PF614-MPAR: A Novel Trypsin Activated Abuse Protected (TAAP) Extended-Release Oxycodone Prodrug with Overdose Protection

PF614-MPAR: A Novel Trypsin Activated Abuse Protected (TAAPä) Extended-Release Oxycodone Prodrug with Overdose Protection

Background: TAAP prodrugs represent novel products that are inactive until swallowed and activated by trypsin in the small intestine (Kirkpatrick et al., 2017), deterring abuse by chemically controlling the rate of release and reducing release by all non-oral modes of administration. PF614 is an oxycodone-derived TAAP prodrug, designed to reduce abuse through its trypsin based extended release profile.  Overdose protection (Multi-Pill Abuse Resistance, MPAR^®) is created by combining a TAAP prodrug with a trypsin inhibitor, nafamostat, in a single capsule or tablet dose unit. PF614-MPAR is the first abuse protected opioid with oral overdose protection in clinical development.

Purpose/Objectives: The purpose of this study was to optimize the formulation of nafamostat in combination with PF614 and to confirm overdose protection when multiple dose units are consumed simultaneously. The goal of MPAR^® is to enable a patient to take up to 2 dose units at a time without compromising the oxycodone release from PF614, while taking more than the prescribed dose (3 or more dose units) reduces the oxycodone release as compared to taking unprotected PF614. Ultimately the goal is to prevent oral overdose of prescription opioids using MPAR.

Method:

The Translational Pharmaceutics approach (rapid manufacturing and clinical testing) provided by Quotient Sciences allowed progressive optimization of nafamostat formulation based on emerging clinical data. The optimized PF614/nafamostat combination (25 mg PF614 + 1 mg controlled-release nafamostat, as 1 dose unit) was then explored for the release of oxycodone when an increasing number of 25 mg PF614-MPAR dose units were consumed orally and simultaneously. Cohorts of 12 to 15 naltrexone-blocked healthy subjects received PF614 25 mg alone or 1, 2, 3, 5 or 8 dose units of PF614-MPAR all at once in six treatment periods; pharmacokinetic samples were taken over a 72 hr period after dosing followed by a 5-day washout between each treatment.  Additionally, PF614-MPAR 25 mg was administered twice a day for a single day to each subject in a 7^th treatment period to evaluate the oxycodone release from each dose to ensure the release was not compromised with sequential dosing 12 hr apart.

Results: Plasma oxycodone and PF614 levels were evaluated from subjects who were administered oral PF614 25 mg alone or 1 to 8 dose units of PF614-MPAR 25 mg simultaneously. The results of the study successfully demonstrated that up to 2 dose units of PF614-MPAR delivered oxycodone at the same level as was derived from PF164 without MPAR. At 3 units of PF614-MPAR the amount of oxycodone delivered was reduced compared to a 75 mg dose of PF614. At 8 dose units there was a significant decrease (p< 0.00333) in the maximal oxycodone plasma concentration (C_max) as compared to that delivered from unprotected PF614 200 mg. In addition, delivering 2 doses of PF614-MPAR sequentially, 12 hr apart did not affect the release of oxycodone from the 2^nd dose.

Conclusions: PF614-MPAR represents the first opioid product that can deliver oxycodone in an extended-release profile that may protect against all four forms of abuse including snorting, chewing, injecting and oral overdose.

References: Kirkpatrick DL, et al. In vitro and in vivo assessment of the abuse potential of PF614, a novel BIO-MD™ prodrug of oxycodone. J Opioid Manag. 2017;13(1):39-49