Appendix: Formulation development and a Phase 1 clinical study of PF614-MPAR, an oxycodone prodrug with oral opioid overdose protection

Introduction: Prevention of oral overdose of opioids is a critical unmet need. PF614-Multi-Pill Abuse Resistance (MPAR®) was designed to deliver desired opioid-level analgesia at therapeutic dose levels while providing overdose protection if consumed at higher-than-intended doses, through a unique trypsin-activated prodrug approach. PF614, a prodrug of oxycodone, releases oxycodone only after oral ingestion and exposure to trypsin in the small intestine. PF614-MPAR, a combination of PF614 and a potent trypsin inhibitor, nafamostat, will reduce oxycodone release if taken at higher-than-intended doses. The goal of this Phase 1 study was to determine the optimal PF614-nafamostat formulation to optimize the overdose protection that PF614-MPAR should provide. Methods: Healthy subjects received oral PF614 25 mg alone or in combination with 10 nafamostat formulations (1-10 mg each), which included immediate-release (IR) solutions, slow or fast extended-release (ER) beads, or a combination of IR/ER nafamostat. Plasma oxycodone concentrations were measured to determine PF614 activation and to identify a nafamostat formulation that would reduce the release of oxycodone only when more than two doses were consumed orally. Once an optimal nafamostat formulation was identified, “PF614-MPAR 25 mg,” overdose protection was evaluated by administering one to eight escalating oral doses to naltrexone-blocked subjects. Results: The selected PF614‑MPAR 25 mg formulation delivered therapeutic oxycodone concentrations equivalent to PF614 alone when administered as one or two doses. However, oxycodone release was suppressed when PF614-MPAR was delivered at 3×, 5×, or 8× doses simultaneously. Conclusion: PF614-MPAR may be the first opioid with both abuse resistance and oral overdose protection.