Pharmacokinetic Study of Fentanyl 400 µg Sublingual Spray, Actiq® 400 µg Transmucosally, and Fentanyl Citrate Injection 100 µg Intravenously (iv)

Study Overview
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Brief Summary
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The objective of this study was to compare the rate of absorption and bioavailability of fentanyl 400 µg sublingual spray, Actiq® 400 µg transmucosally, and fentanyl citrate injection 100 µg intravenously.

Detailed Description
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This was a Phase I, single-dose, open-label, randomized, 3-period, 3-treatment cross over study in which 21 healthy subjects received single doses of fentanyl 400 µg sublingual spray, Actiq® 400 µg transmucosally, and fentanyl citrate injection 100 µg intravenously following a 10-hour overnight fast. There was a 7 day washout period between treatments.

Official Title
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A Single-dose Crossover Study of Fentanyl Sublingual Spray 400 Mcg Versus Actiq® 400 Mcg Versus Fentanyl Citrate Injection (iv) 100 Mcg Under Fasted Conditions

Conditions
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Pain

Intervention / Treatment
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* Drug: Fentanyl 400 µg sublingual spray
* Drug: Actiq® 400 µg transmucosally
* Drug: Fentanyl citrate injection 100 µg intravenously
* Drug: Naltrexone 50 mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or non-pregnant, non-breast-feeding female between the ages of 18-55 inclusive. Body Mass Index (BMI) between 18-30 kg/m^2, inclusive, and body weight of at least 60 kg (132 lbs). Subject was healthy according to the medical history, laboratory results, and physical examination. Exclusion Criteria: Had a presence or history of clinically significant cardiovascular, pulmonary, hepatic, renal, hematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurologic, oncologic, or psychiatric disease or any other condition which, in the opinion of the Investigator would jeopardize the safety of the subject or the validity of the study results. Had a clinically significant abnormal finding on the physical exam, medical history, electrocardiogram (ECG), or clinical laboratory results at screening. Had a significant history of hypersensitivity to opioid analgesics, fentanyl or any related products, naltrexone, or severe hypersensitivity reactions (like angioedema) to any drugs. Had a significantly abnormal diet during the 4 weeks preceding the first dose of study medication. Had donated blood or plasma within 30 days prior to the first dose of study medication or during the course of this study. Had participated in another clinical trial within 30 days prior to the first dose of study medication or during the course of this study. Had used any over-the-counter (OTC) medication, including nutritional supplements, within 7 days prior to the first dose of study medication or during the course of this study. Had used any prescription medication, except hormonal contraceptive or hormonal replacement therapy, within 14 days prior to the first dose of study medication or during the course of this study. Had used enzyme altering drugs such as barbiturates, corticosteroids, phenothiazines, cimetidine, carbamazepine, etc, within 30 days prior to the first dose of study medication or during the course of this study. Had used opioid analgesics within the last 30 days.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 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: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Fentanyl 400 µg sublingual spray + naltrexone 50 mg<br>Patients received a single administration of 400 µg of fentanyl spray sublingually + naltrexone hydrochloride 50 mg orally. | Drug: Fentanyl 400 µg sublingual spray<br> <br> Drug: Naltrexone 50 mg<br>* Naltrexone hydrochloride was administered approximately 12 hours and 1 hour prior to and 12 hours after each dose of fentanyl to minimize the occurrence of unacceptable adverse effects (eg, decreased respiration, nausea) often associated with administration of fentanyl.<br>|
| Active Comparator: Actiq® 400 µg transmucosally + naltrexone 50 mg<br>Patients received a single administration of 400 µg of Actiq® transmucosally + naltrexone hydrochloride 50 mg orally. | Drug: Actiq® 400 µg transmucosally<br>* Actiq® 400 µg is a solid formulation of fentanyl citrate on a plastic stick that dissolves slowly in the mouth for absorption across the buccal mucosa.<br>* Other names: fentanyl citrate;Drug: Naltrexone 50 mg<br>* Naltrexone hydrochloride was administered approximately 12 hours and 1 hour prior to and 12 hours after each dose of fentanyl to minimize the occurrence of unacceptable adverse effects (eg, decreased respiration, nausea) often associated with administration of fentanyl.<br>|
| Active Comparator: Fentanyl citrate injection 100 µg iv + naltrexone 50 mg<br>Patients received a single administration of 100 µg of fentanyl citrate intravenously + naltrexone hydrochloride 50 mg orally. | Drug: Fentanyl citrate injection 100 µg intravenously<br> <br> Drug: Naltrexone 50 mg<br>* Naltrexone hydrochloride was administered approximately 12 hours and 1 hour prior to and 12 hours after each dose of fentanyl to minimize the occurrence of unacceptable adverse effects (eg, decreased respiration, nausea) often associated with administration of fentanyl.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to reach the maximum drug concentration (Tmax) in plasma |  | Up to 60 minutes pre-dose to 36 hours post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum drug concentration (Cmax) in plasma |  | Up to 60 minutes pre-dose to 36 hours post-dose | 
| Area under the plasma concentration-time curve from time-0 to the time of the last quantifiable concentration (AUClast) |  | Up to 60 minutes pre-dose to 36 hours post-dose | 
| Area under the plasma concentration-time curve from time-0 extrapolated to infinity (AUCinf) |  | Up to 60 minutes pre-dose to 36 hours post-dose | 
| Percentage of AUCinf based on extrapolation (AUCextrap) |  | Up to 60 minutes pre-dose to 36 hours post-dose | 
| Observed elimination rate constant (λz) |  | Up to 60 minutes pre-dose to 36 hours post-dose | 
| Observed terminal elimination half-life (T1/2) |  | Up to 60 minutes pre-dose to 36 hours post-dose | 
| Time of the last measurable concentration of drug (Tlast) in plasma |  | Up to 60 minutes pre-dose to 36 hours post-dose | 
| Last quantifiable drug concentration (Clast) in plasma |  | Up to 60 minutes pre-dose to 36 hours post-dose |