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Physiologically Based Biopharmaceutics Model of Vildagliptin Modified Release (MR) Tablets to Predict In Vivo Performance and Establish Clinically Relevant Dissolution Specifications

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Abstract

The objective of the study was to predict pharmacokinetic (PK) and pharmacodynamic (PD) parameters of matrix-based modified release (MR) drug product of vildagliptin. Physiologically based biopharmaceutics modeling (PBBM) was developed using GastroPlus™ based on the available data including immediate-release (IR) drug product of vildagliptin. In vitro–in vivo correlation (IVIVC) was developed using mechanistic deconvolution to predict plasma concentration–time profile and PK parameters for a MR drug product planned for clinical use. Both methods, i.e., PBBM and IVIVC, were compared for the predicted PK parameters. Integration of DDDPlus™ and GastroPlus™ modeling was performed to explore clinically relevant dissolution specifications for vildagliptin MR tablets. The bioequivalence (BE) between batches with different dissolution specifications was evaluated using virtual clinical trials. The PD effect of dipeptidyl peptidase-IV (DPP-IV) inhibition was simulated utilizing PDPlus™ model in GastroPlus™. The results indicated that IVIVC best correlated the simulated PK parameters with those observed with the clinical study. The outcomes highlight the importance of integration of in vitro and in silico tools towards predictability of PK and PD parameters for a MR drug product. However, the post absorptive phase was found to be more dependent on the demographics of the healthy subjects.

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References

  1. Shoback DG, Gardner D, eds. Chapter 17. Greenspan’s basic & clinical endocrinology (9th ed.). 2011. New York: McGraw-Hill Medical. ISBN 978–0–07–162243–1.

  2. Sunkara Gangadhar, Sabo Ron, et al. Dose proportionality and the effect of food on vildagliptin, a novel dipeptidyl peptidase IV inhibitor, healthy volunteers. J Clin Pharmacol. 2007;47:1152–8.

    Article  CAS  Google Scholar 

  3. He Y-L, Sadler BM, et al. The absolute oral bioavailability and population-based pharmacokinetic modelling of a novel dipeptidylpeptidase-IV inhibitor, vildagliptin, in healthy volunteers. Clin Pharmacokinet. 2007;46(9):787–802.

    Article  CAS  Google Scholar 

  4. He Handan, Tran Phi, et al. Absorption, metabolism, and excretion of [14C] vildagliptin, a novel dipeptidyl peptidase 4 inhibitor, in humans. Drug Metabolism and Disposition. 2009;37(3):536–44.

    Article  CAS  Google Scholar 

  5. The use of physiologically based pharmacokinetic analyses – biopharmaceutics applications for oral drug product development, manufacturing changes, and controls. Guidance for Industry. Draft Guidance. U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER), October 2020

  6. Guideline on reporting of physiologically based pharmacokinetic (PBPK) modeling and simulation. Committee for Medicinal Products for Human Use (CHMP), European Medicines Agency (EMA), December 2018.

  7. Extended release oral dosage forms: development, evaluation and application of in vitro/in vivo correlations. Guidance for Industry; U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER), September 1997

  8. Al-Tabakha Moawia M, Alomer Muaed J. In vitro dissolution and in silico modeling shortcuts in bioequivalence testing. Pharmaceutics. 2020;12:45.

    Article  Google Scholar 

  9. McAllister M, Flanagan T, Boon K, et al. Developing relevant dissolution specifications for oral drug products - industrial and regulatory perspectives. Pharmaceutics. 2019;12(1):19.

    Article  Google Scholar 

  10. Sjögren E, Thörn H, Tannergren C. In silico modeling of gastrointestinal drug absorption: predictive performance of three physiologically based absorption models. Mol Pharmaceutics. 2016;13:1763–78.

    Article  Google Scholar 

  11. May Almukainzi, Arthur Okumu, Hai Wei and Raimar Löbenberg. Simulation of in vitro dissolution behavior using DDDPlus™. AAPS PharmSciTech, Vol. 16, No. 1, February 2015

  12. GastroPlus™ User Manual for Version 9.7. Lancaster, CA: Simulations Plus, 2019

  13. DDDPlus® User Manual for Version 6.0. Lancaster, CA: Simulations Plus, 2018

  14. McAllister M, Flanagan T, Boon K, Pepin X, Tistaert C, Jamei M, Abend A, Kotzagiorgis E, Mackie C. Developing clinically relevant dissolution specifications for oral drug products - industrial and regulatory perspectives. Pharmaceutics. 2020;12:19.

    Article  CAS  Google Scholar 

  15. Food and Drug Administration. Guidance for Industry: Extended Release Oral Dosage Forms: Development, Evaluation and Application of In Vitro/In Vivo Correlations. 1997.

  16. European Medicines Agency. Guideline on the pharmacokinetic and clinical evaluation of modified release dosage forms. 2014

  17. DR Mould; RN Upton; Basic Concepts in Population Modeling, Simulation, and Model-Based Drug Development; Pharmacometrics & Systems Pharmacology (2012) 1, e6.

  18. Deurenberg P, Deurenberg-Yap M, Guricci S. Asians are different from Caucasians and from each other in their body mass Index/body fat percent relationship. Obes Rev. 2002;3(3):141–6.

    Article  CAS  Google Scholar 

  19. Zhang X, Lionberger RA, Davit BM, Yu LX. Utility of physiologically based absorption modeling in implementing quality by design in drug development. AAPS J. 2011;13:59–71.

    Article  Google Scholar 

  20. Miller NA, Graves RH, Edwards CD, et al. Physiologically based pharmacokinetic modelling of inhaled nemiralisib: mechanistic components for pulmonary absorption, systemic distribution, and oral absorption. Clin Pharmacokinet. 2021.

  21. Yang F, et al. Prediction of a therapeutic dose for buagafuran, a potent anxiolytic agent by physiologically based pharmacokinetic/pharmacodynamic modeling starting from pharmacokinetics in rats and human. Front Pharmacol. 2017;8:683.

    Article  Google Scholar 

  22. Basu S, et al. Physiologically based pharmacokinetic modeling to evaluate formulation factors influencing bioequivalence of metoprolol extended-release products. J Clin Pharmacol. 2019;59(9):1252–63.

    CAS  PubMed  Google Scholar 

  23. Babiskin A, Zhang X. Application of physiologically based absorption modeling for amphetamine salts drug products in generic drug evaluation. J Pharm Sci. 2015;104:3710–3180.

    Article  Google Scholar 

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Acknowledgements

The authors hereby gratefully acknowledge the efforts from the Novartis associates working in analytical research and development (ARD) for their support in analytical activities, associates from manufacturing plant for supporting manufacturing activities, Biopharmaceutics Expert Group (BPEG), and all those who have played their role during the entire Galvus OD development journey. We thank all the investigators, study coordinators, subjects who participated in the study, and local laboratory and health facility staff present at the clinical study and testing sites. The authors are also grateful to Novartis Global Program Team (GPT) for their scientific guidance and support provided during the development of the drug product.

Funding

The study presented in this article was fully funded by Novartis Healthcare Pvt. Ltd. India.

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Authors and Affiliations

  1. Technical Research and Development, Novartis Healthcare Pvt. Ltd, Hyderabad, India

    Muzaffaruddin Ahmed Madny, Pandurang Deshpande, Venkat Tumuluri & Parag Borde

  2. Pharmacokinetics Sciences, Novartis Healthcare Pvt. Ltd, Hyderabad, India

    Ramachandra Sangana

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  1. Muzaffaruddin Ahmed Madny
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  2. Pandurang Deshpande
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Contributions

Muzaffaruddin Ahmed Madny: conceptualization, data curation, methodology, software, investigation, writing—original draft, formal analysis.

Pandurang Deshpande: resources, data curation, supervision, writing—review and editing.

Venkat Tumuluri: resources, writing—review and editing, project administration.

Parag Borde: conceptualization, supervision, project administration, writing—review and editing.

Ramachandra Sangana: resources, writing—review and editing, validation, formal analysis.

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Correspondence to Muzaffaruddin Ahmed Madny.

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The authors declare no competing interests.

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Madny, M.A., Deshpande, P., Tumuluri, V. et al. Physiologically Based Biopharmaceutics Model of Vildagliptin Modified Release (MR) Tablets to Predict In Vivo Performance and Establish Clinically Relevant Dissolution Specifications. AAPS PharmSciTech 23, 108 (2022). https://doi.org/10.1208/s12249-022-02264-2

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