Pharmacokinetics
Conditions
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.
Interventions
DRUGPF614 solution
PF614 solution is an oxycodone prodrug
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.
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.
Sponsors
Quotient Sciences
National Institute on Drug Abuse (NIDA)
Ensysce Biosciences
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
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 -
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetic T1/2 [Half-life] | pre-dose, 0.5,1,1.5,2,3,4,6,8,12,16,24,36,48 hours | Terminal elimination half-life concentrations of oxycodone following administration of PF614 solution alone and with nafamostat |
| Pharmacokinetic Cmax [Maximum Plasma Concentration] | pre-dose, 0.5,1,1.5,2,3,4,6,8,12,16,24,36,48 hours | Maximum (peak) observed concentration of oxycodone following administration of PF614 solution alone and with nafamostat |
| Pharmacokinetic C24 [Plasma concentration at 24 hours] | 24 hours | Concentration of oxycodone at 24h post-dose following administration of PF614 solution alone and with nafamostat |
| Pharmacokinetic AUC [Area Under the Curve] | pre-dose, 0.5,1,1.5,2,3,4,6,8,12,16,24,36,48 hours | 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 |
| Pharmacokinetic AUC(0-last) | pre-dose, 0.5,1,1.5,2,3,4,6,8,12,16,24,36,48 hours | Area under the concentration-time curve from time 0 extrapolated to time-infinity of oxycodone following administration of PF614 solution alone and with nafamostat |
| Pharmacokinetic Tmax [Time to Maximum Plasma Concentration] | pre-dose, 0.5,1,1.5,2,3,4,6,8,12,16,24,36,48 hours | Time to maximum observed concentrations of oxycodone following administration of PF614 solution alone and with nafamostat |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Bioavailability AUC(0-last) | pre-dose, 0.5,1,1.5,2,3,4,6,8,12,16,24,36,48 hours | 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 |
| Bioavailability AUC(0-inf) | pre-dose, 0.5,1,1.5,2,3,4,6,8,12,16,24,36,48 hours | 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 |
| Incidence of Treatment-Emergent Adverse Effects [Safety and Tolerability] | 30 days | Adverse events (AEs), Significant Adverse Events (SAEs), AEs leading to discontinuation |
| Bioavailability Cmax | pre-dose, 0.5,1,1.5,2,3,4,6,8,12,16,24,36,48 hours | 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 |
Countries
United States
Outcome results
None listed