A single dose dose study to assess the pharmacokinetics (PK) of oxycodone, when PF614 is administered alone and with nafamostat as an immediate-release (IR) solution and/or extended-release(ER) capsule prototypes.
PF614-MPAR is a combination of an oxycodone prodrug (PF614) and a protease inhibitor (nafamostat) that is intended to provide overdose protection when more than a prescribed dose may be taken simultaneously. A previous study (QSC203698) has explored various nafamostat formulations and identified an optimal combination of immediate release (IR) nafamostat and an extended release (ER) bead that when co-administered with 25 mg PF614 does not impact oxycodone exposure. However, when administered in an overdose situation (8 x unit dose level, 200 mg PF614 and 8 mg nafamostat), the nafamostat was able to inhibit trypsin which prevented the conversion of PF614 to oxycodone and hence prevented increased exposure of oxycodone when compared to 200 mg PF614 in the absence of nafamostat. The nafamostat formulation for the PF614 25 mg dose unit was identified 1 mg total nafamostat comprised of 0.75 mg IR and 0.25 mg ER beads (80:20 coating ratio). Ultimately the study defined the PF614-MPAR 25 mg dose unit. Part 1 of the current study aims to define the PF614-MPAR 100 mg dose unit that is intended for commercialization, by exploring the impact of nafamostat on release of oxycodone from PF614 in naltrexone blocked healthy volunteers. Exposure of both oxycodone and PF614 will be evaluated following administration of 100 mg PF614-MPAR (PF614 and nafamostat (1 mg) as single dose unit or when administered up to 5 dose units simultaneously). If the nafamostat dose needs adjusting with 100 mg PF614, then this will also be assessed with the 50 mg PF614 dose unit in optional Part 1b. Part 1 will also assess exposure of a new 100 mg PF614 capsule formulation. In Part 2, the food effect will be assessed at the highest PF614 and nafamostat dose. If Part 1 is able to identify an appropriate PF614-nafamostat ratio then optional Part 3 will investigate PF614 and oxycodone exposure when 25 mg PF614 is co-administered with varying concentrations of nafamostat (IR and ER beads) in both the fed and fasted states. An Optional Period may investigate PF614 administered alone in the fed and fasted state. The current study proposes to dose up to 500 mg PF614 (equivalent to 200 mg oxycodone); the 50 mg daily doses of naltrexone are anticipated to be more than sufficient to block 200 mg of an oxycodone-equivalent exposure.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
30
PF614 capsules (25-100 mg)
Nafamostat IR/ER solution/beads (total 1-10 mg)
Quotient Sciences
Miami, Florida, United States
RECRUITINGPharmacokinetic Tmax [Time to Maximum Plasma Concentration]
Time to maximum observed concentrations of oxycodone following administration of PF614 alone and with nafamostat
Time frame: Parts 1, 2, & 3 (PF614 single dose): predose, 0.25, 0.5, 1, 2, 4, 6, 12, 24, 36, 48, 72 hours.
Pharmacokinetic Cmax [Maximum Plasma Concentration]
Maximum (peak) observed concentration of oxycodone following administration of PF614 alone and with nafamostat
Time frame: Parts 1, 2, & 3 (PF614 single dose): predose, 0.25, 0.5, 1, 2, 4, 6, 12, 24, 36, 48, 72 hours.
Pharmacokinetic C24 [Plasma concentration at 24 hours]
Concentration of oxycodone at 24 hours post-dose following administration of PF614 alone and with nafamostat
Time frame: Parts 1, 2, & 3 (PF614 single dose): predose, 0.25, 0.5, 1, 2, 4, 6, 12, 24, 36, 48, 72 hours.
Pharmacokinetic AUC(0-last) [Area Under the Curve]
Area under the concentration-time curve from time 0 to the time of last measurable concentrations of oxycodone following administration of PF614 alone and with nafamostat
Time frame: Parts 1, 2, & 3 (PF614 single dose): predose, 0.25, 0.5, 1, 2, 4, 6, 12, 24, 36, 48, 72 hours.
Pharmacokinetic AUC(0-inf) [Area Under the Curve]
Area under the concentration-time curve from time 0 extrapolated to time-infinity of oxycodone following administration of PF614 alone and with nafamostat
Time frame: Parts 1, 2, & 3 (PF614 single dose): predose, 0.25, 0.5, 1, 2, 4, 6, 12, 24, 36, 48, 72 hours.
Pharmacokinetic T1/2 [Half-life]
Terminal elimination half-life concentrations of oxycodone following administration of PF614 alone and with nafamostat
Time frame: Parts 1, 2, & 3 (PF614 single dose): predose, 0.25, 0.5, 1, 2, 4, 6, 12, 24, 36, 48, 72 hours.
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Incidence of Treatment-Emergent Adverse Effects [Safety and Tolerability]
Adverse events (AEs) including Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESIs), safety laboratory evaluations (hematology, coagulation, clinical chemistry, urinalysis), 12-lead electrocardiograms (ECGs), vital sign measurements, pulse oximetry and physical examinations.
Time frame: 30 Days