Single Dose Study, Pharmacokinetics of Oxycodone and PF614 Co-Administered With Nafamostat (PF614-MPAR-102)

A Single Dose Study to Evaluate the Pharmacokinetics of Oxycodone and PF614 When PF614 Capsule is Co Administered With Nafamostat as a Combination IR Solution and ER Capsule Formulation in Healthy Subjects

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.

Study Overview

• Status: Recruiting
• Conditions: Pharmacokinetics; Healthy Volunteer
• Intervention / Treatment: Drug: PF614 capsule; Drug: Nafamostat Mesylate

Detailed 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. Part 3 of the study will also assess the impact of dosing PF614 and nafamostat in standard (uncoated) or enteric-coated (EC) capsules on the exposure of oxycodone in both the fed and fasted state. 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
• Enrollment (Estimated): 54
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Lynn Kirkpatrick, PhD; Phone Number: 281-881-4140; Email: lkirkpatrick@ensysce.com
• Study Contact Backup: Name: William K Schmidt, PhD; Phone Number: 650-438-3018; Email: wschmidt@ensysce.com

Study Locations

• United States
  • Florida
    • Miami, Florida, United States, 33126
      • Recruiting
      • Quotient Sciences
      • Contact: Claire Swann; Email: Claire.Swann@quotientsciences.com
      • Principal Investigator: Jeffrey Levy, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

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. Parts 2 and 3 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 <LLN at screening and/or first admission.
15. Subjects with a QT interval corrected using Fridericia's formula (QTcF) above 450 msec at screening and/or first admission.
16. Positive hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab) or human immunodeficiency virus (HIV) antibody results.
17. Positive serum pregnancy test at screening or first admission. Those who are pregnant or lactating will be excluded.
18. Subjects who have received any IMP in a clinical research study within 5 half lives or within 30 days prior to first dose. However, in no event shall the time between last receipt of IMP and first dose be less than 30 days.
19. Subjects who have previously been administered IMP in this study.
20. Subjects who are taking, or have taken, any prescribed or over the counter drug or herbal remedies (other than up to 4 g per day acetaminophen, HRT or hormonal contraception) in the 14 days before study treatment administration (see Section 11.4). Exceptions may apply on a case by case basis, if considered not to interfere with the objectives of the study, as determined by the investigator.
21. Subjects with an anticipated need for requiring aspirin, non-steroidal anti-inflammatory drugs, or anticoagulants in the 14 days after administration of the IMP.
22. History of any drug or alcohol abuse in the past 2 years.
23. Regular alcohol consumption in males >21 units per week and females >14 units per week (1 unit = 12 oz 1 bottle/can of beer, 1 oz 40% spirit, or 5 oz glass of wine).
24. A confirmed positive alcohol urine test at screening or first admission.
25. Current smokers and those who have smoked within the last 12 months.
26. Current users of e-cigarettes and nicotine replacement products and those who have used these products within the last 12 months.
27. A confirmed positive urine cotinine test at screening or first admission.
28. Positive drug screen test result at screening or first admission (drug of abuse tests are listed in Appendix 1).
29. Male subjects with pregnant or lactating partners.
30. Donation of blood within 2 months or donation of plasma within 7 days prior to first dose of study treatment.
31. Subjects who are, or are immediate family members of, a study site or sponsor employee.
32. Failure to satisfy the investigator of fitness to participate for any other reason.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: PF614 capsule with naltrexone HCl; PF614 is an oxycodone prodrug. Part 1 doses = 100, 300 and up to 500 mg. Subjects will receive single daily doses at 5-14 days apart. Naltrexone, 50 mg Oral (Day -1, Day 1 and Day 2). All subjects will receive naltrexone block	Drug: PF614 capsule; PF614 capsules (25-100 mg); Other Names: Oxycodone prodrug; PRF06104
Experimental: PF614 capsule concomitantly with nafamostat and naltrexone HCl; PF614 is an oxycodone prodrug. Part 1 doses = 100, 300 and up to 500 mg. Nafamostat Mesylate is a trypsin inhibitor that blocks PF614 activation. Nafamostat IR solution (0.75 - XX mg); Nafamostat ER beads in capsule formulation (0.25 - YY mg) Naltrexone, 50 mg Oral (Day -1, Day 1 and Day 2). All subjects will receive naltrexone block	Drug: PF614 capsule; PF614 capsules (25-100 mg); Other Names: Oxycodone prodrug; PRF06104; Drug: Nafamostat Mesylate; Nafamostat IR/ER solution/beads/powder (total 1-25 mg); Other Names: Futhan

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetic Tmax [Time to Maximum Plasma Concentration]	Time to maximum observed concentrations of oxycodone following administration of PF614 alone and with nafamostat	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	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	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	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	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	Parts 1, 2, & 3 (PF614 single dose): predose, 0.25, 0.5, 1, 2, 4, 6, 12, 24, 36, 48, 72 hours.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	30 Days

Collaborators and Investigators

• Sponsor: Ensysce Biosciences
• Collaborators: National Institute on Drug Abuse (NIDA); Quotient Sciences
• Investigators: Principal Investigator: Jeffrey Levy, MD, PhD, Medical Director, Quotient Sciences

Publications and helpful links

General Publications

• Kirkpatrick DL, Schmidt WK, Morales R, Cremin J, Seroogy J, Husfeld C, Jenkins T. In vitro and in vivo assessment of the abuse potential of PF614, a novel BIO-MD prodrug of oxycodone. J Opioid Manag. 2017 Jan/Feb;13(1):39-49. doi: 10.5055/jom.2017.0366.
• Kirkpatrick DL, Evans C, Pestano LA, Millard J, Johnston M, Mick E, Schmidt WK. Clinical evaluation of PF614, a novel TAAP prodrug of oxycodone, versus OxyContin in a multi-ascending dose study with a bioequivalence arm in healthy volunteers. Clin Transl Sci. 2024 Mar;17(3):e13765. doi: 10.1111/cts.13765.
• Kirkpatrick DL, Pestano LA, Evans C, Millard J, Levy J, Zann V, Pepper K, Schmidt WK. Formulation development and a Phase 1 clinical study of PF614-MPAR, an oxycodone prodrug with oral opioid overdose protection. J Opioid Manag. 2026 Jan-Feb;22(1):37-A26. doi: 10.5055/jom.0991.

Study record dates

Study Major Dates

• Study Start (Actual): November 24, 2024
• Primary Completion (Estimated): December 22, 2026
• Study Completion (Estimated): April 28, 2027

Study Registration Dates

• First Submitted: July 8, 2024
• First Submitted That Met QC Criteria: July 8, 2024
• First Posted (Actual): July 15, 2024

Study Record Updates

• Last Update Posted (Actual): May 26, 2026
• Last Update Submitted That Met QC Criteria: May 21, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: oxycodone; PF614; nafamostat; MPAR; overdose protection
• Additional Relevant MeSH Terms: Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Inflammatory Agents; Peripheral Nervous System Agents; Protease Inhibitors; Enzyme Inhibitors; Antirheumatic Agents; Central Nervous System Depressants; Sensory System Agents; Analgesics, Non-Narcotic; Analgesics; Analgesics, Opioid; Narcotics; Anti-Inflammatory Agents, Non-Steroidal; Anticoagulants; Serine Proteinase Inhibitors; Complement Inactivating Agents; Trypsin Inhibitors; nafamostat
• Other Study ID Numbers: QSC301193

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No