Intranasal and Oral Human Abuse Potential (HAP) Studies with PF614: A Novel Trypsin Activated Abuse Protected (TAAP) Extended-Release Oxycodone Prodrug

Intranasal and Oral Human Abuse Potential (HAP) Studies with PF614: A Novel Trypsin Activated Abuse Protected (TAAP) Extended-Release Oxycodone Prodrug

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. 

Purpose/Objectives: In previous clinical studies, a 100 mg dose of TAAP oxycodone, PF614, was shown to be bioequivalent to OxyContin 40 mg but with a slow onset of action and a nearly 3x longer half-life than OxyContin (12 hr versus 4.4 hr, respectively). Intranasal and oral human abuse potential (HAP) studies were undertaken to assess the safety, pharmacokinetics, and abuse potential of PF614 compared to immediate-release (IR) oxycodone HCl and placebo. 

Method: In both studies, recreational drug users were pre-qualified to recognize opioid exposure using validated visual analogue scales (VAS). In the intranasal HAP study, PF614 100 mg was compared to 40 mg crushed IR oxycodone HCl and placebo (n=26) in a 3-way double-blind, randomized, crossover trial. All drugs were administered as powder via intranasal cannula from amber dosing vials.  In the oral HAP study, PF614, 50, 100 and 200 mg were compared to 40 mg oxycodone and placebo (n=28) in a 5-way crossover design. Key endpoints for both studies (‘Drug Liking’ and ‘Take Drug Again’) were evaluated for up to 24 hr after dosing.

Results:

Both studies met their primary and secondary endpoints and successfully showed that PF614 had significantly lower HAP scores than the comparators. In the intranasal HAP study, PF614 produced significantly lower peak "Drug Liking at this Moment" (E_max) scores compared oxycodone (p< 0.0001) using the full modified completer population (MCP) with n=26 for both groups in the 3-way crossover comparison with placebo. Similarly, the first period analysis of initial impressions (PF614 administered in sequence before crushed oxycodone) showed that there was significantly less "Drug Liking at this Moment" and “Overall Drug Liking” liking in the PF614 group (n=8) vs. crushed IR oxycodone (n=10) (p=0.0178 and p=0.0054, respectively).  The “Take Drug Again” score for intranasal PF614 was significantly less than that of oxycodone (p< 0.0001) in the MCP for both the 3-way crossover and the first period analyses (p< 0.0001 for both comparisons). The oral HAP study showed that both the low and mid doses of PF614 produced significantly lower scores than 40 mg oxycodone for all endpoints examined. For the primary endpoint, oral PF614 produced statistically lower “Drug Liking at this Moment” than IR oxycodone at the 50 mg dose level (p< 0.0001).  In the secondary liking endpoints, PF614 produced statistically lower “Overall Drug Liking” at both the 50 and 100 mg dose levels (p< 0.0001 and p=0.0025, respectively). PF614 required a significantly longer median time to reach peak effect for “Drug Liking” than oxycodone at all three dose levels. The key secondary endpoint, “Take Drug Again,” was met at both the 50 and 100 mg dose levels of PF614 (p< 0.001 and p=0.0038 respectively) and was still numerically and statistically lower than oral oxycodone even at the highest 200 mg PF614 dose level (p=0.048), demonstrating that recreational drug users should be less motivated to abuse PF614 compared to immediate-release oxycodone.

Conclusions: Both intranasal and oral PF614 showed significantly less abuse potential than IR oxycodone. Intravenous (IV) abuse deterrent studies have not been required by the FDA since IV administered PF614 will never be exposed to trypsin and hence will pass out of the body in an inactive form. Previous studies (Kirkpatrick et al., 2017) show that the abuse-resistance of PF614 is unaffected by simple physical manipulations (e.g., extraction and/or chewing of the dose form) and cannot be manipulated using culinary enzymes, common solvents, or household chemicals at either room temperature or elevated temperatures to release active oxycodone without destroying 90% or more of the parent molecule. We conclude that PF614 could represent a new class of ‘Next Generation of Opioids’ that require trypsin activation, have reduced abuse potential, and cannot be manipulated to release an immediate-onset drug load.

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