Pharmacokinetics of Oxycodone and PF614 Co-Administered With Nafamostat

Pharmacokinetics Clinical Trial

— 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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT05090280
• Other study ID #: QSC203698
• Secondary ID: 5UH3DA047682-04
• Status: Completed
• Phase: Phase 1
• Start date: December 1, 2021
• Est. completion date: April 26, 2023

Study information

• Verified date: January 2024
• Source: Ensysce Biosciences
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 111
• Est. completion date: April 26, 2023
• Est. primary completion date: April 26, 2023
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 55 Years

Eligibility

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 -

Related Conditions & MeSH terms

• Pharmacokinetics

Intervention

Drug:
• PF614 solution
PF614 solution is an oxycodone prodrug
• Naltrexone Hydrochloride
Naltrexone 50 mg has been selected to be administered on Day -1 (single dose), Day 1 (BID), and Day 2 (single-dose) to reduce opioid-related adverse effects.
• Nafamostat Mesylate
Maximum dose of 10 mg nafamostat co-administered with PF614 solution. Nafamostat will be dosed as an immediate-release (IR) solution or as prototype extended-release (ER) capsules.

Locations

Country	Name	City	State
United States	Quotient Sciences	Miami	Florida

Sponsors (3)

Lead Sponsor	Collaborator
Ensysce Biosciences	National Institute on Drug Abuse (NIDA), Quotient Sciences

Country where clinical trial is conducted

United States, 

References & Publications (1)

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Pharmacokinetic Tmax [Time to Maximum Plasma Concentration]	Time to maximum observed concentrations of oxycodone following administration of PF614 solution alone and with nafamostat	pre-dose, 0.5,1,1.5,2,3,4,6,8,12,16,24,36,48 hours
Primary	Pharmacokinetic Cmax [Maximum Plasma Concentration]	Maximum (peak) observed concentration of oxycodone following administration of PF614 solution alone and with nafamostat	pre-dose, 0.5,1,1.5,2,3,4,6,8,12,16,24,36,48 hours
Primary	Pharmacokinetic C24 [Plasma concentration at 24 hours]	Concentration of oxycodone at 24h post-dose following administration of PF614 solution alone and with nafamostat	24 hours
Primary	Pharmacokinetic AUC [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 solution alone and with nafamostat	pre-dose, 0.5,1,1.5,2,3,4,6,8,12,16,24,36,48 hours
Primary	Pharmacokinetic AUC(0-last)	Area under the concentration-time curve from time 0 extrapolated to time-infinity of oxycodone following administration of PF614 solution alone and with nafamostat	pre-dose, 0.5,1,1.5,2,3,4,6,8,12,16,24,36,48 hours
Primary	Pharmacokinetic T1/2 [Half-life]	Terminal elimination half-life concentrations of oxycodone following administration of PF614 solution alone and with nafamostat	pre-dose, 0.5,1,1.5,2,3,4,6,8,12,16,24,36,48 hours
Secondary	Bioavailability Cmax	Comparative evaluation of the bioavailability of oxycodone and PF614 based on Cmax when PF614 solution is co-administered with nafamostat in the fed state compared to the fasted state	pre-dose, 0.5,1,1.5,2,3,4,6,8,12,16,24,36,48 hours
Secondary	Bioavailability AUC(0-last)	Comparative evaluation of the bioavailability of oxycodone and PF614 based on AUC(0-last) when PF614 solution is co-administered with nafamostat in the fed state compared to the fasted state	pre-dose, 0.5,1,1.5,2,3,4,6,8,12,16,24,36,48 hours
Secondary	Bioavailability AUC(0-inf)	Comparative evaluation of the bioavailability of oxycodone and PF614 based on AUC(0-inf) when PF614 solution is co-administered with nafamostat in the fed state compared to the fasted state	pre-dose, 0.5,1,1.5,2,3,4,6,8,12,16,24,36,48 hours
Secondary	Incidence of Treatment-Emergent Adverse Effects [Safety and Tolerability]	Adverse events (AEs), Significant Adverse Events (SAEs), AEs leading to discontinuation	30 days