Overview
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.
Description
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.
Eligibility
Inclusion Criteria:
1. Must be able to understand a written informed consent, which must be obtained prior to initiation of study procedures.
2. Must be willing and able to comply with all study requirements.
3. Aged 18 to 55 years, inclusive, at time of signing informed consent.
4. Must agree to use an adequate method of contraception (as defined in Section 9.4).
5. Healthy males or non pregnant, non lactating healthy females.
6. Body mass index (BMI) of 18.0 to 32.0 kg/m2 as measured at screening or, if outside the range, considered not clinically significant by the investigator.
7. Minimum weight of 50 kg at screening.
Exclusion Criteria:
1. Serious adverse reaction or serious hypersensitivity to any drug or formulation excipients.
2. Presence or history of clinically significant allergy requiring treatment, as judged by the investigator. Hay fever is allowed unless it is active.
3. Significant serious skin disease, including rash, food allergy, eczema, psoriasis, or urticaria.
4. History of clinically significant cardiovascular, renal, hepatic, chronic respiratory or GI disease (Part 1 only: except cholecystectomy), gastrointestinal surgery (e.g. gastric bypass, gastric banding, colectomy), or neurological or psychiatric disorder, as judged by the investigator.
5. Subjects with a history of seizures.
6. Subjects with history of GI bleeding (excluding hemorrhoids) or history of peptic or duodenal ulcer disease.
7. Subjects with a history of bleeding disorders or coagulopathy.
8. Subjects with any personal history of arrhythmias or family history of significant cardiac disease (i.e., sudden death in first degree relative; myocardial infarction prior to 50 years old).
9. Part 2 only: Subjects with a history of cholecystectomy or gall stones.
10. Parts 2 and 3 only: Subjects with a history of opioid intolerance or hypersensitivity based on previous experience receiving any opioid analgesic
11. Have poor venous access that limits phlebotomy.
12. Clinically significant abnormal clinical chemistry, hematology, coagulation or urinalysis as judged by the investigator (laboratory parameters are listed in Appendix 1). Subjects with Gilbert's Syndrome are allowed.
13. Subjects with a platelet count \<150,000/µL or international normalized ratio \>1.1 at screening.
14. Subjects with hemoglobin \
