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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

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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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

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.

Corresponding author

Correspondence to Muzaffaruddin Ahmed Madny.

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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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  • DOI: https://doi.org/10.1208/s12249-022-02264-2

KEY WORDS

  • Vildagliptin
  • Pharmacokinetics (PK)
  • Pharmacodynamics (PD)
  • Physiologically based biopharmaceutical modeling (PBBM)
  • Compartmental modeling
  • In vitro–in vivo correlation (IVIVC)
  • Virtual BE simulation
  • Modified release (MR) drug product