Establishing the Bioequivalence Safe Space for Immediate-Release Oral Dosage Forms using Physiologically Based Biopharmaceutics Modeling (PBBM): Case Studies

Published:September 18, 2021DOI:


      For oral drug products, in vitro dissolution is the most used surrogate of in vivo dissolution and absorption. In the context of drug product quality, safe space is defined as the boundaries of in vitro dissolution, and relevant quality attributes, within which drug product variants are expected to be bioequivalent to each other. It would be highly desirable if the safe space could be established via a direct link between available in vitro data and in vivo pharmacokinetics. In response to the challenges with establishing in vitro-in vivo correlations (IVIVC) with traditional modeling approaches, physiologically based biopharmaceutics modeling (PBBM) has been gaining increased attention. In this manuscript we report five case studies on using PBBM to establish a safe space for BCS Class 2 and 4 across different companies, including applications in an industrial setting for both internal decision making or regulatory applications. The case studies provide an opportunity to reflect on practical vs. ideal datasets for safe space development, the methodologies for incorporating dissolution data in the model and the criteria used for model validation and application. PBBM and safe space, still represent an evolving field and more examples are needed to drive development of best practices.



      API (Active Pharmaceutical Ingredient), BCS (Biopharmaceutics Classification System), BE (Bioequivalence), IR (Immediate Release), IVIVC (In Vitro-In Vivo Correlation), MR (Modified Release), PBBM (Physiologically Based Biopharmaceutics Modeling), MAM (Mechanistic Absorption Modeling), PBPK (Physiologically Based Pharmacokinetics), PK (Pharmacokinetics), PSD (Particle Size Distribution), PE (Prediction Error)
      To read this article in full you will need to make a payment
      APhA Member Login
      APhA Members, full access to the journal is a member benefit. Use your society credentials to access all journal content and features.
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Food and Drug Administration
        The Use of Physiologically Based Pharmacokinetic Analyses — Biopharmaceutics Applications for Oral Drug Product Development, Manufacturing Changes, and Controls Guidance for Industry.
        2020 (Available at: https://wwwfdagov/media/142500/download. Accessed October 12, 2021)
        • Suarez-Sharp S
        • Cohen M
        • Kesisoglou F
        • et al.
        Applications of clinically relevant dissolution testing: workshop summary report.
        AAPS J. 2018; 20: 93
        • Suarez-Sharp S
        • Li M
        • Duan J
        • Shah H
        • Seo P
        Regulatory experience with In Vivo In Vitro Correlations (IVIVC) in new drug applications.
        AAPS J. 2016; 18: 1379-1390
        • Suarez-Sharp S
        • Lindahl A
        • Heimbach T
        • et al.
        Translational modeling strategies for orally administered drug products: academic, industrial and regulatory perspectives.
        Pharm Res. 2020; 37: 95
        • Heimbach T
        • Suarez-Sharp S
        • Kakhi M
        • et al.
        Dissolution and translational modeling strategies toward establishing an in vitro-in vivo link-a workshop summary report.
        AAPS J. 2019; 21: 29
        • Food and Drug Administration
        Guidance for Industry Extended Release Oral Dosage Forms: Development, Evaluation, and Application of In Vitro/In Vivo Correlations.
        FDA, 1997 (Available at: https://wwwfdagov/media/70939/download. Accessed October 12, 2021)
        • Jones RD
        • Jones HM
        • Rowland M
        • et al.
        PhRMA CPCDC initiative on predictive models of human pharmacokinetics, part 2: comparative assessment of prediction methods of human volume of distribution.
        J Pharm Sci. 2011; 100: 4074-4089
        • Nguyen MA
        • Flanagan T
        • Brewster M
        • 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
        • Stillhart C
        • Pepin X
        • Tistaert C
        • et al.
        PBPK absorption modeling: establishing the in vitro-in vivo link-industry perspective.
        AAPS J. 2019; 21: 19
        • Zhao L
        • Seo P
        • Lionberger R
        Current scientific considerations to verify physiologically-based pharmacokinetic models and their implications for locally acting products.
        CPT. 2019; 8: 347-351
        • Dickinson PA
        • Lee WW
        • Stott PW
        • et al.
        Clinical relevance of dissolution testing in quality by design.
        AAPS J. 2008; 10: 380-390
        • Martin P
        • Oliver S
        • Kennedy SJ
        • et al.
        Pharmacokinetics of vandetanib: three phase I studies in healthy subjects.
        Clin Ther. 2012; 34: 221-237
      1. Australian Public Assessment Report for Vandetanib.
        Australian Government, Department of Health and Aging, 2013 (Available at: Accessed October 12, 2021)
        • Martin P
        • Oliver S
        • Robertson J
        • Kennedy SJ
        • Read J
        • Duvauchelle T
        Pharmacokinetic drug interactions with vandetanib during coadministration with rifampicin or itraconazole.
        Drugs R&D. 2011; 11: 37-51
        • Agrawal NGB
        • Porras AG
        • Matthews CZ
        • et al.
        Single- and multiple-dose pharmacokinetics of etoricoxib, a selective inhibitor of cyclooxygenase-2, in man.
        J Clin Pharmacol. 2003; 43: 268-276
        • Mitra A
        • Kesisoglou F
        • Dogterom P
        Application of absorption modeling to predict bioequivalence outcome of two batches of etoricoxib tablets.
        AAPS PharmSciTech. 2015; 16: 76-84
        • Rodrigues AD
        • Halpin RA
        • Geer LA
        • et al.
        Absorption, metabolism, and excretion of etoricoxib, a potent and selective cyclooxygenase-2 inhibitor, in healthy male volunteers.
        Drug Metab Dispos. 2003; 31: 224-232
        • Pepin XJH
        • Sanderson NJ
        • Blanazs A
        • Grover S
        • Ingallinera TG
        • Mann JC
        Bridging in vitro dissolution and in vivo exposure for acalabrutinib. Part I. Mechanistic modelling of drug product dissolution to derive a P-PSD for PBPK model input.
        Eur J Pharm Biopharm. 2019; 142: 421-434
        • Tsume Y
        • Takeuchi S
        • Matsui K
        • Amidon GE
        • Amidon GL
        In vitro dissolution methodology, mini-Gastrointestinal Simulator (mGIS), predicts better in vivo dissolution of a weak base drug, dasatinib.
        Eur J Pharm Sci. 2015; 76: 203-212
        • Wajima T
        • Yano Y
        • Fukumura K
        • Oguma T
        Prediction of human pharmacokinetic profile in animal scale up based on normalizing time course profiles.
        J Pharm Sci. 2004; 93: 1890-1900
        • Rostami-Hodjegan A
        • Tucker GT
        The effects of portal shunts on intestinal cytochrome P450 3A activity.
        Hepatology. 2002; 35 (author reply 1550-1541): 1549-1550
        • McAllister M
        • Flanagan T
        • Boon K
        • et al.
        Developing clinically relevant dissolution specifications for oral drug products-industrial and regulatory perspectives.
        Pharmaceutics. 2019; 12
        • Mann J
        • Dressman J
        • Rosenblatt K
        • et al.
        Validation of dissolution testing with biorelevant media: an OrBiTo study.
        Mol Pharm. 2017; 14: 4192-4201
        • Mitra A
        • Suarez-Sharp S
        • Pepin XJH
        • et al.
        Applications of physiologically based biopharmaceutics modeling (PBBM) to support drug product quality: a workshop summary report.
        J Pharm Sci. 2021; 110: 594-609
        • Jamei M
        • Abrahamsson B
        • Brown J
        • et al.
        Current status and future opportunities for incorporation of dissolution data in PBPK modeling for pharmaceutical development and regulatory applications: OrBiTo consortium commentary.
        Eur J Pharm Biopharm. 2020; 155: 55-68
        • 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; 13: 3256-3269
        • Parrott N
        • Suarez-Sharp S
        • Kesisoglou F
        • et al.
        Best practices in the development and validation of physiologically based biopharmaceutics modeling. a workshop summary report.
        J Pharm Sci. 2021; 110: 584-593
        • Wu F
        • Shah H
        • Li M
        • et al.
        Biopharmaceutics applications of physiologically based pharmacokinetic absorption modeling and simulation in regulatory submissions to the U.S. food and drug administration for new Drugs.
        Aaps j. 2021; 23: 31
        • Kuemmel C
        • Yang Y
        • Zhang X
        • et al.
        Consideration of a credibility assessment framework in model-informed drug development: potential application to physiologically-based pharmacokinetic modeling and simulation.
        CPT. 2020; 9: 21-28
      2. EGATEN (Triclabendazole) Tablets, NDA 208711, 2018.
        Food and Drug Administration, 2007 (Available at: ChemR.pdf. Accessed October 12, 2021)