Oxycodone and Nafamostat for Pharmacokinetics

Overseen By Lynn Kirkpatrick, PhD

Age: 18 - 65

Sex: Any

Trial Phase: Phase 1

Sponsor: Ensysce Biosciences

Must not be taking: Aspirin, NSAIDs, Anticoagulants, others

Disqualifiers: Cardiovascular, Renal, Hepatic, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 2

50 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial studies how the body processes oxycodone in a new formulation called PF614 (an extended-release oxycodone prodrug), both with and without nafamostat. Researchers aim to better understand the effectiveness and safety of these drugs by examining their absorption, distribution, and elimination. The trial includes different groups receiving varying doses and combinations to observe interactions. Ideal participants are healthy men and women who have not smoked or used nicotine products in the past year and have no history of significant allergies or medical conditions. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new formulation.

Do I have to stop taking my current medications for the trial?

Yes, you must stop taking any prescribed or over-the-counter drugs or herbal remedies 14 days before the study, except for up to 4 g per day of acetaminophen, HRT, or hormonal contraception. Exceptions may apply on a case-by-case basis.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that PF614, a modified form of oxycodone, safely releases oxycodone in the body. Studies have demonstrated that PF614 has a safety profile similar to OxyContin, a well-known pain reliever, and participants tolerated PF614 well when taken alone.

The trial also tests PF614 with nafamostat and naltrexone. Although detailed safety information for PF614 with nafamostat is not yet available, PF614 alone has shown positive safety results. This trial is in its early stages, focusing on how the body processes the drug rather than proving its effectiveness. Early-stage trials typically concentrate on safety and determining the right dose. Participants are closely monitored for any side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

PF614 is unique because it is a prodrug of oxycodone, meaning it is designed to become active only after it's processed by the body. This approach could potentially minimize the risk of abuse common with standard oxycodone treatments. Additionally, the use of nafamostat as a trypsin inhibitor adds another layer of control by blocking the activation of PF614, offering a novel mechanism to regulate oxycodone release. Researchers are excited because this combination may offer effective pain relief while reducing the potential for misuse, which is a significant challenge with current opioid therapies.

What evidence suggests that this trial's treatments could be effective?

Research shows that PF614, a new form of oxycodone, may help relieve pain. In this trial, participants will receive PF614 in different treatment arms. Studies have found that a 100 mg dose of PF614 releases oxycodone similarly to 40 mg of OxyContin, a well-known pain medication. This suggests PF614 could effectively treat severe or long-lasting pain. In one arm of this trial, PF614 is combined with nafamostat, a substance that blocks certain enzymes, to control PF614's release, potentially preventing overdoses. In both arms, PF614 is combined with naltrexone, a drug that blocks opioid effects, which may also reduce the risk of misuse while still providing pain relief. Overall, early evidence suggests PF614 could be a safer option compared to traditional oxycodone treatments. ^{1 2 3 6 7}

Who Is on the Research Team?

Jeffrey Levy, MD, PhD

Principal Investigator

Medical Director, Quotient Sciences

Are You a Good Fit for This Trial?

This trial is for individuals who can safely receive oxycodone and PF614, a pain medication. Participants should not have any health conditions that interfere with drug absorption or processing.

Inclusion Criteria

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

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

Exclusion Criteria

I drink more than the recommended weekly alcohol limit.

I haven't taken any experimental drugs in the last 30 days or within their half-life period.

History of any drug or alcohol abuse in the past 2 years

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment Part 1

Single and multiple-dose administration of PF614-MPAR to evaluate pharmacokinetics in naltrexone blocked healthy volunteers

5-14 days

Multiple visits for dosing and monitoring

Treatment Part 2

Assessment of food effect on PF614 and nafamostat at the highest dose

5-14 days

Multiple visits for dosing and monitoring

Treatment Part 3

Multiple dosing (BID for 4.5 days) of optimized PF614-MPAR doses or PF614 alone

4.5 days

Daily visits for dosing and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

2 visits (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Oxycodone
• PF614

Trial Overview The study is testing how the body processes oxycodone when taken alone and together with nafamostat, both as an immediate-release solution and extended-release capsule, to understand their combined effects on pain relief.

How Is the Trial Designed?

Group I: PF614 capsule with naltrexone HCl Experimental Treatment 1 Intervention

PF614 is an oxycodone prodrug. Part 1 doses = 100, 300 and up to 500 mg. Subjects will receive single daily doses at 5-14 days apart. Naltrexone, 50 mg Oral (Day -1, Day 1 and Day 2). All subjects will receive naltrexone block

Group II: PF614 capsule concomitantly with nafamostat and naltrexone HCl Experimental Treatment 2 Interventions

PF614 is an oxycodone prodrug. Part 1 doses = 100, 300 and up to 500 mg. Nafamostat Mesylate is a trypsin inhibitor that blocks PF614 activation. Nafamostat IR solution (0.75 - XX mg); Nafamostat ER beads in capsule formulation (0.25 - YY mg) Naltrexone, 50 mg Oral (Day -1, Day 1 and Day 2). All subjects will receive naltrexone block

Oxycodone is already approved in United States, European Union, Canada for the following indications:

Approved in United States as OxyContin for:

• Moderate to severe pain
• Chronic pain

Approved in European Union as OxyContin for:

• Severe pain
• Cancer pain

Approved in Canada as OxyContin for:

• Moderate to severe pain

Who Is Running the Clinical Trial?

Ensysce Biosciences

Lead Sponsor

Trials

9

Recruited

700+

Quotient Sciences

Industry Sponsor

Trials

52

Recruited

1,600+

Published Research Related to This Trial

PF614, a new prodrug of oxycodone designed for chronic pain relief, demonstrated a favorable safety profile in nonclinical studies, with no significant genotoxicity or metabolic instability observed in rats, dogs, and humans.

In toxicity studies, PF614 was well tolerated at daily doses of 25 mg/kg in rats and 18 mg/kg in dogs over 14 days, supporting its potential for further clinical evaluation as an analgesic with abuse-resistant properties.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nonclinical safety assessment of PF614: A novel TAAP prodrug of oxycodone for chronic pain indication. Joshi, PS., Sanakkayala, N., Kirkpatrick, L., et al.[2020]

Microneedle (MN) technology can enhance the delivery of drugs like naltrexone (NTX) through the skin, but the skin's natural healing process limits the effectiveness of this delivery to about 7 days.

Using a codrug approach that combines NTX with diclofenac (DIC), a cyclooxygenase inhibitor, helps maintain open micropores in the skin for longer, allowing for effective transdermal delivery, although further optimization of the codrug's stability and solubility is needed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development of a codrug approach for sustained drug delivery across microneedle-treated skin. Ghosh, P., Pinninti, RR., Hammell, DC., et al.[2013]

The study optimized codrugs of naltrexone and diclofenac for extended transdermal delivery, demonstrating that polyethylene glycol-linked structures enhance stability and drug flux across microneedle-treated skin.

All tested codrugs bioconverted in the skin, with phenol-linked codrugs showing higher flux for naltrexone, but the polyethylene glycol-linked codrug was identified as the most effective for a 7-day delivery system.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Optimization of naltrexone diclofenac codrugs for sustained drug delivery across microneedle-treated skin. Ghosh, P., Lee, D., Kim, KB., et al.[2021]

Oxycodone, a commonly used opioid for moderate-to-severe pain, has a higher bioavailability and longer half-life compared to oral morphine, which is important for its effective use in various patient populations.

The pharmacokinetics of oxycodone can vary significantly among individuals, especially in special populations like children and those with liver or renal failure, highlighting the need for careful dosing to maximize pain relief while minimizing side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The pharmacokinetics of oxycodone. Lugo, RA., Kern, SE.[2022]

Oxycodone is an effective opioid analgesic for various types of pain, including acute and chronic conditions, but its mechanism of action is complex due to its low binding potential at μ-opioid receptors compared to its strong analgesic effects.

The drug's efficacy may be enhanced by its active metabolites and its ability to cross the blood-brain barrier, with pharmacogenomics playing a significant role in individual responses to oxycodone compared to morphine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Does the pharmacology of oxycodone justify its increasing use as an analgesic? Olkkola, KT., Kontinen, VK., Saari, TI., et al.[2013]

In two phase 1 studies involving subjects aged 18-80, it was found that as renal or hepatic function decreased, the levels of oxycodone in the blood (Cmax and AUC) increased significantly, indicating that patients with impaired kidney or liver function may experience higher exposure to the drug.

The study suggests that lower doses of the abuse-deterrent formulation Remoxy may be safely prescribed to individuals with renal or hepatic impairment, as adverse events were consistent with typical opioid side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The pharmacokinetics of oxycodone and its metabolites following single oral doses of Remoxy®, an abuse-deterrent formulation of extended-release oxycodone, in patients with hepatic or renal impairment. Malhotra, BK., Schoenhard, GL., de Kater, AW., et al.[2015]

The study synthesized various amide prodrugs of ketorolac and found that while these prodrugs showed increased lipophilicity (logP up to 4.28), their skin permeation rates did not significantly improve due to low aqueous solubility.

The prodrugs were only converted back to ketorolac in rat liver homogenate, indicating that while they may be stable in skin, modifications are needed to enhance their effectiveness for transdermal delivery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ketorolac amide prodrugs for transdermal delivery: stability and in vitro rat skin permeation studies. Kim, BY., Doh, HJ., Le, TN., et al.[2014]

The study developed transdermal patches for lornoxicam using a combination of hydrophilic and hydrophobic polymers, which significantly enhanced the drug's bioavailability by 3.1 and 2.7 times compared to oral administration.

Formulations A3 and B3 not only showed the highest cumulative drug release but also effectively controlled inflammation and provided analgesic effects within the first hour of application, indicating their potential as effective pain relief options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development of matrix-type transdermal delivery of lornoxicam: in vitro evaluation and pharmacodynamic and pharmacokinetic studies in albino rats. Baviskar, DT., Parik, VB., Jain, DJ.[2022]

The developed transdermal patch containing teriflunomide (TEF) and lornoxicam (LOX) effectively enhances drug delivery across the skin, with optimal formulations showing improved permeation rates, particularly with the use of specific amine salts.

In vivo studies demonstrated that while the patch can deliver drugs to superficial joint tissues through direct diffusion, deeper tissues like synovial fluid receive the drugs primarily through systemic circulation, indicating a dual mechanism of action for pain relief and inflammation reduction in rheumatoid arthritis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intra-articular drug delivery from an optimized topical patch containing teriflunomide and lornoxicam for rheumatoid arthritis treatment: does the topical patch really enhance a local treatment? Xi, H., Cun, D., Xiang, R., et al.[2021]

PF614, an extended-release prodrug of oxycodone, is designed to be effective when taken orally while significantly reducing the potential for abuse through intravenous or nasal routes, as it remains pharmacologically inactive when administered non-orally.

In laboratory tests, PF614 showed stability against common solvents and household chemicals, and its release of oxycodone was controlled, demonstrating a safer alternative to traditional opioids that can be misused.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In vitro and in vivo assessment of the abuse potential of PF614, a novel BIO-MD™ prodrug of oxycodone. Kirkpatrick, DL., Schmidt, WK., Morales, R., et al.[2018]

Oxycodone, particularly in its controlled-release form Oxycontin, is a potent opioid analgesic that has been linked to numerous cases of toxicity, with 36 out of 67 detected cases involving this formulation, highlighting its significant presence in postmortem analyses.

The study introduced the concept of 'ghost pills,' which are intact but drug-free tablets that can complicate the identification of oxycodone in toxicology cases, emphasizing the need for careful analysis in postmortem investigations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oxycontin: the concept of a "ghost pill" and the postmortem tissue distribution of oxycodone in 36 cases. Anderson, DT., Fritz, KL., Muto, JJ.[2019]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10955611/

Clinical evaluation of PF614, a novel TAAP prodrug of ... This study confirms findings from our single‐ascending dose study, showing that PF614 100 mg releases oxycodone with a PK profile comparable to 40 mg OxyContin.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT02454712

Study of PF614 Compared to OxyContin® in Healthy ... This Single Ascending Dose (SAD) study is designed to assess the safety and pharmacokinetics (PK) of PF614 in comparison to standard doses of OxyContin.

3. ensysce.com ensysce.com/our-strategy/

Our Strategy PF614 is our lead abuse-protectant TAAP™ product, designed to treat severe and/or chronic pain. What is PF614? Proven Pain Relief PF614 is an oxycodone-based ...

4. ir.ensysce.com ir.ensysce.com/news/press-releases/detail/180/ensysce-biosciences-announces-positive-interim-data-for

Ensysce Biosciences Announces Positive Interim Data for ... The PF614-MPAR-102 study showed that a 100 mg dosage form of PF614-MPAR provides overdose protection when a greater-than-prescribed dose is consumed at one ...

5. sec.gov sec.gov/Archives/edgar/data/1716947/000149315221016422/ex99-1.htm

Untitled The Phase 1 study trial, “A Single Dose Study to Evaluate the Pharmacokinetics of oxycodone and PF614, when PF614 Solution is Co-Administered ...

6. adisinsight.springer.com adisinsight.springer.com/drugs/800034449

PF 614 - AdisInsight - Springer An orally available, extended release oxycodone prodrug, designated as PF 614, is being developed by Ensysce Biosciences (previously ...

7. ir.ensysce.com ir.ensysce.com/news/press-releases/detail/24/ensysce-biosciences-inc-initiates-phase-1-clinical-trial

Ensysce Biosciences Inc. Initiates Phase 1 Clinical Trial to ... PF614 is a trypsin-activated BIO-MD™ extended-release oxycodone prodrug with inherent abuse deterrence since it is pharmacologically and ...