Open Label Crossover Study Pharmacokinetics (PK) Study in Healthy Volunteers Receiving Various Forms of Fentanyl

Study Overview
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Brief Summary
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A partially randomized, open-label, 3-way crossover, single-center, systemic and CSF PK and bioavailability study in healthy volunteers.

Detailed Description
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An Open-Label Single-Dose Crossover Study Comparing the Plasma and Cerebrospinal Fluid Pharmacokinetics and Bioavailability of Fentanyl Delivered Intranasally Versus Sublingually Versus Intravenously in Healthy Volunteers

Official Title
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An Open-Label Single-Dose Crossover Study Comparing the Plasma and Cerebrospinal Fluid Pharmacokinetics and Bioavailability of Fentanyl Delivered Intranasally Versus Sublingually Versus Intravenously in Healthy Volunteers

Conditions
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Healthy

Intervention / Treatment
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* Drug: Fentanyl


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Normal healthy male or female between the ages of 18 to 65 years. Never smokers or Non-smokers (cessation of smoking ≥ 6 months ago). Body Mass Index (BMI = weight/height2) greater than or equal to 18.5 kg/m2 and less than or equal to 32.0 kg/m2. No clinically meaningful findings in the physical examination, oral and nasal examination and 12-lead electrocardiogram. Negative for drugs of abuse, alcohol, and nicotine. Negative for hepatitis A, B, and C and Human Immunodeficiency Virus (HIV). No clinical laboratory values outside of the acceptable range, unless, in the opinion of the Principal Investigator, they are deemed not clinically significant. Exclusion Criteria: Subject has a known history of allergic reaction, hypersensitivity, or clinically significant intolerance to opioids, fentanyl or components of the study drugs. 2. Subjects with a high potential for opioid addiction (personal or family history). 3. Subject is lactating or considered at risk of pregnancy. 4. Subject has impaired liver function (e.g., alanine aminotransferase [ALT] ≥ 3 times the upper limit of normal [ULN] or bilirubin ≥ 3 times ULN), known active hepatic disease (e.g., hepatitis), or evidence of clinically significant liver disease or other condition affecting the liver that may suggest the potential for an increased susceptibility to hepatic toxicity with oral diclofenac exposure. 5. Subject has any history of renal disease that, in the opinion of the investigator, would contraindicate study participation; or subject has significantly impaired renal function as evidenced by an estimated GFR of ≤60 ml/min/1.73m2. 6. Subject has a history or evidence of significant nasal pathology, including polyps or nasal obstructions.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Other
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Nasal fentanyl<br>nasal fentanyl, 200 μg, administered as one 100 μg spray (100 μL) to each nostril; both completed within one minute. Will be administered on either study day 1 or 3 per protocol and randomization. | Drug: Fentanyl<br>* Lazanda (nasal spray), Subsys (sub-lingual) and intravenous fentanyl<br>* Other names: Lazanda, Subsys, IV fentanyl;|
| Active Comparator: Sub-Lingual fentanyl<br>sublingual fentanyl, 200 μg, administered as a single spray (100 μL) under the tongue. Will be administered on either study day 1 or 3 per protocol and randomization. | Drug: Fentanyl<br>* Lazanda (nasal spray), Subsys (sub-lingual) and intravenous fentanyl<br>* Other names: Lazanda, Subsys, IV fentanyl;|
| Active Comparator: IV fentanyl<br>IV fentanyl, 100 μg in 2 mL administered as an intravenous injection over 1-3 minutes. Will be administered on study day 5 per protocol. | Drug: Fentanyl<br>* Lazanda (nasal spray), Subsys (sub-lingual) and intravenous fentanyl<br>* Other names: Lazanda, Subsys, IV fentanyl;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Reach Maximum Observed Concentration (Tmax) of Fentanyl in Cerebrospinal Fluid (CSF) (1 of 3) |  | 6 hrs (pre-dose, 5, 10, 20, 30, 45, & 60 min, and 2, 3, 4, & 6 hrs post-dose on Study Days 1 & 3) | 
| Maximum Observed Concentration (Cmax) of Fentanyl in Cerebrospinal Fluid (CSF) (2 of 3) |  | 6 hrs (pre-dose, 5, 10, 20, 30, 45, & 60 min, and 2, 3, 4, & 6 hrs post-dose on Study Days 1 & 3) | 
| Area Under the Concentration-Time Curve From Hour 0 to Hour 6 (AUC 0-6h) of Fentanyl in Cerebrospinal Fluid (CSF) (3 of 3) |  | 6 hrs (pre-dose, 5, 10, 20, 30, 45, & 60 min, and 2, 3, 4, & 6 hrs post-dose on Study Days 1 & 3) | 
| Maximum Observed Concentration (Cmax) of Fentanyl in Plasma (1 of 5) | Cmax (pg/mL) | 24 hrs (pre-dose, 5, 10, 15, 20, 30, 45, & 60 min, and 1.5, 2, 3, 4, 6, 8, 12, & 24 hrs on Study Days 1 & 3 for Nasal Fentanyl / Sublingual Fentanyl; pre-dose, 2, 5, 10, 20, 30, & 60 min, and 2, 4, 6, 8, 12, & 24 hrs on Study Day 5 for IV Fentanyl) | 
| Area Under the Concentration-Time Curve From Time 0 to the Last Quantifiable Concentration (AUC 0-tlast) of Fentanyl in Plasma (2 of 5) | AUC 0-tlast (pg*h/mL) | 24 hrs (pre-dose, 5, 10, 15, 20, 30, 45, & 60 min, and 1.5, 2, 3, 4, 6, 8, 12, & 24 hrs on Study Days 1 & 3 for Nasal Fentanyl / Sublingual Fentanyl; pre-dose, 2, 5, 10, 20, 30, & 60 min, and 2, 4, 6, 8, 12, & 24 hrs on Study Day 5 for IV Fentanyl) | 
| Area Under the Concentration-Time Curve From Time 0 Extrapolated to Infinity (AUC 0-inf) of Fentanyl in Plasma (3 of 5) | AUC 0-inf (pg*h/mL) | 24 hrs (pre-dose, 5, 10, 15, 20, 30, 45, & 60 min, and 1.5, 2, 3, 4, 6, 8, 12, & 24 hrs on Study Days 1 & 3 for Nasal Fentanyl / Sublingual Fentanyl; pre-dose, 2, 5, 10, 20, 30, & 60 min, and 2, 4, 6, 8, 12, & 24 hrs on Study Day 5 for IV Fentanyl) | 
| Time to Reach Maximum Observed Concentration (Tmax) of Fentanyl in Plasma (4 of 5) | Tmax (h) | 24 hrs (pre-dose, 5, 10, 15, 20, 30, 45, & 60 min, and 1.5, 2, 3, 4, 6, 8, 12, & 24 hrs on Study Days 1 & 3 for Nasal Fentanyl / Sublingual Fentanyl; pre-dose, 2, 5, 10, 20, 30, & 60 min, and 2, 4, 6, 8, 12, & 24 hrs on Study Day 5 for IV Fentanyl) | 
| Terminal Elimination Half-Life (t1/2) of Fentanyl in Plasma (5 of 5) | t1/2 (h) | 24 hrs (pre-dose, 5, 10, 15, 20, 30, 45, & 60 min, and 1.5, 2, 3, 4, 6, 8, 12, & 24 hrs on Study Days 1 & 3 for Nasal Fentanyl / Sublingual Fentanyl; pre-dose, 2, 5, 10, 20, 30, & 60 min, and 2, 4, 6, 8, 12, & 24 hrs on Study Day 5 for IV Fentanyl) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Volunteer, Pharmacokenetics (PK) (plasma and Cerebrospinal Fluid [CSF])