Batch‐to‐batch pharmacokinetic variability confounds current bioequivalence regulations: A dry powder inhaler randomized clinical trial
Open Access
- 2 April 2016
- journal article
- research article
- Published by Wiley in Clinical Pharmacology & Therapeutics
- Vol. 100 (3), 223-231
- https://doi.org/10.1002/cpt.373
Abstract
Current pharmacokinetic (PK) bioequivalence guidelines do not account for batch‐to‐batch variability in study design or analysis. Here we evaluate the magnitude of batch‐to‐batch PK variability for Advair Diskus 100/50. Single doses of fluticasone propionate and salmeterol combinations were administered by oral inhalation to healthy subjects in a randomized clinical crossover study comparing three different batches purchased from the market, with one batch replicated across two treatment periods. All pairwise comparisons between different batches failed the PK bioequivalence statistical test, demonstrating substantial PK differences between batches that were large enough to demonstrate bio‐inequivalence in some cases. In contrast, between‐replicate PK bioequivalence was demonstrated for the replicated batch. Between‐batch variance was ∼40–70% of the estimated residual error. This large additional source of variability necessitates re‐evaluation of bioequivalence assessment criteria to yield a result that is both generalizable and consistent with the principles of type I and type II error rate control.Keywords
This publication has 16 references indexed in Scilit:
- Randomized equivalence trial: A novel multidose dry powder inhaler and originator device in adult and adolescent asthmaAllergy and Asthma Proceedings, 2015
- Regulatory Considerations for Approval of Generic Inhalation Drug Products in the US, EU, Brazil, China, and IndiaThe AAPS Journal, 2015
- Pharmacokinetics of Orally Inhaled Drug ProductsThe AAPS Journal, 2015
- Comparing Generic and Innovator Drugs: A Review of 12 Years of Bioequivalence Data from the United States Food and Drug AdministrationAnnals of Pharmacotherapy, 2009
- Fluticasone propionate hydrofluoroalkane inhalation aerosol in patients receiving inhaled corticosteroidsAnnals of Allergy, Asthma & Immunology, 2006
- AnIn VivoandIn VitroComparison of Two Powder Inhalers following Storage at Hot/Humid ConditionsJournal of Aerosol Medicine, 2005
- Dose response of inhaled corticosteroids on bronchial hyperresponsiveness: a meta-analysisAnnals of Allergy, Asthma & Immunology, 2003
- Salmeterol and fluticasone propionate given as a combinationEuropean Journal of Clinical Pharmacology, 2001
- Comparison of pharmacokinetics and systemic effects of inhaled fluticasone propionate in patients with asthma and healthy volunteers: a randomised crossover studyThe Lancet, 2000
- Dose‐response study with high‐dose inhaled salmeterol in healthy subjects.British Journal of Clinical Pharmacology, 1992