A Phase 1, Single-Center, Dose-Ranging, Multi-Treatment Study to Determine the Safety and Pharmacokinetics of Single Oral Dose Combinations of PF329 and Nafamostat Mesilate in Healthy Subjects

INTERVENTION: This study is designed to assess the effects of varying doses of nafamostat mesilate on the pharmacokinetics ("PK") of PF329. PF329 is a prodrug of the currently used opioid hydromorphone. An understanding of the dose‐response relationship of PF329 and nafamostat combinations is the key first step in demonstrating the viability of the MPAR concept in humans (MPAR = Multi‐Pill Abuse‐Resistance, or overdose protection). Data from this study will inform later assessments to confirm that there is a combination of the agents that will have a minimal effect on the conversion of PF329 to hydromorphone when administered as prescribed, but will substantially reduce that conversion when multiple pills are taken in an overdose or abuse situation. Subjects will receive PF329 alone and in combination with nafamostat at doses sufficient to characterize the dose response curve of the impact of nafamostat on the pharmacokinetics of a dose of PF329. Both PF329 and nafamostat will be given as oral solutions during the study. During each treatment with PF329, subjects will receive naltrexone to block the opioid effects. The study is a 4 to 6 treatment open‐label, single‐dose, crossover in up to 14 subjects to determine the dose‐response curve of nafamostat co‐administered with PF329 and the effects on the "PK" of PF329. The following treatments will be administered with a washout period of at least 7 days between treatments. Safety and "PK" data will be reviewed between treatments (for treatments 1(a) and 1(b) the review will be conducted after the complete crossover) to determine nafamostat doses for subsequent treatments. 1. Baseline PK and maximal effect dose of nafamostat: All subjects will receive treatment 1(a) and treatment 1(b) in random order, followed by treatment 1(c) if indicated: 1(a): 4 mg PF329 to determine baseline "PK" of hydromorphone 1(b): 4 mg PF329 co‐administered with 10 mg nafamostat to achieve a reduction of at least 50% (maximal effect) in the AUC (AUC = Area under the Curve, or amount) of hydromorphone produced from PF329 as compared to baseline. 1(c): If the maximal effect is not achieved in Treatment 1(b) with 10 mg nafamostat, an additional treatment will be administered with 4 mg PF329 and 20 mg of nafamostat. 2. Minimal effect dose of nafamostat (dose that results in hydromorphone AUC that is > 80% of baseline): 2(a): 4 mg PF329 co‐administered with 1/10th the nafamostat dose shown to have maximal effect on hydromorphone AUC in Treatment 1. 2(b): If the minimal effect is not observed at the 1/10th dose the nafamostat dose will be reduced by 10‐fold and the treatment will be repeated. 3. Intermediate effect dose of nafamostat: 4 mg PF329 co‐administered with a dose of nafamostat that is midway (in the log domain) between the maximal and minimal effect doses determined in 1 and 2 above. 3(a): 4 mg PF329 + 3X the nafamostat dose from treatment 2 that produced no / minimal effect on the "PK" of a 4 mg dose of PF329. 3(b): If the effect is not intermediate, then the dose of nafamostat will be adjusted up or down 1.8 fold CONDITION: The compound PF329 is intended for eventual use in patients for the treatment of pain. This current study is being conducted in healthy volunteers to learn about the way this drug behaves in the body when it is given in combination with nafamostat. The combination of PF329 and nafamostat may provide safeguards against either intentional overdose (abuse) or unintentional overdose (misuse or error). This study will provide the information needed to determine the feasibility and utility of this combination for the intended use. PRIMARY OUTCOME: PHARMACOKINETICS, assessed by measurement of drug in plasma or blood samples. SAFETY, assessed by measurement of vital signs and assessment of reported adverse events. ; The risks associated with PF329 include low blood pressure, slow breathing and lower levels of oxygen in the blood. ; In general, nafamostat mesilate is well tolerated and the most significant adverse reactions tend to be allergic reactions with the IV product. Exacerbation of bleeding may occur with nafamostat mesilate. This risk will be monitored via blood clotting tests. ; The risks associated with naltrexone include difficulty sleeping, anxiety, nervousness, abdominal pains/cramps, nausea and/or vomiting, low energy, joint and muscle pain, increased appetite, weight loss, yawning, somnolence, fever, dry mouth, cold feet, hot spells, light sensitivity, palpitations, tachycardia, sneezing and headache. Subjects will be observed for these adverse events. Should any of these events occur, they should occur within hours of naltrexone administration, during which the subjects will be under continuous observation in the clinic. TOLERABILITY, assessed by reported adverse events. ; The risks associated with PF329 include low blood pressure, slow breathing and lower levels of oxygen in the blood. ; In general, nafamostat mesilate is well tolerated and the most significant adverse reactions tend to be allergic reactions with the IV product. Exacerbation of bleeding may occur with nafamostat mesilate. This risk will be monitored via blood clotting tests. ; The risks associated with naltrexone include difficulty sleeping, anxiety, nervousness, abdominal pains/cramps, nausea and/or vomiting, low energy, joint and muscle pain, increased appetite, weight loss, yawning, somnolence, fever, dry mouth, cold feet, hot spells, light sensitivity, palpitations, tachycardia, sneezing and headache. Subjects will be observed for these adverse events. Should any of these events occur, they should occur within hours of naltrexone administration, during which the subjects will be under continuous observation in the clinic. SECONDARY OUTCOME: Nil INCLUSION CRITERIA: 1. Males or females, ages 18‐50 years in good general health 2. Body Mass Index (BMI) between 18 and 30 kg/m2 (inclusive) 3. Subjects must have a negative screen for drugs of abuse, alcohol, hepatitis B‐surface antigen, hepatitis C and HIV. 4. Female subjects must have a negative serum pregnancy test at screening and a negative urine pregnancy test at randomization. 5. Female subjects must use a medically acceptable method of birth control (oral or transdermal contraceptives, condom, spermicidal foam, IUD, progestin implant or injection, abstinence, vaginal ring, or sterilization of partner) from the time of screening through two weeks after the last study treatment. 6. Subjects must have normal findings in a physical examination and a 12‐lead ECG, and normal vital signs (respiratory rate between 12 and 20 breaths per minute, blood pressure (sitting) between 100‐140/60‐90 mmHg, heart rate (sitting) between 48‐99 beats per minute, temperature b