Evaluation of Oral PF614 Relative to OxyContin

Study Overview
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Brief Summary
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This is a single-center study incorporating 2 parts: A Multiple Ascending Dose Study (Part A) and a comparative Bioavailability/Bioequivalence and Food Effect study (Part B). Both parts of the study will be conducted in healthy adult subjects.

Detailed Description
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This study is intended to evaluate the pharmacokinetics of OxyContin (oxycodone ER) and PF614, as well as PF614 fragments, following administration of multiple ascending doses of PF614, and to compare to steady-state pharmacokinetics to those of OxyContin. (Part A) In addition, oral bioavailability of oxycodone derived from single doses of PF614 of the to-be-marketed capsule formulation will be compared to that of the reference drug, OxyContin, in the fasted and fed condition. A pivotal food effect assessment will be incorporated into the study to determine the impact of a high fat meal on the bioavailability of oxycodone, following oral single-dose administration of PF614 (Part B).

Official Title
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A Phase 1b, Randomized 2-Part Single-Center Study to Evaluate the PK and Safety of Multiple Ascending Oral Doses of PF614 and the Food Effect and BA/BE of Single Oral Doses of PF614 Relative to OxyContin in Healthy Adult Subjects

Conditions
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Healthy Volunteers

Intervention / Treatment
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* Drug: PF614
* Drug: Naltrexone Hydrochloride
* Drug: OxyContin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males or females, ages 18-50 years in good general health, BMI between 18 and 32 kg/m (inclusive) Subjects must have a negative screen for drugs of abuse, nicotine, alcohol, Hepatitis B, Hepatitis C, and HIV. Female subjects of child bearing potential must have a negative serum pregnancy test at randomization Females must be of non-child bearing potential (e.g. postmenopausal) or of childbearing potential and agree to use a highly effective form of contraception from the time of screening to two weeks after last dose of study medication. Subjects must have normal findings in a physical examination and 12 lead ECG and normal Vital Signs Clinical laboratory values must be Within Normal limits as defined by the clinical laboratory Subjects must be able to provide coherent written informed consent Subjects must be willing and able to follow study instructions and be likely to complete all study requirements. Exclusion Criteria: History of allergy or sensitivity to oxycodone History of loud snoring or sleep apnea History of medical problems encountered with opioid therapy Urinary cotinine levels indicative of smoking or history of smoking or regular tobacco use with 2 months prior to screening History of alcoholism or drug abuse Use of prescription medications within 14 days of study drug administration with exception of contraceptives used by female subjects Use of any opioid within 30 days prior to screening History of allergy or sensitivity to naltrexone History of allergy or sensitivity to naloxone Donation of blood within 30 days prior to screening Donation of plasma within 30 days prior to screening Acute illness at admission of clinical study unit History of GI disturbance requiring use of antacid twice weekly or more Females who are breastfeeding Anticipated need for surgery or hospitalization during the study Enrollment in an investigational drug study within 30 days prior to screening Any condition that in the Investigator's opinion puts the subject at significant risk, could confound the study results, or may interfere significantly with the subject's participation in the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 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: Crossover Assignment
Interventional Model Description: Part A will utilize a randomized, open label, multiple-ascending dose design with up to 3 separate dose groups of 8 subjects per group. Part B will utilize an open-label, single-dose, randomized, 4-way crossover design with 13 subjects in each treatment sequence.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PF614<br>Part A will utilize a randomized, open-label, multiple-ascending dose design with up to 3 separate dose groups of 8 subjects. Within each dose group, subjects will be randomized to receive repeated BID doses, planned to be 12 hours apart over a 5 day period, for a total of 9 doses. Dose escalation to Dose Groups 2 and 3 will follow a review of pharmacokinetic, safety and tolerability data up to Day 10 of the preceding group. The doses or dosing regimen for Dose groups 2 and 3 may be modified based on a review of the data. | Drug: PF614<br>* PF614 is an oxycodone prodrug<br>* Other names: oxycodone prodrug;Drug: Naltrexone Hydrochloride<br>* Naltrexone HCl tablets, 50 mg, will be used to block the opioid effects in healthy volunteers<br>* Other names: ReVia;|
| Active Comparator: Part B Compare Bioavailability and Bioequivalence<br>Part B will utilize an open-label, single-dose, randomized, 4-way crossover design. Following confirmation of eligibility, subjects will be randomized to receive each of the single oral doses of study drugs (one at each treatment period). PF614 100 mg administered under fasted conditions; PF614 100 mg administered under fed conditions; OxyContin 40 mg administered under fasted conditions; OxyContin 40 mg administered under fed conditions | Drug: PF614<br>* PF614 is an oxycodone prodrug<br>* Other names: oxycodone prodrug;Drug: Naltrexone Hydrochloride<br>* Naltrexone HCl tablets, 50 mg, will be used to block the opioid effects in healthy volunteers<br>* Other names: ReVia;Drug: OxyContin<br>* Bioequivalence single-dose comparison to OxyContin<br>* Other names: OxyContin 40 mg Extended-Release Tablet;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] | Adverse Events, Significant Adverse Events, Adverse Events leading to discontinuation | 30 days | 
| Pharmacokinetics AUC [Area Under the Curve] | Area under the concentration-time curve from the time of dosing to the start of the next dosing interval using PF614 concentrations and oxycodone concentrations in plasma. | Full PK sampling time points will be 0, 30 minutes; 1, 2, 3, 4, 6, 8, and 12 hours | 
| Pharmacokinetics Cmax [Maximum Plasma Concentration] | Maximum (peak) plasma concentration first dose | PK sampling time points will be 0, 30 minutes; 1, 2, 3, 4, 6, 8, and 12 hours | 
| Pharmacokinetics Tlag [Time to first measurable plasma concentration] | Time prior to the time corresponding to the first measurable (non-zero) concentration | PK sampling time points will be 0, 30 minutes; 1, 2, 3, 4, 6, 8, and 12 hours | 
| Pharmacokinetics Tmax [Time to maximum plasma concentration] | Time to maximum plasma concentration on Day 1 (first dose) | PK sampling time points 30 minutes; 1, 2, 3, 4, 6, 8, and 12 hours | 
| Pharmacokinetics AUC, Steady State | Steady-state (Day 5) area under the concentration-time curve from the time of dosing extrapolated to time infinity | PK sampling time points 0, 30 minutes; 1, 2, 3, 4, 6, 8, and 12 hours | 
| Pharmacokinetics CL/F [Clearance] | Apparent total systemic clearance | PK sampling time points 0, 30 minutes; 1, 2, 3, 4, 6, 8, and 12 hours | 
| Pharmacokinetics Cmax, Steady State | Maximum (peak) plasma concentration at steady-state on Day 5 | PK sampling time points 0, 30 minutes; 1, 2, 3, 4, 6, 8, and 12 hours | 
| Pharmacokinetics Tmax, Steady State | Time to maximum plasma concentration on Day 5 | PK sampling time points 0, 30 minutes; 1, 2, 3, 4, 6, 8, and 12 hours | 
| Pharmacokinetics t1/2 [Half-life] | Terminal elimination half-life | PK sampling time points 0, 30 minutes; 1, 2, 3, 4, 6, 8, and 12 hours | 
| Pharmacokinetics Vz/F [Volume of Distribution] | Apparent volume of distribution during the terminal-elimination phase | PK sampling time points 0, 30 minutes; 1, 2, 3, 4, 6, 8, and 12 hours | 
| Pharmacokinetics elimination rate | Terminal elimination rate/constant | PK sampling time points 0, 30 minutes; 1, 2, 3, 4, 6, 8, and 12 hours | 
| Pharmacokinetics Ctrough [Minimum Plasma Concentration before next dose] | Concentrations prior to dosing | Prior to dosing on Days 2, 3, and 4 | 
| Pharmacokinetics Part B AUC | Area under the concentration-time curve from the time of dosing extrapolated to time infinity in fed vs fasted state | PK sampling time points 0, 30 minutes; 1, 2, 3, 4, 6, 8, and 12 hours | 
| Pharmacokinetics Part B AUC 0-t | Area under the concentration-time curve from the time of dosing to the last measurable concentration in fed vs fasted state | PK sampling time points 0, 30 minutes; 1, 2, 3, 4, 6, 8, and 12 hours | 
| Pharmacokinetics Part B Cmax | Maximum (peak) plasma concentration in fed vs fasted state | PK sampling time points 0, 30 minutes; 1, 2, 3, 4, 6, 8, and 12 hours | 
| Bioavailability and Bioequivalence | Bioavailability and Bioequivalence of single oral doses of PF614 prodrug and oxycodone derived from from PF614 vs. oxycodone derived from OxyContin in healthy adult subjects (Part B) | PK sampling time points 0, 30 minutes; 1, 2, 3, 4, 6, 8, and 12 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics Part B CL/F | Apparent total systemic clearance | PK sampling time points 0, 30 minutes; 1, 2, 3, 4, 6, 8, and 12 hours | 
| Pharmacokinetics Part B pAUC | Partial area under the concentration-time curve from the time of dosing to 12 hours post dose | PK sampling time points 0, 30 minutes; 1, 2, 3, 4, 6, 8, and 12 hours | 
| Pharmacokinetics Part B Tlag | Time prior to the time corresponding to the first measurable dose (non-zero) concentration | PK sampling time points 0, 30 minutes; 1, 2, 3, 4, 6, 8, and 12 hours | 
| Pharmacokinetics Part B Tmax | Time to maximum plasma concentration on Day 1 (first dose) | PK sampling time points 0, 30 minutes; 1, 2, 3, 4, 6, 8, and 12 hours | 
| Pharmacokinetics Part B t1/2 | Terminal elimination half life | PK sampling time points 0, 30 minutes; 1, 2, 3, 4, 6, 8, and 12 hours | 
| Pharmacokinetics Part B Vz/F | Apparent volume of distribution during the terminal elimination phase | PK sampling time points 0, 30 minutes; 1, 2, 3, 4, 6, 8, and 12 hours | 
| Pharmacokinetics Part B Terminal elimination rate | Terminal elimination rate constant | PK sampling time points 0, 30 minutes; 1, 2, 3, 4, 6, 8, and 12 hours | 
| Plasma Concentration of inactive metabolic fragment #1 | Evaluate plasma concentrations of PFR06082 (Part A only) | PK sampling time points 0, 30 minutes; 1, 2, 3, 4, 6, 8, and 12 hours | 
| Plasma Concentration of inactive metabolic fragment #2 | Evaluate plasma concentrations of PFR06110 (Part A only) | PK sampling time points 0, 30 minutes; 1, 2, 3, 4, 6, 8, and 12 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Prodrug, PF614, OxyContin, oral