Demonstrating Efficacy When Clinical Trials Are Impossible: QSP Modeling to Support a New Dose Application

For over 50 years, fentanyl has been used in anesthesia and pain control, with naloxone as a counter agent to reverse overdoses. The increasing abuse of synthetic opioids has necessitated expanding the use of naloxone from hospitals and clinics to community use. The need for increased naloxone dosing, speed of onset, and ease of use has led to the development of intramuscular (IM) dosing devices for community use. Because overdose clinical trials are problematic to implement and require consent after the opioid has been administered, the FDA has recommended modeling of opioid receptor displacement of potent opioids with naloxone as an alternative method to guide dose recommendations.This webinar discusses the development of a mu-opioid receptor binding quantitative systems pharmacology (QSP) model with competing drug treatments (naloxone, fentanyl). The model was used to support regulatory approval of a higher clinical dose of naloxone in an IM device to address the unmet medical need. Simulations using the model demonstrated the added utility of higher naloxone doses in displacing fentanyl from the mu receptor. QSP modeling demonstrated that higher doses of naloxone lead to a greater displacement of fentanyl from the mu receptor and reduce the time it takes for fentanyl binding to dip below a critical threshold for overdose reversal. The modeling increased confidence in the added utility of the higher-dose naloxone product and supported approval by the FDA.