Abstract
Pharmacokinetic differences between manufacturing batches, well established for inhaled drug products, preclude control of patient risk in the customary two-way (single batch) pharmacokinetic bioequivalence crossover design if batches are randomly chosen. European regulators have recommended selecting a “typical” in vitro batch to represent each product in pharmacokinetic bioequivalence testing. We explored the feasibility of this approach to control patient risk (the “false equivalence”, or Type I, error rate). The probability of achieving a Test/Reference 90% confidence interval within (0.80, 1.25) for a true (non-equivalent) value of 1.25 was simulated for a two-way crossover design using the median in vitro batch across a range of number of in vitro batches, in vitro/in vivo correlation (IVIVC) quality (correlation coefficient, r, of zero to one), and within-subject between-batch pharmacokinetic variability. Even under extremely optimistic conditions, e.g., r=0.95 and >100 batches per product screened in vitro, patient risk for typical between-batch variability levels remained at least threefold higher than the 5% regulatory expectation for the significance level (the false equivalence error rate) of the pharmacokinetic bioequivalence test. This elevated error rate in bioequivalence decision-making occurs because of incomplete confidence that the true product average has been identified, and, importantly, omission of this uncertainty from the bioequivalence confidence interval.
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01 September 2021
Reference #8 has been updated.
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Acknowledgements
E.B.G. is an employee of Oriel Therapeutics, an indirect wholly owned subsidiary of Novartis Pharma AG. K.J.C. and L.Z.B. are paid consultants to Oriel Therapeutics. B.J. and J.M. are employees of Novartis Pharma AG. J.M. was supported by the Swiss State Secretariat for Education, Research and Innovation, contract number 999754557. Opinions expressed and arguments employed herein do not necessarily reflect the official views of the Swiss Government. J.M.’s work is part of the IDEAS European training network (http://www.ideas-itn.eu/) from the European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement No. 633567. The work was paid for by Oriel Therapeutics.
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All authors were employed by their indicated affiliated company at the time of this work. K.J.C. and L.Z.B are paid consultants to Oriel Therapeutics.
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All authors contributed to development of the work scope, interpretation of results, and preparation of the article. K.J.C. developed the statistical framework and performed the simulations. J.M. and B.J. confirmed the statistical methodology.
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The authors, excluding K.J.C and L.Z.B., are employed by companies that perform, interpret, and report pharmacokinetic bioequivalence testing of inhaled drug products.
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Burmeister Getz, E., Carroll, K.J., Mielke, J. et al. Batch Selection via In Vitro/In Vivo Correlation in Pharmacokinetic Bioequivalence Testing. AAPS PharmSciTech 22, 224 (2021). https://doi.org/10.1208/s12249-021-02064-0
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DOI: https://doi.org/10.1208/s12249-021-02064-0