AAPS PharmSciTech

, 20:59 | Cite as

PBPK Absorption Modeling of Food Effect and Bioequivalence in Fed State for Two Formulations with Crystalline and Amorphous Forms of BCS 2 Class Drug in Generic Drug Development

  • Jereb RebekaEmail author
  • Opara Jerneja
  • Legen Igor
  • Petek Boštjan
  • Bajc Aleksander
  • Žakelj Simon
  • Kristl Albin
Research Article


Prediction of the effect of food on drug’s pharmacokinetics using modeling and simulation could cause difficulties due to complex in vivo processes. A generic formulation with amorphous form of BCS 2 class drug substance was developed and compared in vitro and in vivo to the reference drug product with drug substance in crystalline form. In order to approve generic formulation, some regulatory agencies are requesting to perform bioequivalence (BE) studies also in fed state. Food can have various effects on drug dissolution and absorption, depending also on drug’s properties. A physiologically based pharmacokinetic (PBPK) absorption model was built in GastroPlus™ to predict the food effect on generic and reference formulation and to predict the fed BE study outcome. During model development, we were searching for model inputs that impact and describe in vivo behavior of amorphous and crystalline forms of active pharmaceutical ingredient (API) in fast and fed conditions. The developed model was able to predict the food effect with up to 10% prediction error (PE). Performed virtual BE trials confirmed the BE of drug products in fed state. Our model was able to capture the difference between the two drug products containing different forms of API (amorphous and crystalline) and predict the food effect on both formulations.


physiologically based pharmacokinetic (PBPK) modeling food effect BCS bioequivalence amorphous formulation 



The authors would like to acknowledge coworkers in Sandoz for conducting experiments, sharing data, and valuable consultations regarding modeling.

Compliance with Ethical Standards

BE studies were performed for regulatory submission and were conducted in full accordance with the principles stated in the International Conference on Harmonization, Good Clinical Practice guidelines, and the Declaration of Helsinki.

Conflict of Interest

The authors declare that they have no conflicts of interest.


  1. 1.
    Jones HM, Parrott N, Ohlenbusch G, Lavé T. Predicting pharmacokinetic food effects using biorelevant solubility media and physiologically based modelling. Clin Pharmacokinet. 2006;45(12):1213–26.CrossRefGoogle Scholar
  2. 2.
    Abuhelwa AY, Williams DB, Upton RN, Foster DRJ. Food, gastrointestinal pH, and models of oral drug absorption. Eur J Pharm Biopharm. 2017;112:234–48. Scholar
  3. 3.
    Singhal D, Curatolo W. Drug polymorphism and dosage form design: a practical perspective. Adv Drug Deliv Rev. 2004;56(3):335–47.CrossRefGoogle Scholar
  4. 4.
    Honorio Tda S, Pinto EC, Rocha HV, Esteves VS, dos Santos TC, Castro HC, et al. In vitro–in vivo correlation of efavirenz tablets using GastroPlus. AAPS PharmSciTech. 2013;14(3):1244–54. Scholar
  5. 5.
    Parrott N, Lukacova V, Fraczkiewicz G, Bolger M. Predicting pharmacokinetics of drugs using physiologically based modeling—application to food effects. AAPS J. 2009;11(1):45–53. Scholar
  6. 6.
    Li M, Zhao P, Pan Y, Wagner C. Predictive performance of physiologically based pharmacokinetic models for the effect of food on oral drug absorption: current status. CPT Pharmacometrics Syst Pharmacol. 2018;7:82–9. Scholar
  7. 7.
    Food and Drug Administration. Guidance for industry: waiver of in vivo bioavailability and bioequivalence studies for immediate-release solid oral dosage forms based on a Biopharmaceutics Classification System [Internet]. 2017. Available from: Accessed 27 June 2018.
  8. 8.
    Xia B, Heimbach T, Lin T, Li S, Zhang H, Sheng J, et al. Utility of physiologically based modeling and preclinical in vitro/in vivo data to mitigate positive food effect in a BCS class 2 compound. AAPS PharmSciTech. 2013;14(3):1255–66. Scholar
  9. 9.
    Food and Drug Administration. Guidance for industry: bioequivalence studies with pharmacokinetic endpoints for drugs submitted under an ANDA [Internet]. 2013. Available from: Accessed 27 June 2018.
  10. 10.
    Peternel L, Kristan K, Petruševska M, Rižner TL, Legen I. Suitability of isolated rat jejunum model for demonstration of complete absorption in humans for BCS-based biowaiver request. J Pharm Sci. 2012;101(4):1436–49. Scholar
  11. 11.
    Simulations Plus. Manual GastroPlus™. California: EUA; 2010.Google Scholar
  12. 12.
    Takano R, Sugano K, Higashida A, Hayashi Y, Machida M, Aso Y, et al. Oral absorption of poorly water-soluble drugs: computer simulation of fraction absorbed in humans from a miniscale dissolution test. Pharm Res. 2006;23(6):1144–56. Scholar
  13. 13.
    Pepin XJ, Flanagan TR, Holt DJ, Eidelman A, Treacy D, Rowlingy CE. Justification of drug product dissolution rate and drug substance particle size specifications based on absorption PBPK modeling for Lesinurad immediate release tablets. Mol Pharm. 2016;13(9):3256–56. Scholar
  14. 14.
    Sutton SC. Role of physiological intestinal water in oral absorption. AAPS J. 2009;11(2):277–85. Scholar
  15. 15.
    Food and Drug Administration. Guidance for industry: extended release oral dosage forms: development, evaluation, and application of in vitro/in vivo correlations [Internet]. 1997. Available from: Accessed 27 June 2018.Google Scholar
  16. 16.
    Food and Drug Administration. Guidance for industry: food-effect bioavailability and fed bioequivalence studies [Internet]. 2002. Available from: Accessed 27 June 2018.
  17. 17.
    Flanagan T, Van Peer A, Lindahl A. Use of physiologically relevant biopharmaceutics tools within the pharmaceutical industry and in regulatory sciences: where are we now and what are the gaps? Eur J Pharm Sci. 2016;91:83–90. CrossRefGoogle Scholar
  18. 18.
    Parrott NJ, Li JY, Takano R, Nakamura M, Morcos PN. Physiologically based absorption modeling to explore the impact of food and gastric pH changes on the pharmacokinetics of alectinib. AAPS J. 2016;18(6):1464–74.CrossRefGoogle Scholar
  19. 19.
    Mitra A, Zhu W, Kesisoglou F. Physiologically based absorption modeling for amorphous solid dispersion formulations. Mol Pharm. 2016;13(9):3206–15. Scholar
  20. 20.
    Schiller C, Fröhlich CP, Giessmann T, Siegmund W, Mönnikes H, Hosten N, et al. Intestinal fluid volumes and transit of dosage forms as assessed by magnetic resonance imaging. Aliment Pharmacol Ther. 2005;22(10):971–9. Scholar
  21. 21.
    Mudie DM, Murray K, Hoad CL, Pritchard SE, Garnett MC, Amidon GL, et al. Quantification of gastrointestinal liquid volumes and distribution following a 240 mL dose of water in the fasted state. Mol Pharm. 2014;11(9):3039–47. Scholar
  22. 22.
    Purohit SH, Trasi NS, Sun DD, Chow ECY, Wen H, Zhang X, et al. Investigating the impact of drug crystallinity in amorphous tacrolimus capsules on pharmacokinetics and bioequivalence using discriminatory in vitro dissolution testing and physiologically based pharmacokinetic modeling and simulation. J Pharm Sci. 2018;107(5):1330–41. Scholar
  23. 23.
    Zhang X, Lionberger RA. Modeling and simulation of biopharmaceuticals performance. Clin Pharmacol Ther. 2014;95(5):480–2. Scholar
  24. 24.
    Jones HM, Chen Y, Gibson C, Heimbach T, Parrott N, Peters SA, et al. Physiologically based pharmacokinetic modeling in drug discovery and development: a pharmaceutical industry perspective. Clin Pharmacol Ther. 2015;97(3):247–62. Scholar
  25. 25.
    Food and Drug Administration. Guidance for industry: physiologically based pharmacokinetic analyses – format and content [Internet]. 2016. Available from: Accessed 27 June 2018.
  26. 26.
    European Medicines Agency. Guideline on the qualification and reporting of physiologically based pharmacokinetic (PBPK) modelling and simulation [Internet]. 2016. Available from: Accessed 27 June 2018.

Copyright information

© American Association of Pharmaceutical Scientists 2019

Authors and Affiliations

  1. 1.Faculty of PharmacyUniversity of LjubljanaLjubljanaSlovenia
  2. 2.IVIVC GroupSandoz Development CenterLjubljanaSlovenia

Personalised recommendations