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

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.

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.

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.

PF614-MPAR may be the first opioid with both abuse resistance and oral overdose protection.