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Using Physiologically Based Pharmacokinetic Modeling to Assess the Risks of Failing Bioequivalence Criteria: a Tale of Two Ibuprofen Products

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Abstract

The aims of the proposed study were to develop and verify a quantitative model-based framework to anticipate the in vivo bioequivalence of ibuprofen immediate release formulations. This stepwise approach integrated virtual bioequivalence trials to simulate the test to reference (T/R) ratio for positive (i.e., bioequivalent) and negative (i.e., non-bioequivalent) control formulations containing ibuprofen, approximated distribution of interoccasion variability (IOV) on ibuprofen peak (Cmax) and extent of exposure (AUC) by bootstrapping resampling methods, post hoc incorporation of IOV to simulated T/R ratios, and power curve analysis. After post hoc incorporation of the bootstrapped IOV to the simulated Cmax T/R geometric mean ratios, the resulting 90% confidence intervals overlapped with the in vivo observations for both pairwise comparisons. On the other hand, simulated and observed AUC TNBE/R geometric mean ratios differed, likely due to the lack of propagating clearance-related IOV to the simulations. This approach is in line with modern regulatory initiatives that advocate leveraging quantitative methods and modeling to modernize generic drug development and review.

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Acknowledgments

The authors thank Simcyp® Limited for providing an academic license of the Simcyp® Simulator v18.2 and 19.1 as well as the license of the SIVA® toolkit v3 to the Center for Pharmacometrics and Systems Pharmacology, University of Florida without charge. Bart Hens acknowledges the Flemish Research Council (FWO: applicant number 12R2119N). Ioannis Loisios-Konstantinidis would like to thank the European Union’s Horizon 2020 Research and Innovation Program under grant agreement No 674909 (PEARRL).

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No funding was received for this research.

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Authors and Affiliations

  1. Institute of Pharmaceutical Technology, Goethe University, Frankfurt am Main, Germany

    Ioannis Loisios-Konstantinidis

  2. Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium

    Bart Hens

  3. Clinical Pharmacology and Pharmacometrics, Janssen Pharmaceutical Companies of Johnson & Johnson, Horsham, Pennsylvania, USA

    Amitava Mitra

  4. Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, College of Pharmacy,, University of Florida, 6550 Sanger Road, Office 146, Orlando, Florida, 32827, USA

    Sarah Kim & Rodrigo Cristofoletti

  5. Institute of Mathematics and Statistics, University of Sao Paulo, Sao Paulo, Brazil

    Chang Chiann

Authors
  1. Ioannis Loisios-Konstantinidis
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  3. Amitava Mitra
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  4. Sarah Kim
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  6. Rodrigo Cristofoletti
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Contributions

I.L.K., B.H, A.M., S.K., C.C., and R.C. wrote the manuscript; R.C. designed the research; I.L.K., B.H. and R.C. performed the research; I.L.K., B.H., S.K., C.C., and R.C. analyzed the data.

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Correspondence to Rodrigo Cristofoletti.

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Ioannis Loisios-Konstantinidis and Bart Hens are equal first authors

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Loisios-Konstantinidis, I., Hens, B., Mitra, A. et al. Using Physiologically Based Pharmacokinetic Modeling to Assess the Risks of Failing Bioequivalence Criteria: a Tale of Two Ibuprofen Products. AAPS J 22, 113 (2020). https://doi.org/10.1208/s12248-020-00495-4

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