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

Trial Summary

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.

What data supports the idea that Oxycodone and Nafamostat for Pharmacokinetics is an effective drug?

The available research shows that PF614, a prodrug of oxycodone, is designed to be effective for pain relief while reducing the risk of abuse. Studies indicate that PF614 is well-tolerated in animals, with a favorable safety profile, supporting its potential use in humans. Additionally, PF614 is designed to release oxycodone effectively when taken orally, but it resists being misused through other methods like injection or snorting. This makes it a safer option compared to traditional oxycodone formulations. Furthermore, oxycodone itself is known to be effective for moderate-to-severe pain and has a higher bioavailability compared to morphine, meaning more of the drug is available to the body when taken. This supports its effectiveness as a pain reliever. ^{1 2 3 4 5}

What safety data exists for the treatment involving Oxycodone and Nafamostat?

The provided research does not contain any safety data related to the treatment involving Oxycodone and Nafamostat or its various formulations and brand names. The studies focus on different drugs and delivery systems, such as teriflunomide, lornoxicam, naltrexone, diclofenac, and ketorolac, none of which are related to Oxycodone or Nafamostat. ^{6 7 8 9 10}

Is the drug PF614 a promising treatment?

Yes, PF614 is a promising drug because it is designed to release oxycodone slowly, making it effective for long-term pain relief. It also has features that make it less likely to be abused, which is important for safety. ^{1 2 3 4 11}

What is the purpose of this trial?

A single and multiple-dose dose study to assess the pharmacokinetics (PK) of oxycodone, when PF614 is administered alone and with nafamostat as an immediate-release (IR) solution and/or extended-release(ER) capsule prototypes.

Research Team

Jeffrey Levy, MD, PhD

Principal Investigator

Medical Director, Quotient Sciences

Eligibility Criteria

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

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)

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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 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]

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]

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 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 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]

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 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]

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, 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]

References

1. Netherlands pubmed.ncbi.nlm.nih.gov

Nonclinical safety assessment of PF614: A novel TAAP prodrug of oxycodone for chronic pain indication. [2020]

2. United States pubmed.ncbi.nlm.nih.gov

In vitro and in vivo assessment of the abuse potential of PF614, a novel BIO-MD™ prodrug of oxycodone. [2018]

3. England pubmed.ncbi.nlm.nih.gov

Does the pharmacology of oxycodone justify its increasing use as an analgesic? [2013]

4. England pubmed.ncbi.nlm.nih.gov

The pharmacokinetics of oxycodone. [2022]

5. United States 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. [2015]

6. United States pubmed.ncbi.nlm.nih.gov

Development of matrix-type transdermal delivery of lornoxicam: in vitro evaluation and pharmacodynamic and pharmacokinetic studies in albino rats. [2022]

7. Netherlands pubmed.ncbi.nlm.nih.gov

Ketorolac amide prodrugs for transdermal delivery: stability and in vitro rat skin permeation studies. [2014]

8. United States pubmed.ncbi.nlm.nih.gov

Development of a codrug approach for sustained drug delivery across microneedle-treated skin. [2013]

9. Netherlands 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? [2021]

10. United States pubmed.ncbi.nlm.nih.gov

Optimization of naltrexone diclofenac codrugs for sustained drug delivery across microneedle-treated skin. [2021]

11. England pubmed.ncbi.nlm.nih.gov

Oxycontin: the concept of a "ghost pill" and the postmortem tissue distribution of oxycodone in 36 cases. [2019]