Healthy
Conditions
Keywords
Volunteer, Pharmacokenetics (PK) (plasma and Cerebrospinal Fluid [CSF])
Brief summary
A partially randomized, open-label, 3-way crossover, single-center, systemic and CSF PK and bioavailability study in healthy volunteers.
Detailed description
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
Interventions
DRUGFentanyl
Lazanda (nasal spray), Subsys (sub-lingual) and intravenous fentanyl
Sponsors
Depomed
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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) | 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) | Cmax (pg/mL) |
| Area Under the Concentration-Time Curve From Time 0 to the Last Quantifiable Concentration (AUC 0-tlast) of Fentanyl in Plasma (2 of 5) | 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) | AUC 0-tlast (pg\*h/mL) |
| Area Under the Concentration-Time Curve From Time 0 Extrapolated to Infinity (AUC 0-inf) of Fentanyl in Plasma (3 of 5) | 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) | AUC 0-inf (pg\*h/mL) |
| Time to Reach Maximum Observed Concentration (Tmax) of Fentanyl in Plasma (4 of 5) | 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) | Tmax (h) |
| Terminal Elimination Half-Life (t1/2) of Fentanyl in Plasma (5 of 5) | 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) | t1/2 (h) |
Participant flow
Pre-assignment details
A total of 13 healthy subjects were randomly assigned to treatment in this crossover study: 6 in the Nasal Fentanyl First, then Sublingual Fentanyl and IV Fentanyl arm and 7 in the Sublingual Fentanyl First, then Nasal Fentanyl and IV Fentanyl arm.
Participants by arm
| Arm | Count |
|---|---|
| Nasal Fentanyl First, Then Sublingual Fentanyl and IV Fentanyl Nasal Fentanyl, 200 μg, administered as one 100 μg spray (100 μL) to each nostril; both completed within one minute on Study Day 1 per protocol.
Sublingual Fentanyl, 200 μg, administered as a single spray (100 μL) under the tongue on Study Day 3 per protocol.
IV Fentanyl, 100 μg in 2 mL administered as an intravenous injection over 1-3 minutes on Study Day 5 per protocol. | 6 |
| Sublingual Fentanyl First, Then Nasal Fentanyl and IV Fentanyl Sublingual Fentanyl, 200 μg, administered as a single spray (100 μL) under the tongue on Study Day 1 per protocol.
Nasal Fentanyl, 200 μg, administered as one 100 μg spray (100 μL) to each nostril; both completed within one minute on Study Day 3 per protocol.
IV Fentanyl, 100 μg in 2 mL administered as an intravenous injection over 1-3 minutes on Study Day 5 per protocol. | 7 |
| Total | 13 |
Baseline characteristics
| Characteristic | Nasal Fentanyl First, Then Sublingual Fentanyl and IV Fentanyl | Sublingual Fentanyl First, Then Nasal Fentanyl and IV Fentanyl | Total |
|---|---|---|---|
| Age, Continuous | 39.0 years STANDARD_DEVIATION 14.38 | 43.0 years STANDARD_DEVIATION 9.5 | 41.2 years STANDARD_DEVIATION 11.65 |
| Sex: Female, Male Female | 4 Participants | 4 Participants | 8 Participants |
| Sex: Female, Male Male | 2 Participants | 3 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 2 / 12 | 6 / 13 | 0 / 12 |
| serious Total, serious adverse events | 0 / 12 | 1 / 13 | 0 / 12 |
Outcome results
Primary
Area Under the Concentration-Time Curve From Hour 0 to Hour 6 (AUC 0-6h) of Fentanyl in Cerebrospinal Fluid (CSF) (3 of 3)
Time frame: 6 hrs (pre-dose, 5, 10, 20, 30, 45, & 60 min, and 2, 3, 4, & 6 hrs post-dose on Study Days 1 & 3)
Population: The CSF PK population included all subjects who completed all study periods and Cmax was less than 5% pre-dose. The above CSF PK outcome compares nasal and sublingual fentanyl interventions.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Nasal Fentanyl | Area Under the Concentration-Time Curve From Hour 0 to Hour 6 (AUC 0-6h) of Fentanyl in Cerebrospinal Fluid (CSF) (3 of 3) | 300.25 pg*h/mL | Standard Deviation 121.93 |
| Sublingual Fentanyl | Area Under the Concentration-Time Curve From Hour 0 to Hour 6 (AUC 0-6h) of Fentanyl in Cerebrospinal Fluid (CSF) (3 of 3) | 221.49 pg*h/mL | Standard Deviation 76.82 |
Primary
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)
Time frame: 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)
Population: The Plasma PK population included all subjects who received at least 1 dose of study drug and had at least 1 evaluable PK parameter. The AUC 0-inf values were excluded where %AUC extrap was greater than 20%.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Nasal Fentanyl | Area Under the Concentration-Time Curve From Time 0 Extrapolated to Infinity (AUC 0-inf) of Fentanyl in Plasma (3 of 5) | 3413.80 pg*h/mL | Geometric Coefficient of Variation 34.8 |
| Sublingual Fentanyl | Area Under the Concentration-Time Curve From Time 0 Extrapolated to Infinity (AUC 0-inf) of Fentanyl in Plasma (3 of 5) | 2879.85 pg*h/mL | Geometric Coefficient of Variation 26 |
| IV Fentanyl | Area Under the Concentration-Time Curve From Time 0 Extrapolated to Infinity (AUC 0-inf) of Fentanyl in Plasma (3 of 5) | 2871.89 pg*h/mL | Geometric Coefficient of Variation 17.7 |
Primary
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)
Time frame: 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)
Population: The Plasma PK population included all subjects who received at least 1 dose of study drug and had at least 1 evaluable PK parameter.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Nasal 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) | 2752.51 pg*h/mL | Geometric Coefficient of Variation 37.3 |
| Sublingual 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) | 2359.08 pg*h/mL | Geometric Coefficient of Variation 27.5 |
| 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) | 2236.46 pg*h/mL | Geometric Coefficient of Variation 26.5 |
Primary
Maximum Observed Concentration (Cmax) of Fentanyl in Cerebrospinal Fluid (CSF) (2 of 3)
Time frame: 6 hrs (pre-dose, 5, 10, 20, 30, 45, & 60 min, and 2, 3, 4, & 6 hrs post-dose on Study Days 1 & 3)
Population: The CSF PK population included all subjects who completed all study periods and Cmax was less than 5% pre-dose. The above CSF PK outcome compares nasal and sublingual fentanyl interventions.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Nasal Fentanyl | Maximum Observed Concentration (Cmax) of Fentanyl in Cerebrospinal Fluid (CSF) (2 of 3) | 84.54 pg/mL | Standard Deviation 47.1 |
| Sublingual Fentanyl | Maximum Observed Concentration (Cmax) of Fentanyl in Cerebrospinal Fluid (CSF) (2 of 3) | 56.37 pg/mL | Standard Deviation 22.13 |
Primary
Maximum Observed Concentration (Cmax) of Fentanyl in Plasma (1 of 5)
Cmax (pg/mL)
Time frame: 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)
Population: The Plasma PK population included all subjects who received at least 1 dose of study drug and had at least 1 evaluable PK parameter.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Nasal Fentanyl | Maximum Observed Concentration (Cmax) of Fentanyl in Plasma (1 of 5) | 541.28 pg/mL | Geometric Coefficient of Variation 78.1 |
| Sublingual Fentanyl | Maximum Observed Concentration (Cmax) of Fentanyl in Plasma (1 of 5) | 369.59 pg/mL | Geometric Coefficient of Variation 41.4 |
| IV Fentanyl | Maximum Observed Concentration (Cmax) of Fentanyl in Plasma (1 of 5) | 1166.51 pg/mL | Geometric Coefficient of Variation 130.8 |
Primary
Terminal Elimination Half-Life (t1/2) of Fentanyl in Plasma (5 of 5)
t1/2 (h)
Time frame: 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)
Population: The Plasma PK population included all subjects who received at least 1 dose of study drug and had at least 1 evaluable PK parameter.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Nasal Fentanyl | Terminal Elimination Half-Life (t1/2) of Fentanyl in Plasma (5 of 5) | 12.08 h | Geometric Coefficient of Variation 40 |
| Sublingual Fentanyl | Terminal Elimination Half-Life (t1/2) of Fentanyl in Plasma (5 of 5) | 10.73 h | Geometric Coefficient of Variation 39.6 |
| IV Fentanyl | Terminal Elimination Half-Life (t1/2) of Fentanyl in Plasma (5 of 5) | 12.25 h | Geometric Coefficient of Variation 24.2 |
Primary
Time to Reach Maximum Observed Concentration (Tmax) of Fentanyl in Cerebrospinal Fluid (CSF) (1 of 3)
Time frame: 6 hrs (pre-dose, 5, 10, 20, 30, 45, & 60 min, and 2, 3, 4, & 6 hrs post-dose on Study Days 1 & 3)
Population: The CSF PK population included all subjects who completed all study periods and Cmax was less than 5% pre-dose. The above CSF PK outcome compares nasal and sublingual fentanyl interventions.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Nasal Fentanyl | Time to Reach Maximum Observed Concentration (Tmax) of Fentanyl in Cerebrospinal Fluid (CSF) (1 of 3) | 1.01 h |
| Sublingual Fentanyl | Time to Reach Maximum Observed Concentration (Tmax) of Fentanyl in Cerebrospinal Fluid (CSF) (1 of 3) | 2.00 h |
Primary
Time to Reach Maximum Observed Concentration (Tmax) of Fentanyl in Plasma (4 of 5)
Tmax (h)
Time frame: 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)
Population: The Plasma PK population included all subjects who received at least 1 dose of study drug and had at least 1 evaluable PK parameter.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Nasal Fentanyl | Time to Reach Maximum Observed Concentration (Tmax) of Fentanyl in Plasma (4 of 5) | 0.63 h |
| Sublingual Fentanyl | Time to Reach Maximum Observed Concentration (Tmax) of Fentanyl in Plasma (4 of 5) | 0.75 h |
| IV Fentanyl | Time to Reach Maximum Observed Concentration (Tmax) of Fentanyl in Plasma (4 of 5) | 0.07 h |