Clinical trial NCT05090280: Pharmacokinetics of Oxycodone and PF614 Co-Administered with Nafamostat (PF614-MPAR-101)
Official title: A Single Dose Study to Evaluate the Pharmacokinetics of Oxycodone and PF614 When PF614 Solution is Co-Administered with Nafamostat, As an Immediate Release Solution And/or Extended Release (ER) Capsule Formulations in Healthy Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Pharmacokinetics
Lead sponsor: Ensysce Biosciences
Sponsor class: INDUSTRY
Collaborators: name: Quotient Sciences
name: National Institute on Drug Abuse (NIDA)
First posted: 2021-10-22
Enrollment: 111
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: A single dose study to assess the pharmacokinetics (PK) of oxycodone, when PF614 is solution is administered alone and with nafamostat as an immediate-release (IR) solution and/or extended-release (ER) capsule prototypes.

Detailed description: This is a single center, randomized, open-label formulation development study for the nafamostat formulation (IR solution and/or ER prototype capsules) and will have the option to assess the effect of food on a selected formulation of healthy subjects. Parts 1 and 2 are planned to enroll a total of 64 healthy subjects, with roughly equal number of males and an even number of females with roughly equal number of males and females in each cohort if possible. Subjects will be randomized to regimen stratified by gender prior to first dose. Cohort 1 and Cohort 6 will consist of 8 subjects who will receive dosing on two occasions in a 2-period sequential design. Cohorts 2 to 5 and Cohorts 7 to 10 will consist of 6 subjects in each cohort and they will receive dosing on a single occasion only. Cohorts 2 to 5 and Cohorts 7 to 10 can be dosed in parallel after Cohort 1 dosing.

Part 1 (with naltrexone blockade) and Part 2 (without naltrexone), Cohorts 1-10, were later expanded to include 6-13 subjects each.

In Cohort 1 and Cohort 6, subjects will receive the PF614 solution alone and concomitantly with nafamostat. In addition, prior to and following each regimen in all periods, subjects will receive blocking doses of the opiate antagonist naltrexone to reduce the opioid-related side effects.

Interim reviews of the safety and PK data for oxycodone and PF614 to 48h post-dose will take place after Cohorts 1 and 6, Cohorts 2 and 7, Cohorts 3 and 8 and Cohorts 4 and 9 to decide upon the following: nafamostat formulation to dose in the subsequent period; After Cohorts 3 and 8 only: The prandial status (fed vs fasted) for Cohort 4 and Cohort 9.

Extended-release prototype capsule formulations will be selected from a 2-dimensional design space describing formulation variables for release rate and dose; however the maximum nafamostat dose to be administered with be 10 mg.

Part 3 (N=12 subjects) was added as a 7-period open-label cross-over study to assess the selected combination of nafamostat IR solution and/or ER prototype capsule(s) identified from Part 2 who were administered with PF614 solution at increasing dose levels to simulate overdose. All subjects in Part 3 received naltrexone blockade.

Eligibility criteria: Inclusion Criteria:

1. Healthy males or non-pregnant, non-lactating healthy females
2. Ages 18 to 55 years, inclusive, at time of signing informed consent
3. Body mass index of 18.0 to 32.0 kg/m2 as measured at screening or, if outside the range, considered not clinically significant by the investigator
4. Minimum weight of 50kg at screening
5. Must be willing and able to comply with all study requirements
6. Must be able to understand a written informed consent, which must be obtained prior to initiation of study procedures
7. Must agree to use an adequate method of contraception

Exclusion Criteria:

1. Subjects who have received any Investigational Medical Product (IMP) in a clinical research study within 5 half-lives or within 30 days prior to first dose
2. Subjects who are, or are immediate family members of, a study site or sponsor employee
3. Evidence of current SARS-CoV-2 infection
4. Subjects who have previously been administered IMP in this study
5. History of any drug or alcohol abuse in the past 2 years
6. Regular alcohol consumption in males \>21 units per week and females \>14 units per week
7. A confirmed positive alcohol urine test at screening or admission
8. Current smokers and those who have smoked within the last 12 months. A confirmed positive urine cotinine test at screening or first admission
9. Current users of e-cigarettes and nicotine replacement products and those who have used these products within the last 12 months
10. Females of childbearing potential must have a negative serum pregnancy test at screening and negative urine pregnancy test at each admission
11. Females who are expected to have their menses during the dosing period
12. Male subjects with pregnant or lactating partners
13. Have poor venous access that limits phlebotomy
14. Clinically significant abnormal chemistry, hematology, coagulation, or urinalysis as judged by the investigator
15. Positive drugs of abuse test result
16. Positive hepatis B surface antigen, hepatitis C virus antibody or human immunodeficiency virus antibody results
17. History of clinically significant cardiovascular, renal, hepatic, chronic respiratory or GI disease, neurological or psychiatric disorder, as judged by the investigator
18. Subjects with a history of cholecystectomy or gall stones
19. Subjects with a history of seizures
20. Serious adverse reaction or serious hypersensitivity to any drug or the formulation excipients
21. Presence or history of clinically significant allergy requiring treatment, as judged by the investigator. Hay fever is allowed unless it is active
22. Donation of blood within 2 months or donation of plasma within 7 days prior to first dose of study medication -

Primary outcomes:
measure: Pharmacokinetic Tmax [Time to Maximum Plasma Concentration]
timeFrame: pre-dose, 0.5,1,1.5,2,3,4,6,8,12,16,24,36,48 hours
measure: Pharmacokinetic Cmax [Maximum Plasma Concentration]
timeFrame: pre-dose, 0.5,1,1.5,2,3,4,6,8,12,16,24,36,48 hours
measure: Pharmacokinetic C24 [Plasma concentration at 24 hours]
timeFrame: 24 hours
measure: Pharmacokinetic AUC [Area Under the Curve]
timeFrame: pre-dose, 0.5,1,1.5,2,3,4,6,8,12,16,24,36,48 hours
measure: Pharmacokinetic AUC(0-last)
timeFrame: pre-dose, 0.5,1,1.5,2,3,4,6,8,12,16,24,36,48 hours
measure: Pharmacokinetic T1/2 [Half-life]
timeFrame: pre-dose, 0.5,1,1.5,2,3,4,6,8,12,16,24,36,48 hours
Secondary outcomes:
measure: Bioavailability Cmax
timeFrame: pre-dose, 0.5,1,1.5,2,3,4,6,8,12,16,24,36,48 hours
measure: Bioavailability AUC(0-last)
timeFrame: pre-dose, 0.5,1,1.5,2,3,4,6,8,12,16,24,36,48 hours
measure: Bioavailability AUC(0-inf)
timeFrame: pre-dose, 0.5,1,1.5,2,3,4,6,8,12,16,24,36,48 hours
measure: Incidence of Treatment-Emergent Adverse Effects [Safety and Tolerability]
timeFrame: 30 days
Other outcomes:
Locations:
city: Miami
country: United States
facility: Quotient Sciences
state: Florida
Study officials:
affiliation: Medical Director, Quotient Sciences
name: Jeffrey Levy, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.