(W0930-10-64) A Science-Based Approach for Recommendation of Antagonist Blockade in the Bioequivalence Studies of Opioid Drug Products

Purpose: Antagonist blockade is often used in the in vivo studies of opioid drug products in support of new drug application (NDA) and abbreviated new drug application (ANDA) submissions to reduce or mitigate the risk of opioid-related serious adverse events and drug liking or addiction potential in study subjects. A preliminary review of 50 product-specific guidances (PSGs) of opioid drug products published by the U.S. Food and Drug Administration showed that use of antagonist blockade is not routinely recommended for opioid drug products, including potent opioids. This study aims to identify a science-based approach to standardize the PSG recommendation of antagonist blockade for in vivo pharmacokinetic (PK) bioequivalence (BE) studies of oral opioid drug products for generic drug development.

Methods: This study was conducted using a systematic review of literature (e.g., in vivo studies) and submitted NDAs and ANDAs of 47 oral opioid drug products (e.g., hydromorphone, hydrocodone). Oral opioid agonists were categorized based on potency relative to morphine. Furthermore, the dosage form (e.g., immediate-release, extended-release) was considered for antagonist blockade use in the relative bioavailability (BA)/BE studies of opioid drug products.

Results: A literature review indicates that antagonist blockade reduces/mitigates the frequency and severity of opioid-related adverse events without impact on the PK profiles of morphine and oxycodone. From NDA and ANDA review, we observed that antagonist blockade use in relative BA/BE studies of opioid drug products is mainly related with the intrinsic potency of opioids and the opioid drug loads. Antagonist blockade was invariably used in relative BA/BE studies of all the high potent oral opioids (e.g., hydromorphone, oxymorphone). However, not all high potent oral opioids had antagonist blockade recommendation in their respective PSGs (e.g., hydromorphone). For opioids with intermediate potency (e.g., hydrocodone, oxycodone), use of antagonist blockade was in general observed for drug products with higher drug loads. For instance, antagonist blockade was used in relative BA/BE studies of a drug product with drug content ≥20 mg but not for those with drug content ≤10 mg. For the same drug products, antagonist blockade was recommended with drug content ≥20 mg in their respective PSGs. However, other intermediate potent product with low drug load had antagonist blockade used in the studies but did not have antagonist blockade recommendation in the PSG. In the case of opioids with low potency (e.g., tramadol), antagonist blockade was consistently not used in the studies and this is reflected in the PSGs.

Conclusion: For a science-based approach for the necessity of antagonist blockade in the BE studies for opioid drug products, assessment of the following factors should be considered: (i) intrinsic pharmacological properties of opioids (e.g., receptor binding affinity, potency); and (ii) drug product-related factors (e.g., drug load, dosage form, PK characteristics, and adverse effects). A standardized recommendation of antagonist blockade will be employed on identified PSGs of opioid drug products for generic drug development.

Acknowledgements: This project was supported in part by an appointment (C. Oh) to the Research Participation Program at the U.S. Food and Drug Administration administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration.