Batch Selection via In Vitro/In Vivo Correlation in Pharmacokinetic Bioequivalence Testing
- 19 August 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in AAPS PharmSciTech
- Vol. 22 (7), 1-8
- https://doi.org/10.1208/s12249-021-02064-0
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.Keywords
This publication has 14 references indexed in Scilit:
- Predicting Exposure After Oral Inhalation of the Selective Glucocorticoid Receptor Modulator, AZD5423, Based on Dose, Deposition Pattern, and Mechanistic Modeling of Pulmonary DispositionJournal of Aerosol Medicine and Pulmonary Drug Delivery, 2017
- Batch‐to‐batch pharmacokinetic variability confounds current bioequivalence regulations: A dry powder inhaler randomized clinical trialClinical Pharmacology & Therapeutics, 2016
- Equivalent Lung Dose and Systemic Exposure of Budesonide/Formoterol Combination via Easyhaler and TurbuhalerJournal of Aerosol Medicine and Pulmonary Drug Delivery, 2015
- Current Scientific and Regulatory Approaches for Development of Orally Inhaled and Nasal Drug Products: Overview of the IPAC-RS/University of Florida Orlando Inhalation ConferenceThe AAPS Journal, 2015
- Regulatory Considerations for Approval of Generic Inhalation Drug Products in the US, EU, Brazil, China, and IndiaThe AAPS Journal, 2015
- In Vitro Testing for Orally Inhaled Products: Developments in Science-Based Regulatory ApproachesThe AAPS Journal, 2015
- Pharmacokinetics of Orally Inhaled Drug ProductsThe AAPS Journal, 2015
- A Pharmacokinetic Simulation Tool for Inhaled CorticosteroidsThe AAPS Journal, 2012
- Equivalence Considerations for Orally Inhaled Products for Local Action—ISAM/IPAC-RS European Workshop ReportJournal of Aerosol Medicine and Pulmonary Drug Delivery, 2012
- Comparing Generic and Innovator Drugs: A Review of 12 Years of Bioequivalence Data from the United States Food and Drug AdministrationAnnals of Pharmacotherapy, 2009