Opioid Overdose
Conditions
Keywords
Pharmacokinetics
Brief summary
This study is to compare the pharmacokinetics (how the body absorbs, breaks down and eliminates drug from your body) of nalmefene when given as a single dose intranasally (IN;into the nose), as a single dose in each nostril and as two doses in one nostrils; and to evaluate the safety and tolerability of nalmefene IN.
Detailed description
Open-label, randomized, 3-period, 3-treatment, 6-sequence, ranodmised crossover study in 24 healthy volunteers. Subjects will be assigned to each of the 6 possible sequences. Each subject will receive 3 intranasal (IN) nalmefene doses: * 3mg IN dose (one 0.1mL spray of a 30mg/mL solution in one nostril) * 6mg IN dose (one 0.1mL spray of a 30mg/mL solution in each nostril) * 6mg IN dose (two 0.1mL sprays of a 30mg/mL solution in one nostril) There will be a 6 day washout period between doses. Screening can occur up to 28 days before admission, subjects will then stay in the inpatient facility for 16 days to complete the treatment phase of the study and will be discharged following completion of the discharge procedures at the end of the last period. Subjects will be called 3 to 5 days after discharge to inquire concerning Adverse Events (AEs) and concomitant medications since discharge.
Interventions
30 mg/mL solution
Sponsors
Opiant Pharmaceuticals Inc
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* Male or female aged 18 to 55 years inclusive * BMI ranging from 18 to 30 kg/m2, inclusive * Adequate venous access * Subjects must be non-smokers * On screening and admission, the following standards had to be met before dosing and were permitted to be repeated once: * Systolic blood pressure: 140 mmHg or less and equal to or greater than 90 mmHg * Diastolic blood pressure: 90 mmHg or less and equal to or greater than 55 mmHg * Heart rate: 100 beats per minute (bpm) or less and equal to or greater than 40 bpm * Respiratory rate: 20 respirations per minute (rpm) or less and equal to or greater than 8 rpm
Exclusion criteria
* History of clinically significant disease * Significant trauma injury, major surgery, open biopsy within 30 days prior to screening * Following an abnormal diet 4 weeks prior to screening * Use of prescribed or over the counter medications, dietary supplements, herbal products, vitamins or opioid analgesics 14 days before intervention and throughout the study * Use of enzyme altering drugs 30 days before intervention or during the study * Use of nasal products 28 days before intervention and throughout the study * Experimental agents used at least 8 weeks prior to initial dosing for a period equivalent to 5 half-lives of the agent (whichever was longer). * Positive urine drug test for alcohol, opioids, cocaine, methamphetamine, benzodiazepines, tetrahydrocannabinol (THC), barbiturates, or methadone at screening or admission. * Previous or current opioid, alcohol, or other drug dependence (excluding nicotine and caffeine) * Positive urine screen for cotinine (smoking and the use of tobacco products were not permitted for 4 weeks prior to the first dose of study drug and throughout the duration of the study). * An ECG QTcF interval \>450 msec for males and \> or equal to 470 msec for females. * Clinically significant concurrent medical conditions * Donated or received blood 30 days before intervention * Women who are pregnant or breastfeeding at screening and prior to each administration of study drug * Women of childbearing potential unless surgically sterile or use effective contraception * Male subjects of childbearing potential that do not agree to use effective contraception * Male subjects who plan to donate sperm or have female partner(s) who are pregnant, lactating or planning to attempt to become pregnant during the study or within 4 weeks after completion of the study * Positive test for HBsAg, HCVAb, or HIVAb at screening * Current or recent upper respiratory tract infection * Current or recent use of any decongestants * Allergic to nalmefene * Those who would not abstain from engaging in strenuous exercise during the inpatient stay of the study. * Those who would not abstain from consuming poppy seed or similar opium derived food stuff during the study. * Those who would not abstain from ingesting alcohol, drinks containing xanthine \>500 mg/day (e.g., Coca Cola®, coffee, tea, etc.), or grapefruit/grapefruit juice 72 hours before initial dosing and throughout the duration of the study. * Those deemed unlikely to be able to comply with the requirements of the protocol. * Those with any laboratory tests from samples taken at screening considered clinically significant. * Those with a known intolerance to continuous ECG lead adhesive exposure. * Brief Smell Identification Test (BSIT) score \< 5 at screening. * Those with a known hypersensitivity reaction to plastic.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Plasma Concentration (Cmax) | 48 hours | Maximum concentration of plasma nalmefene comparing 1 dose of IN in one nostril to 2 doses of IN in 1 nostril to 1 dose of IN in each nostril |
| Time to Maximum Plasma Concentration (Tmax) | 48 hours | Time to maximum concentration of plasma nalmefene comparing 1 dose of IN in one nostril to 2 doses of IN in 1 nostril to 1 dose of IN in each nostril |
| Area Under the Curve (AUC) | 48 hours | Area under the curve of plasma nalmefene comparing 1 dose of IN in one nostril to 2 doses of IN in 1 nostril to 1 dose of IN in each nostril |
| Half-life (t1/2) | 48 hours | Half life of plasma nalmefene comparing 1 dose of IN in one nostril to 2 doses of IN in 1 nostril to 1 dose of IN in each nostril |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Sequence 1 Sequence 1 represents subjects taking
* Treatment A in period 1 (3 mg IN nalmefene dose \[one 0.1 mL spray of a 30 mg/mL solution in one nostril\])
* Treatment B in period 2 (6 mg IN nalmefene dose \[one 0.1 mL spray of a 30 mg/mL solution in each nostril\])
* Treatment C in period 3 (6 mg IN nalmefene dose \[two 0.1 mL sprays of a 30 mg/mL solution in one nostril\]) | 4 |
| Sequence 2 Sequence 2 represents subjects taking
* Treatment B in period 1 (6 mg IN nalmefene dose \[one 0.1 mL spray of a 30 mg/mL solution in each nostril\])
* Treatment C in period 2 (6 mg IN nalmefene dose \[two 0.1 mL sprays of a 30 mg/mL solution in one nostril\])
* Treatment A in period 3 (3 mg IN nalmefene dose \[one 0.1 mL spray of a 30 mg/mL solution in one nostril\]) | 4 |
| Sequence 3 Sequence 3 represents subjects taking
* Treatment C in period 1 (6 mg IN nalmefene dose \[two 0.1 mL sprays of a 30 mg/mL solution in one nostril\])
* Treatment A in period 2 (3 mg IN nalmefene dose \[one 0.1 mL spray of a 30 mg/mL solution in one nostril\])
* Treatment B in period 3 (6 mg IN nalmefene dose \[one 0.1 mL spray of a 30 mg/mL solution in each nostril\]) | 4 |
| Sequence 4 Sequence 4 represents subjects taking
* Treatment A in period 1 (3 mg IN nalmefene dose \[one 0.1 mL spray of a 30 mg/mL solution in one nostril\])
* Treatment C in period 2 (6 mg IN nalmefene dose \[two 0.1 mL sprays of a 30 mg/mL solution in one nostril\])
* Treatment B in period 3 (6 mg IN nalmefene dose \[one 0.1 mL spray of a 30 mg/mL solution in each nostril\]) | 4 |
| Sequence 5 Sequence 5 represents subjects taking
* Treatment B in period 1 (6 mg IN nalmefene dose \[one 0.1 mL spray of a 30 mg/mL solution in each nostril\])
* Treatment A in period 2 (3 mg IN nalmefene dose \[one 0.1 mL spray of a 30 mg/mL solution in one nostril\])
* Treatment C in period 3 (6 mg IN nalmefene dose \[two 0.1 mL sprays of a 30 mg/mL solution in one nostril\]) | 4 |
| Sequence 6 Sequence 6 represents subjects taking
* Treatment C in period 1 (6 mg IN nalmefene dose \[two 0.1 mL sprays of a 30 mg/mL solution in one nostril\])
* Treatment B in period 2 (6 mg IN nalmefene dose \[one 0.1 mL spray of a 30 mg/mL solution in each nostril\])
* Treatment A in period 3 (3 mg IN nalmefene dose \[one 0.1 mL spray of a 30 mg/mL solution in one nostril\]) | 4 |
| Total | 24 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Period 1 (1 Day) | Withdrawal by Subject | 0 | 0 | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Sequence 1 | Sequence 2 | Sequence 3 | Sequence 4 | Sequence 5 | Sequence 6 | Total |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 27.8 years STANDARD_DEVIATION 5.91 | 32.0 years STANDARD_DEVIATION 9.2 | 35.0 years STANDARD_DEVIATION 8.29 | 37.5 years STANDARD_DEVIATION 12.4 | 28.0 years STANDARD_DEVIATION 6.73 | 27.0 years STANDARD_DEVIATION 6.06 | 31.2 years STANDARD_DEVIATION 8.47 |
| BMI | 26.28 kg/m2 STANDARD_DEVIATION 4.853 | 25.80 kg/m2 STANDARD_DEVIATION 2.226 | 24.30 kg/m2 STANDARD_DEVIATION 2.426 | 23.18 kg/m2 STANDARD_DEVIATION 4.921 | 23.00 kg/m2 STANDARD_DEVIATION 2.362 | 24.58 kg/m2 STANDARD_DEVIATION 3.222 | 24.52 kg/m2 STANDARD_DEVIATION 3.357 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 2 Participants | 0 Participants | 1 Participants | 3 Participants | 2 Participants | 10 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 2 Participants | 2 Participants | 3 Participants | 2 Participants | 1 Participants | 2 Participants | 12 Participants |
| Region of Enrollment United States | 4 participants | 4 participants | 4 participants | 4 participants | 4 participants | 4 participants | 24 participants |
| Sex: Female, Male Female | 2 Participants | 3 Participants | 3 Participants | 1 Participants | 3 Participants | 3 Participants | 15 Participants |
| Sex: Female, Male Male | 2 Participants | 1 Participants | 1 Participants | 3 Participants | 1 Participants | 1 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 23 | 0 / 24 | 0 / 23 |
| other Total, other adverse events | 9 / 23 | 16 / 24 | 12 / 23 |
| serious Total, serious adverse events | 0 / 23 | 0 / 24 | 0 / 23 |
Outcome results
Primary
Area Under the Curve (AUC)
Area under the curve of plasma nalmefene comparing 1 dose of IN in one nostril to 2 doses of IN in 1 nostril to 1 dose of IN in each nostril
Time frame: 48 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intranasal Nalmefene 1 Spray in 1 Nostril | Area Under the Curve (AUC) | 46.8 AUCinf (ng·h/mL) | Standard Deviation 10.1 |
| Intranasal Nalmefene 2 Sprays in 1 Nostril | Area Under the Curve (AUC) | 85.7 AUCinf (ng·h/mL) | Standard Deviation 18.7 |
| Intranasal Nalmefene 1 Spray in Each Nostril | Area Under the Curve (AUC) | 89.5 AUCinf (ng·h/mL) | Standard Deviation 17 |
Primary
Half-life (t1/2)
Half life of plasma nalmefene comparing 1 dose of IN in one nostril to 2 doses of IN in 1 nostril to 1 dose of IN in each nostril
Time frame: 48 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intranasal Nalmefene 1 Spray in 1 Nostril | Half-life (t1/2) | 11.4 hour | Standard Deviation 2.51 |
| Intranasal Nalmefene 2 Sprays in 1 Nostril | Half-life (t1/2) | 11.3 hour | Standard Deviation 1.86 |
| Intranasal Nalmefene 1 Spray in Each Nostril | Half-life (t1/2) | 11.3 hour | Standard Deviation 1.87 |
Primary
Maximum Plasma Concentration (Cmax)
Maximum concentration of plasma nalmefene comparing 1 dose of IN in one nostril to 2 doses of IN in 1 nostril to 1 dose of IN in each nostril
Time frame: 48 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intranasal Nalmefene 1 Spray in 1 Nostril | Maximum Plasma Concentration (Cmax) | 10.8 ng/ml | Standard Deviation 4.87 |
| Intranasal Nalmefene 2 Sprays in 1 Nostril | Maximum Plasma Concentration (Cmax) | 18.9 ng/ml | Standard Deviation 11.2 |
| Intranasal Nalmefene 1 Spray in Each Nostril | Maximum Plasma Concentration (Cmax) | 22.2 ng/ml | Standard Deviation 13.5 |
Primary
Time to Maximum Plasma Concentration (Tmax)
Time to maximum concentration of plasma nalmefene comparing 1 dose of IN in one nostril to 2 doses of IN in 1 nostril to 1 dose of IN in each nostril
Time frame: 48 hours
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Intranasal Nalmefene 1 Spray in 1 Nostril | Time to Maximum Plasma Concentration (Tmax) | 0.267 hours |
| Intranasal Nalmefene 2 Sprays in 1 Nostril | Time to Maximum Plasma Concentration (Tmax) | 0.25 hours |
| Intranasal Nalmefene 1 Spray in Each Nostril | Time to Maximum Plasma Concentration (Tmax) | 0.25 hours |