Pharmacokinetics of Oxycodone and PF614 Co-Administered With Nafamostat

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Pharmacokinetics

Intervention / Treatment
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* Drug: PF614 solution
* Drug: Naltrexone Hydrochloride
* Drug: Nafamostat Mesylate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy males or non-pregnant, non-lactating healthy females Ages 18 to 55 years, inclusive, at time of signing informed consent 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 Minimum weight of 50kg at screening Must be willing and able to comply with all study requirements Must be able to understand a written informed consent, which must be obtained prior to initiation of study procedures Must agree to use an adequate method of contraception Exclusion Criteria: 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 Subjects who are, or are immediate family members of, a study site or sponsor employee Evidence of current SARS-CoV-2 infection Subjects who have previously been administered IMP in this study History of any drug or alcohol abuse in the past 2 years Regular alcohol consumption in males >21 units per week and females >14 units per week A confirmed positive alcohol urine test at screening or admission Current smokers and those who have smoked within the last 12 months. A confirmed positive urine cotinine test at screening or first admission Current users of e-cigarettes and nicotine replacement products and those who have used these products within the last 12 months Females of childbearing potential must have a negative serum pregnancy test at screening and negative urine pregnancy test at each admission Females who are expected to have their menses during the dosing period Male subjects with pregnant or lactating partners Have poor venous access that limits phlebotomy Clinically significant abnormal chemistry, hematology, coagulation, or urinalysis as judged by the investigator Positive drugs of abuse test result Positive hepatis B surface antigen, hepatitis C virus antibody or human immunodeficiency virus antibody results History of clinically significant cardiovascular, renal, hepatic, chronic respiratory or GI disease, neurological or psychiatric disorder, as judged by the investigator Subjects with a history of cholecystectomy or gall stones Subjects with a history of seizures Serious adverse reaction or serious hypersensitivity to any drug or the formulation excipients Presence or history of clinically significant allergy requiring treatment, as judged by the investigator. Hay fever is allowed unless it is active Donation of blood within 2 months or donation of plasma within 7 days prior to first dose of study medication -

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PF614 solution<br>Cohort 1 and 6 will consist of 6 evaluable subjects. Subjects will receive the PF614 solution alone and concomitantly with nafamostat as an IR solution and/or ER prototype capsules. Subjects will receive naltrexone prior to and following each regimen. Cohorts 2 to 5 and Cohorts 7 to 10 will consist of 5 evaluable subjects in each cohort. Only 2 sentinel subjects will be dosed (one male and one female) in Period 2, Cohort 1. After review of the PK data and safety data, the safety advisory committee will decide the nafamostat dose level. After Cohorts 3 and 8 only: The fed vs fasted regimen will be determined for Cohorts 4 and 9. | Drug: PF614 solution<br>* PF614 solution is an oxycodone prodrug<br>* Other names: Oxycodone prodrug;Drug: Naltrexone Hydrochloride<br>* 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.<br>* Other names: ReVia;|
| Experimental: PF614 solution concomitantly with nafamostat<br>Cohort 1 and 6 will consist of 6 evaluable subjects. Subjects will receive the PF614 solution alone and concomitantly with nafamostat as an IR solution and/or ER prototype capsules. Subjects will receive naltrexone prior to and following each regimen. Cohorts 2 to 5 and Cohorts 7 to 10 will consist of 5 evaluable subjects in each cohort. Only 2 sentinel subjects will be dosed (one male and one female) in Period 2, Cohort 1. After review of the PK data and safety data, the safety advisory committee will decide the nafamostat dose level. After Cohorts 3 and 8 only: The fed vs fasted regimen will be determined for Cohorts 4 and 9. | Drug: PF614 solution<br>* PF614 solution is an oxycodone prodrug<br>* Other names: Oxycodone prodrug;Drug: Naltrexone Hydrochloride<br>* 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.<br>* Other names: ReVia;Drug: Nafamostat Mesylate<br>* 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.<br>* Other names: Futhan;|

What is the study measuring?
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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 solution alone and with nafamostat | pre-dose, 0.5,1,1.5,2,3,4,6,8,12,16,24,36,48 hours | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| Incidence of Treatment-Emergent Adverse Effects [Safety and Tolerability] | Adverse events (AEs), Significant Adverse Events (SAEs), AEs leading to discontinuation | 30 days |