022.106265.

    Article  CAS  PubMed  Google Scholar 

  15. Wu D, Tsekouras AA, Macheras P, Kesisoglou F. Physiologically based pharmacokinetic models under the prism of the finite absorption time concept. Pharm Res. 2023;40:419–29. https://doi.org/10.1007/s11095-022-03357-0.

    Article  CAS  PubMed  Google Scholar 

  16. Macheras P, Tsekouras AA. Revising Oral Pharmacokinetics, Bioavailability and Bioequivalence Based on the Finite Absorption Time Concept. Cham: Springer; 2023. https://doi.org/10.1007/978-3-031-20025-0.

    Book  Google Scholar 

  17. Food and Drug Administration. Center for Drug Evaluation and Research (CDER). Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System. Guidance for Industry U.S. Department of Health and Human Services. 2017.

  18. European Medicines Agency. Committee for medicinal products for human use (CHMP) Guideline on the investigation of bioequivalence. London, Jan. 2017.

  19. Charalabidis A, Sfouni M, Bergström C, Macheras P. BCS and BDDCS: Beyond guidelines. Int J Pharm. 2019;566:264–81. https://doi.org/10.1016/j.ijpharm.2019.05.041.

    Article  CAS  PubMed  Google Scholar 

  20. Raffa RB, Pergolizzi JV Jr, Taylor R Jr, Decker JF, Patrick JT. Acetaminophen (paracetamol) oral absorption and clinical influences. Pain Pract. 2014Sep;14(7):668–77. https://doi.org/10.1111/papr.12130.

    Article  PubMed  Google Scholar 

  21. Forrest JA, Clements JA, Prescott LF. Clinical pharmacokinetics of paracetamol. Clin Pharmacokinet. 1982;7(2):93–107. https://doi.org/10.2165/00003088-198207020-00001.

    Article  CAS  PubMed  Google Scholar 

  22. Dokoumetzidis A, Papadopoulou V, Macheras P. Analysis of Dissolution Data Using Modified Versions of Noyes-Whitney Equation and the Weibull Function. Pharm Res. 2006;23:256–61. https://doi.org/10.1007/s11095-006-9093-3.

    Article  PubMed  Google Scholar 

  23. Dokoumetzidis A, Macheras P. IVIVC of controlled release formulations: physiological-dynamical reasons for their failure. J Control Release. 2008Jul 14;129(2):76–8. https://doi.org/10.1016/j.jconrel.2008.04.005.

    Article  CAS  PubMed  Google Scholar 

  24. Mircioiu C, Mircioiu I, Voicu V, Miron D. Dissolution-bioequivalence non-correlations. Basic Clin Pharmacol Toxicol. 2005Mar;96(3):262–4. https://doi.org/10.1111/j.1742-7843.2005.pto960324.x.

    Article  CAS  PubMed  Google Scholar 

  25. Cardot JM, Davit BM. In vitro-in vivo correlations: tricks and traps. AAPS J. 2012Sep;14(3):491–9. https://doi.org/10.1208/s12248-012-9359-0.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Bransford P, Cook J, Gupta M, Haertter S, He H, Ju R, Kanodia J, Lennernäs H, Lindley D, Polli JE, Wenning L, Wu Y. ICH M9 Guideline in Development on Biopharmaceutics Classification System-Based Biowaivers: An Industrial Perspective from the IQ Consortium. Mol Pharm. 2020Feb 3;17(2):361–72. https://doi.org/10.1021/acs.molpharmaceut.9b01062.

    Article  CAS  PubMed  Google Scholar 

  27. Alimpertis N, Tsekouras AA, Macheras P, Revising the assessment of bioequivalence in the light of finite absorption time (FAT) concept: The axitinib case. 30th PAGE meeting Ljubljana 28 June-1 July, 2022.

  28. Food and Drug Administration, Code of Federal Regulations Title 21, 5 Subpart B - Procedures for Determining the Bioavailability or Bioequivalence of Drug Products. 1971. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=320.21. Accessed 27 Jul 2023

  29. European Medicines Agency. Committee for medicinal products for human use (CHMP) guideline on the investigation of bioequivalence. London, Jan. 2010. https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-investigation-bioequivalence-rev1_en.pdf

  30. Yamaoka K, Nakagawa T, Uno T. Statistical moments in pharmacokinetics. J Pharmacokinet Biopharm. 1978;6:547–58. https://doi.org/10.1007/BF01062109.

    Article  CAS  PubMed  Google Scholar 

  31. Benet LZ, Sodhi JK. The Uses and Advantages of Kirchhoff’s Laws vs. Differential Equations in Pharmacology, Pharmacokinetics, and (Even) Chemistry. AAPS J. 2023;25(3):38. https://doi.org/10.1208/s12248-023-00801-w.

    Article  PubMed  Google Scholar 

  32. Sjögren E, Westergren J, Grant I, Hanisch G, Lindfors L, Lennernäs H, et al. In silico predictions of gastrointestinal drug absorption in pharmaceutical product development: application of the mechanistic absorption model GI-Sim. Eur J Pharm Sci. 2013;49(4):679–98. https://doi.org/10.1016/j.ejps.2013.05.019.

    Article  CAS  PubMed  Google Scholar 

  33. Sager JE, Yu J, Ragueneau-Majlessi I, Isoherranen N. Physiologically based pharmacokinetic (PBPK) modeling and simulation approaches: a systematic review of published models, applications, and model verification. Drug Metab Dispos. 2015;43(11):1823–37. https://doi.org/10.1124/dmd.115.065920.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Alimpertis N, Tsekouras AA, Macheras P. The estimates for the absorption rate constant in pharmacokinetics and pharmacometrics are wrong: A new era based on the finite absorption time concept rises, talk presented at PAGE 2023, A Coruña, Spain, 28–30 June 2023. https://www.page-meeting.org/default.asp?abstract=10610. Accessed 27 Jul 2023

Download references

Acknowledgements

The authors are indebted to Professor Leslie Benet for his advice on an advanced draft of the manuscript. We also thank an anonymous reviewer for his constructive critique. Dedicated to the memory of the hero pilots Christos Moulas, 34, and Periclis Stefanidis, 27, both of the Greek Hellenic Air Force who died fighting devastating wildfires in Greece on July 25, 2023.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author information

Authors and Affiliations

  1. Faculty of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece

    Nikolaos Alimpertis & Panos Macheras

  2. PharmaInformatics Unit, ATHENA Research Center, Athens, Greece

    Nikolaos Alimpertis, Athanasios A. Tsekouras & Panos Macheras

  3. Department of Chemistry, National and Kapodistrian University of Athens, Athens, Greece

    Athanasios A. Tsekouras

Authors
  1. Nikolaos Alimpertis
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Athanasios A. Tsekouras
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Panos Macheras
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Panos Macheras.

Ethics declarations

Conflict of Interest

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 319 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Alimpertis, N., Tsekouras, A.A. & Macheras, P. Revamping Biopharmaceutics-Pharmacokinetics with Scientific and Regulatory Implications for Oral Drug Absorption. Pharm Res 40, 2167–2175 (2023). https://doi.org/10.1007/s11095-023-03578-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-023-03578-x

Keywords

Search

Navigation