020: A Science-based Approach for Recommendation of Antagonist Blockade in the Bioequivalence Studies of Opioid Drug Products

Statement of 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. However, use of antagonist blockade was not consistently utilized across the in vivo studies. A preliminary review of 50 product-specific guidances (PSGs) of opioid drug products published by the US Food & Drug Administration showed that use of antagonist blockade is not routinely recommended for all opioid drug products, including potent opioids. This study aims to identify a science-based approach to standardize the recommendation of antagonist blockade for in vivo pharmacokinetic (PK) bioequivalence (BE) studies of opioid drug products for generic drug development.

Description of Methods & Materials: This study was conducted using a systematic review of literature and NDAs and ANDAs of opioid drug products. The rank ordering of various opioid agonists was developed based on their pharmacological properties such as receptor binding affinity and 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.

Data & 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 mainly correlates with the intrinsic potency of opioids and the opioid drug loads. Antagonist blockade was invariably used in relative BA/BE studies of all the highly potent oral opioids (potency relative to morphine (PRM): ≥3X). For opioids with intermediate potency (PRM: 0.33-1.5X), use of antagonist blockade was 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. No antagonist blockade was recommended for the drug products with drug content ≤10 mg whereas antagonist blockade was recommended for the same drug product with drug content ≥20 mg in the PSG. In the case of opioids with significantly lower potency compared to morphine (PRM: ≤0.1X), antagonist blockade was consistently not used in the studies and antagonist blockade was consistently not recommended in the PSGs. More consistent antagonist blockade use was seen for immediate-release dosage form over the extended-release dosage form of the intermediate and high potent oral opioid products in the BA/BE studies submitted to NDA and ANDA studies.

Interpretation, Conclusion or Significance: 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.

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