Dissolution and Translational Modeling Strategies Toward Establishing an In Vitro-In Vivo Link—a Workshop Summary Report

ABSTRACTThis publication summarizes the proceedings of day 2 of a 3-day workshop on “Dissolution and Translational Modeling Strategies Enabling Patient-Centric Product Development.” Patient-centric drug product development from a drug product quality perspective necessitates the establishment of clinically relevant drug product specifications via an in vitro-in vivo link. Modeling and simulation offer a path to establish this link; in this regard, physiologically based modeling has been implemented successfully to support regulatory decision-making and drug product labeling. In this manuscript, case studies of physiologically based biopharmaceutics modeling (PBBM) applied to drug product quality are presented and summarized. These case studies exemplify a possible path to achieve an in vitro-in vivo link and encompass (a) development of biopredictive dissolution methods to support biowaivers, (b) model-informed formulation selection, (c) predicting clinical formulation performance, and (d) defining a safe space for regulatory flexibility via virtual bioequivalence (BE). Workflows for the development and verification of absorption models/PBBM and for the establishment of a safe space using dissolution as an input are described with examples. Breakout session discussions on topics, such as current challenges and some best practices in model development and verification, are included as part of the Supplementary material.

[1]  Amitava Mitra,et al.  Maximizing the Role of Physiologically Based Oral Absorption Modeling in Generic Drug Development , 2018, Clinical pharmacology and therapeutics.

[2]  Andre Hermans,et al.  Dissolution Testing in Drug Product Development: Workshop Summary Report , 2019, The AAPS Journal.

[3]  Filippos Kesisoglou,et al.  Applications of Clinically Relevant Dissolution Testing: Workshop Summary Report , 2018, The AAPS Journal.

[4]  Filippos Kesisoglou,et al.  Dissolution and Translational Modeling Strategies Enabling Patient-Centric Drug Product Development: the M-CERSI Workshop Summary Report , 2018, The AAPS Journal.

[5]  Heidi J Einolf,et al.  Physiologically Based Pharmacokinetic Model Predictions of Panobinostat (LBH589) as a Victim and Perpetrator of Drug-Drug Interactions , 2017, Drug Metabolism and Disposition.

[6]  P. Chalus,et al.  Characterising Drug Release from Immediate-Release Formulations of a Poorly Soluble Compound, Basmisanil, Through Absorption Modelling and Dissolution Testing , 2017, The AAPS Journal.

[7]  Avijit Ghosh,et al.  Development of a Novel Simplified PBPK Absorption Model to Explain the Higher Relative Bioavailability of the OROS® Formulation of Oxybutynin , 2016, The AAPS Journal.

[8]  Sandra Suarez-Sharp,et al.  Regulatory Experience with In Vivo In Vitro Correlations (IVIVC) in New Drug Applications , 2016, The AAPS Journal.

[9]  Anna Eidelman,et al.  Justification of Drug Product Dissolution Rate and Drug Substance Particle Size Specifications Based on Absorption PBPK Modeling for Lesinurad Immediate Release Tablets. , 2016, Molecular pharmaceutics.

[10]  S. Marshall,et al.  Good Practices in Model‐Informed Drug Discovery and Development: Practice, Application, and Documentation , 2016, CPT: pharmacometrics & systems pharmacology.

[11]  Guideline on the qualification and reporting of 4 physiologically based pharmacokinetic ( PBPK ) modelling 5 and simulation , 2016 .

[12]  Emmanuel Scheubel,et al.  Physiologically Based Absorption Modelling to Predict the Impact of Drug Properties on Pharmacokinetics of Bitopertin , 2014, The AAPS Journal.

[13]  Martin Bergstrand,et al.  PBPK models for the prediction of in vivo performance of oral dosage forms. , 2014, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[14]  Maziar Kakhi,et al.  Modeling of pharmacokinetic systems using stochastic deconvolution. , 2013, Journal of pharmaceutical sciences.

[15]  A. Parr,et al.  Re-introduction of a Novel Approach to the Use of Stable Isotopes in Pharmacokinetic Studies , 2012, The AAPS Journal.

[16]  Malcolm Rowland,et al.  Physiologically-based pharmacokinetics in drug development and regulatory science. , 2011, Annual review of pharmacology and toxicology.

[17]  Lawrence X. Yu,et al.  Utility of Physiologically Based Absorption Modeling in Implementing Quality by Design in Drug Development , 2011, The AAPS Journal.

[18]  T. Lavé,et al.  A Novel Strategy for Physiologically Based Predictions of Human Pharmacokinetics , 2006, Clinical pharmacokinetics.

[19]  M. Anbar,et al.  Bioavailability of imipramine tablets relative to a stable isotope-labeled internal standard: Increasing the power of bioavailability tests , 1979, Journal of Pharmacokinetics and Biopharmaceutics.

[20]  J. Crison,et al.  A Theoretical Basis for a Biopharmaceutic Drug Classification: The Correlation of in Vitro Drug Product Dissolution and in Vivo Bioavailability , 1995, Pharmaceutical Research.