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

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

• Fentanyl (Drug), also known as Lazanda, Subsys, IV fentanyl: Lazanda (nasal spray), Subsys (sub-lingual) and intravenous fentanyl

Primary outcomes

• 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)

Sex: All, ages: 18 Years to 65 Years, accepts healthy volunteers

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.

Participant flow

Outcome results

• Time to Reach Maximum Observed Concentration (Tmax) of Fentanyl in Cerebrospinal Fluid (CSF) (1 of 3) (Primary), Median, h: Nasal Fentanyl 1.01 (0.75 to 3.00); Sublingual Fentanyl 2.00 (0.75 to 3.00)
• Maximum Observed Concentration (Cmax) of Fentanyl in Cerebrospinal Fluid (CSF) (2 of 3) (Primary), Mean, pg/mL: Nasal Fentanyl 84.54 +/- 47.10; Sublingual Fentanyl 56.37 +/- 22.13
• Area Under the Concentration-Time Curve From Hour 0 to Hour 6 (AUC 0-6h) of Fentanyl in Cerebrospinal Fluid (CSF) (3 of 3) (Primary), Mean, pg*h/mL: Nasal Fentanyl 300.25 +/- 121.93; Sublingual Fentanyl 221.49 +/- 76.82
• Maximum Observed Concentration (Cmax) of Fentanyl in Plasma (1 of 5) (Primary), Geometric mean, pg/mL: Nasal Fentanyl 541.28 +/- 78.1; Sublingual Fentanyl 369.59 +/- 41.4; IV Fentanyl 1166.51 +/- 130.8
• Area Under the Concentration-Time Curve From Time 0 to the Last Quantifiable Concentration (AUC 0-tlast) of Fentanyl in Plasma (2 of 5) (Primary), Geometric mean, pg*h/mL: Nasal Fentanyl 2752.51 +/- 37.3; Sublingual Fentanyl 2359.08 +/- 27.5; IV Fentanyl 2236.46 +/- 26.5
• Area Under the Concentration-Time Curve From Time 0 Extrapolated to Infinity (AUC 0-inf) of Fentanyl in Plasma (3 of 5) (Primary), Geometric mean, pg*h/mL: Nasal Fentanyl 3413.80 +/- 34.8; Sublingual Fentanyl 2879.85 +/- 26.0; IV Fentanyl 2871.89 +/- 17.7
• Time to Reach Maximum Observed Concentration (Tmax) of Fentanyl in Plasma (4 of 5) (Primary), Median, h: Nasal Fentanyl 0.63 (0.17 to 2.00); Sublingual Fentanyl 0.75 (0.25 to 4.00); IV Fentanyl 0.07 (0.03 to 1.00)
• Terminal Elimination Half-Life (t1/2) of Fentanyl in Plasma (5 of 5) (Primary), Geometric mean, h: Nasal Fentanyl 12.08 +/- 40.0; Sublingual Fentanyl 10.73 +/- 39.6; IV Fentanyl 12.25 +/- 24.2

Adverse events

Time frame: 8 weeks

Serious adverse events by term

Other adverse events by term

• Head of R&D, Study director, Depomed