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In vitro–In vivo Relationship and Bioequivalence Prediction for Modified-Release Capsules Based on a PBPK Absorption Model

AAPS PharmSciTech volume 21, Article number: 18 (2020) Cite this article

Abstract

A physiologically based pharmacokinetic (PBPK) absorption model was developed in GastroPlus™ based on data on intravenous, immediate-release (IR), and modified-release (MR) drug products. The predictability of the model was evaluated by comparing predicted and observed plasma concentration profiles; average prediction errors (PE) were below 10%. IVIVR was developed using mechanistic deconvolution for a MR drug product to evaluate the in vivo effect of a proposed change in dissolution specification. The predictability of the IVIVR was evaluated and PE were below 10%; however, external validation was not possible due to the lack of data. The developed PBPK absorption model and IVIVR were used to predict plasma concentration profiles and pharmacokinetic (PK) parameters for a hypothetical formulation with 0% of drug dissolved in 2 h in in vitro dissolution test. Both methods predicted the insignificant effect of a change in in vitro dissolution profile on in vivo product performance. The bioequivalence of a hypothetical formulation to the test product was evaluated using virtual clinical trial. The performed analysis supported the proposed change in dissolution specification. A validated PBPK absorption model was proposed as an adequate alternative to IVIVC, when IVIVC could not have been developed according to the guidelines.

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References

  1. Emami J. In vitro – in vivo correlation: from theory to applications. J Pharm Pharmaceut Sci. 2006;9(2):31–51.

    Google Scholar 

  2. 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: https://www.fda.gov/media/70939/download. Accessed 31 May 2019.

  3. European Medicines Agency. Guideline on quality of oral modified release products [Internet]. 2014. Available from: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-quality-oral-modified-release-products_en.pdf. Accessed 31 May 2019.

  4. European Medicines Agency. Guideline on the pharmacokinetic and clinical evaluation of modified release dosage forms [Internet]. 2014. Available from: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-pharmacokinetic-clinical-evaluation-modified-release-dosage-forms_en.pdf. Accessed 31 May 2019.

  5. Nguyen MA, Flanagan T, Brewster M, Kesisoglou F, Beato S, Biewenga J, et al. A survey on IVIVC/IVIVR development in the pharmaceutical industry—past experience and current perspectives. Eur J Pharm Sci. 2017;102:1–13. https://doi.org/10.1016/j.ejps.2017.02.029.

    Article  CAS  PubMed  Google Scholar 

  6. Gonzalez-Garcia I, Mangas-Sanjuan V, Merion-Sanjuan M, Bermejo M. In vitro-in vivo correlations: general concepts, methodologies and regulatory applications. Drug Dev Ind Pharm. 2015;41(12):1935–47. https://doi.org/10.3109/03639045.2015.1054833.

    Article  CAS  PubMed  Google Scholar 

  7. Simulations Plus, Manual GastroPlus™, California, EUA; 2010.

  8. Kaur P, Jiang X, Duan J, Stier E. Applications of in vitro–in vivo correlations in generic drug development: case studies. AAPS J. 2015;17(4):1035–9. https://doi.org/10.1208/s12248-015-9765-1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Suarez-Sharp S, Cohen M, Kesisoglou F, Abend A, Marroum P, Delvadia P, et al. Applications of clinically relevant dissolution testing: workshop summary report. AAPS J. 2018;20(6):93. https://doi.org/10.1208/s12248-018-0252-3.

    Article  PubMed  Google Scholar 

  10. Stillhart C, Pepin X, Tistaert C, Good D, Van Den Bergh A, Parrott N, et al. PBPK absorption modeling: establishing the in vitro-in vivo link-industry perspective. AAPS J. 2019;21(2):19. https://doi.org/10.1208/s12248-019-0292-3.

    Article  PubMed  Google Scholar 

  11. Pepin XJ, Flanagan TR, Holt DJ, Eidelman A, Treacy D, Rowlings 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 Sep 6;13(9):3256–69. https://doi.org/10.1021/acs.molpharmaceut.6b00497.

    Article  CAS  PubMed  Google Scholar 

  12. Babiskin AH, Zhang X. Application of physiologically based absorption modeling for amphetamine salts drug products in generic drug evaluation. J Pharm Sci. 2015 Sep;104(9):3170–82. https://doi.org/10.1002/jps.24474.

    Article  CAS  PubMed  Google Scholar 

  13. Food and Drug Administration. Drug Databases, Dissolution Methods. https://www.accessdata.fda.gov/scripts/cder/dissolution/dsp_getallData.cfm. Accessed 24 Jul 2019.

  14. van Hoogdalem EJ, Soeishi Y, Matsushima H, Higuchi S. Disposition of the selective alpha1A-adrenoceptor antagonist tamsulosin in humans: comparison with data from interspecies scaling. J Pharm Sci. 1997;86(10):1156–61. https://doi.org/10.1021/js960303k.

    Article  PubMed  Google Scholar 

  15. Matsushima H, Kamimura H, Soeishi Y, Watanabe T, Higuchi S, Tsunoo M. Pharmacokinetics and plasma protein binding of tamsulosin hydrochloride in rats, dogs, and humans. Drug Metab Dispos. 1998;26(3):240–5.

    CAS  PubMed  Google Scholar 

  16. Food and Drug Administration. NDA 20–579 [Internet]. 1997. Available from: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-pharmacokinetic-clinical-evaluation-modified-release-dosage-forms_en.pdf. Accessed 31 May 2019.

  17. Dahlgren D, Roos C, Sjögren E, Lennernäs H. Direct in vivo human intestinal permeability (Peff ) determined with different clinical perfusion and intubation methods. J Pharm Sci. 2015 Sep;104(9):2702–26. https://doi.org/10.1002/jps.24258.

    Article  CAS  PubMed  Google Scholar 

  18. Davit BM, Nwakama PE, Buegler GJ, Conner DP, Haidar SH, Patel DT, et al. Comparing generic and innovator drugs: a review of 12 years of bioequivalence data from the United States Food and Drug Administration. Ann Pharmacother. 2009;43(10):1583–97. https://doi.org/10.1345/aph.1M141.

    Article  CAS  PubMed  Google Scholar 

  19. Mitra A. Maximizing the role of physiologically based oral absorption modeling in generic drug development. Clin Pharmacol Ther. 2019;105(2):307–9. https://doi.org/10.1002/cpt.1242.

    Article  PubMed  Google Scholar 

  20. Rebeka J, Jerneja O, Igor L, Boštjan P, Aleksander B, Simon Ž, et al. 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. AAPS PharmSciTech. 2019 Jan 8;20(2):59. https://doi.org/10.1208/s12249-018-1285-8.

    Article  CAS  PubMed  Google Scholar 

  21. Li X, Yang Y, Zhang Y, Wu C, Jiang Q, Wang W, et al. Justification of biowaiver and dissolution rate specifications for Piroxicam immediate release products based on physiologically based pharmacokinetic modeling: an in-depth analysis. Mol Pharm. 2019 Sep 3;16(9):3780–90. https://doi.org/10.1021/acs.molpharmaceut.9b00350.

    Article  CAS  PubMed  Google Scholar 

  22. European Medicines Agency. Guideline on the qualification and reporting of physiologically based pharmacokinetic (PBPK) modelling and simulation [Internet]. 2018. Available from: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-reporting-physiologically-based-pharmacokinetic-pbpk-modelling-simulation_en.pdf. Accessed 26 Sep 2019.

  23. Food and Drug Administration. Guidance for industry: physiologically based pharmacokinetic analyses – format and content [Internet]. 2018. Available from: https://www.fda.gov/media/101469/download. Accessed 26 Sep 2019.

  24. 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 Feb;7(2):82–9. https://doi.org/10.1002/psp4.12260.

    Article  CAS  PubMed  Google Scholar 

  25. Heimbach T, Suarez-Sharp S, Kakhi M, Holmstock N, Olivares-Morales A, Pepin X, et al. Dissolution and translational modeling strategies toward establishing an in vitro-in vivo link—a workshop summary report. AAPS J. 2019 Feb 11;21(2):29. https://doi.org/10.1208/s12248-019-0298-x.

    Article  PubMed  Google Scholar 

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Acknowledgments

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

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Authors and Affiliations

  1. Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, 1000, Ljubljana, Slovenia

    Rebeka Jereb

  2. Lek Pharmaceuticals d.d., a Sandoz Company, Verovškova ulica 57, 1000, Ljubljana, Slovenia

    Jerneja Opara, Igor Legen, Boštjan Petek & Darja Grabnar-Peklar

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  1. Rebeka Jereb
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  2. Jerneja Opara
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Correspondence to Rebeka Jereb.

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Jereb, R., Opara, J., Legen, I. et al. In vitro–In vivo Relationship and Bioequivalence Prediction for Modified-Release Capsules Based on a PBPK Absorption Model. AAPS PharmSciTech 21, 18 (2020). https://doi.org/10.1208/s12249-019-1566-x

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  • DOI: https://doi.org/10.1208/s12249-019-1566-x

KEY WORDS

  • IVIVC
  • PBPK absorption modeling
  • modified release
  • bioequivalence