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Scientific Rationale for Determining the Bioequivalence of Inhaled Drugs

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Abstract

In recent years, pathways for the development and approval of bioequivalent inhaled products have been established for regulated markets, including the European Union (EU), and a number of orally inhaled products (OIPs) have been approved in the EU solely on the basis of in vitro and pharmacokinetic data. This review describes how these development pathways are structured and their implications for the treatment of airway diseases such as asthma. The EU guidance follows a stepwise approach that includes in vitro criteria as the first step. If all in vitro criteria are not met, the second step is based on pharmacokinetic evaluations, which include assessments of lung and systemic bioavailability. If all pharmacokinetic criteria are not met, the third step is based on clinical endpoint studies. In this review, the scientific rationale of the European Medicines Agency guidance for the development of bioequivalent OIPs is reviewed with the focus on the development of bioequivalent OIPs in the EU. Indeed, we discuss the advantages and disadvantages of the weight-of-evidence and stepwise approaches. The evidence indicates that the EU guidance is robust and, unlike clinical endpoint studies, the pharmacokinetic studies are far more sensitive to measure the minor differences, i.e. deposition and absorption rates, in drug delivery from the test and reference products and, thus, should be best suited for assessing bioequivalence. The acceptance range of the 90% confidence intervals for pharmacokinetic bioequivalence (i.e. 80–125% for both the area under the plasma concentration–time curve and maximum plasma concentration) represent appropriately conservative margins for ensuring equivalent safety and efficacy of the test and reference products.

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Acknowledgements

The authors thank Dr. Paul Dorinsky, Ms. Juliet Robello, Ms. Nazma Morde, Ms. Mayuri Mangle and Dr. Sudipta Ganguli for valuable relevant discussions.

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Authors and Affiliations

  1. Airways Disease Section, National Heart and Lung Institute, Imperial College London and Royal Brompton Hospital, Dovehouse Street, London, SW3 6LY, UK

    Omar S. Usmani

  2. Department of Medical Pharmacology, CHU and University of Bordeaux, Bordeaux, France

    Mathieu Molimard

  3. Global Medical Affairs, Cipla Ltd, Mumbai, India

    Vaibhav Gaur & Jaideep Gogtay

  4. Research and Development, Cipla Ltd, Mumbai, India

    Gur Jai Pal Singh & Geena Malhotra

  5. Department of Internal Medicine, Ghent University Hospital, Ghent, Belgium

    Eric Derom

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Dr. Usmani reports having received consulting fees, honorarium, institutional grants and payments for lectures from Boehringer Ingelheim, AstraZeneca, Chiesi, Napp, Mundipharma, Aerocrine, GlaxoSmithKline (GSK), Sandoz, Takeda, Edmond Pharma, Zentiva and Cipla outside of the submitted work. Dr Molimard reports having received consulting fees from Novartis Pharma, GSK and Mundipharma outside of the submitted work. Dr Derom reports that he has received travel grants from Boehringer Ingelheim, GSK and AstraZeneca to attend international congresses, participated in advisory boards by Boehringer Ingelheim, Chiesi, Cipla and Astra Zeneca, for which a fee was given, and received speaker’s fees from Boehringer Ingelheim, GSK, Astra Zeneca and Menarini to give scientific presentations to Belgian general practitioner groupings (all of which are not related to this work). His clinical department received financial support from Boehringer Ingelheim and Novartis to perform clinical studies. Drs Gaur, Gogtay, Singh and Malhotra are full-time employees of Cipla Ltd, Mumbai, India.

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Usmani, O.S., Molimard, M., Gaur, V. et al. Scientific Rationale for Determining the Bioequivalence of Inhaled Drugs. Clin Pharmacokinet 56, 1139–1154 (2017). https://doi.org/10.1007/s40262-017-0524-6

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