Pharmacokinetics
`
`Pharmacokinetic Properties and Human Use
`Characteristics of an FDA-Approved
`Intranasal Naloxone Product for the
`Treatment of Opioid Overdose
`
`The Journal of Clinical Pharmacology
`2016, 00(0) 1–11
`C(cid:2) 2016, The American College of
`Clinical Pharmacology
`DOI: 10.1002/jcph.759
`
`Philip Krieter, PhD1, Nora Chiang, PhD1, Shwe Gyaw, MD1, Phil Skolnick, PhD, DSc
`(hon)1, Roger Crystal, MD2, Fintan Keegan, MSc3, Julie Aker, MT (ASCP)4,
`Melissa Beck, BA4, and Jennifer Harris, BA4
`
`Abstract
`Parenteral naloxone has been approved to treat opiate overdose for over 4 decades. Intranasal naloxone, administered “off label” using improvised
`devices, has been widely used by both first responders and the lay public to treat overdose. However, these improvised devices require training for
`effective use, and the recommended volumes (2 to 4 mL) exceed those considered optimum for intranasal administration. The present study compared
`the pharmacokinetic properties of intranasal naloxone (2 to 8 mg) delivered in low volumes (0.1 to 0.2 mL) using an Aptar Unit-Dose device to an
`approved (0.4 mg) intramuscular dose. A parallel study assessed the ease of use of this device in a simulated overdose situation. All doses of intranasal
`naloxone resulted in plasma concentrations and areas under the curve greater than those observed following the intramuscular dose; the time to
`reach maximum plasma concentrations was not different following intranasal and intramuscular administration. Plasma concentrations of naloxone
`were dose proportional between 2 and 8 mg and independent of whether drug was administered to 1 or both nostrils. In a study using individuals
`representative of the general population, >90% were able to perform both critical tasks (inserting nozzle into a nostril and pressing plunger) needed
`to deliver a simulated dose of naloxone without prior training. Based on both pharmacokinetic and human use studies, a 4-mg dose delivered in a
`single device (0.1 mL) was selected as the final product. This product can be used by first responders and the lay public, providing an important and
`potentially life-saving intervention for victims of an opioid overdose.
`
`Keywords
`intranasal, naloxone, opioid overdose, pharmacokinetics, Narcan R(cid:2)
`
`Nasal Spray
`
`Opioid overdose is a serious and evolving public health
`problem in the United States.1,2 Thus, more than 28,000
`overdose deaths3 and 750,000 annual emergency de-
`partment visits4 have been attributed to prescription
`opioids (eg, oxycodone, methadone) and heroin. Al-
`though the introduction of abuse deterrent formula-
`tions has apparently stabilized the death rate due to
`prescription opioids, an unintended consequence has
`been a dramatic rise in the rate of heroin-induced
`fatalities.1,5 As part of a comprehensive effort to
`limit opioid-induced fatalities, multiple government
`agencies6 have endorsed wider access to naloxone (17-
`allyl-4,5α-epoxy-3,14-dihyroxymorphinan-6-one HCl),
`a high-affinity opiate receptor antagonist that has been
`used to treat the symptoms of opioid overdose, includ-
`ing respiratory depression, for over 40 years.7,8
`Naloxone has been approved by the US Food and
`Drug Administration (FDA) for parenteral administra-
`tion, but in an attempt to reduce the morbidity and
`mortality associated with opioid overdose, there has
`been a dramatic increase in its off-label use by the
`
`intranasal (IN) route.9–11 Although most morbidity and
`mortality incidents are the result of accidental overdose
`involving prescription opioids,12 the distribution of im-
`provised IN naloxone “kits” has largely been confined
`to individuals with opiate (eg, heroin) use disorders at
`high risk of overdose, the friends and family of these
`individuals, and first responders.10 These improvised
`IN naloxone kits generally consist of 1 or 2 pre-
`filled syringes, each containing 2 mL of naloxone HCl
`(1 mg/mL) and a mucosal atomizing device. Individuals
`
`1National
`Institute on Drug Abuse, National
`Bethesda, MD, USA
`2Lightlake Therapeutics, New York, NY, USA
`3Adapt Pharma, Ltd, Dublin, Ireland
`4Concentrics Research, Indianapolis, IN, USA
`
`Institutes of Health,
`
`Submitted for publication 26 February 2016; accepted 27 April 2016.
`
`Corresponding Author:
`Phil Skolnick, PhD, National Institute on Drug Abuse, 6001 Executive
`Boulevard, Bethesda, MD 20892-9551
`Email: phil.skolnick@nih.gov
`
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`The Journal of Clinical Pharmacology / Vol 00 No 0 2016
`
`administering the naloxone are instructed to give half
`a vial, or 1 mL,
`in each nostril (for a total dose
`of 2 mL); a second dose can be administered if the
`patient has not responded to the first dose.9,10 Despite
`multiple reports describing the effectiveness of using
`these improvised intranasal devices in reversing opiate
`overdose,9–11,13,14 a high error rate has been associated
`with both kit assembly and proper IN administration,
`even in individuals receiving training.15 Moreover, it
`is not known if the pharmacokinetic (PK) properties
`of naloxone produced by these improvised IN devices
`are equivalent to the approved dose of parenterally
`administered naloxone. Here, we describe the PK prop-
`erties and usability profile of an IN naloxone HCl
`formulation delivered in low volume (0.1 mL) that was
`recently approved by the FDA for the treatment of
`opioid overdose.
`
`Methods
`Pharmacokinetic Study
`Study Participants. The PK study was approved by
`the MidLands Independent Review Board (Overland
`Park, Kansas); all subjects gave written informed
`consent before participation. The study was carried
`out in accordance with the International Confer-
`ence on Harmonisation for Good Clinical Practices
`guidelines.16 This trial was registered as NCT02572089
`(www.clinicaltrials.gov).
`Male and female volunteers aged 18 to 55 years with
`body mass index (BMI) 18 to 30 kg/m2 participated
`in the PK study. Subjects were currently not taking
`either prescription or over-the-counter medications;
`nonsmokers and subjects who smoked 20 or fewer
`cigarettes per day were enrolled. Screening procedures
`conducted within 21 days of study initiation included
`the following: medical history, physical examination,
`evidence of nasal irritation, 12-lead electrocardiogram,
`complete blood count, clinical chemistry, coagula-
`tion markers, hepatitis and human immunodeficiency
`screening, urinalysis, and urine drug screen. Female
`subjects were tested for pregnancy at screening and
`admission to the clinic. Subjects were excluded if they
`had either abnormal nasal anatomy or symptoms, an
`upper respiratory tract infection, used opioid analgesics
`for pain relief within the previous 14 days, or,
`in
`the judgment of the investigator, had significant acute
`or chronic medical conditions. Subjects were required
`to abstain from grapefruit juice and alcohol from
`72 hours prior to admission to the end of the last blood
`draw of the study and from nicotine- and caffeine-
`containing products and food for at least 1 hour prior
`to and 2 hours after dose administration. On days of
`dosing, a subject’s vital signs were required to be within
`the normal range before administration of naloxone,
`
`defined as systolic blood pressure >90 mm Hg and
`ࣘ140 mm Hg; diastolic blood pressure >55 mm Hg
`and ࣘ90 mm Hg; resting heart rate >40 beats per
`minute (bpm) and ࣘ100 bpm; and respiratory rate >8
`respirations per minute (rpm) and ࣘ20 rpm.
`Study Design. The PK study was an inpatient, open-
`label, randomized, 5-period, 5-treatment, 5-sequence,
`crossover study conducted at Vince & Associates Clin-
`ical Research (Overland Park, Kansas). Subjects were
`randomly assigned to 1 of the 5 sequences to ensure
`at least 6 subjects in each sequence. On the day after
`clinic admission, participants were administered the
`study drug in randomized order with a 4-day washout
`period between doses. Subjects remained in the clinic
`for 19 days until all 5 treatments were administered and
`returned 3 to 5 days after discharge for a follow-up visit.
`Subjects were fasted overnight before each dosing day
`and received 1 of the following 5 treatments:
`
`A. 2 mg naloxone IN (a single 0.1-mL spray of the
`20 mg/mL formulation in 1 nostril)
`B. 4 mg naloxone IN (a single 0.1-mL spray of the
`20 mg/mL formulation in each nostril)
`C. 4 mg naloxone IN (a single 0.1-mL spray of the
`40 mg/mL formulation in 1 nostril)
`D. 8 mg naloxone IN (a single 0.1-mL spray of the
`40 mg/mL formulation in each nostril)
`E. 0.4 mg naloxone IM (1.0 mL of the 0.4 mg/mL
`naloxone HCl for injection in the gluteus maximus)
`
`These doses were chosen based on a pilot study
`using 2 mg and 4 mg naloxone delivered in low volumes
`(0.1-0.2 mL) with a different device (data not shown).
`The IN devices were coded so that neither the staff
`nor the subjects knew the concentration of naloxone
`solution administered. IN naloxone was administered
`in the supine position, and subjects remained in
`this position for approximately 1 hour after dosing.
`Subjects were instructed not to breathe when the drug
`was administered to simulate an opioid overdose with
`a patient in respiratory arrest. The nasal passage was
`examined by medical personnel for irritation using a
`6-point scale at predose and at 5 minutes and 0.5, 1,
`4, and 24 hours postdose. Nasal irritation was scored
`as follows: 0 (normal-appearing mucosa, no bleeding);
`1 (inflamed mucosa, no bleeding); 2 (minor bleeding
`that stops within 1 minute); 3 (minor bleeding taking
`1 to 5 minutes to stop); 4 (substantial bleeding for 4
`to 60 minutes, does not require medical intervention);
`and 5 (ulcerated lesions, bleeding that requires medical
`intervention). Twelve-lead ECGs were
`collected
`predose and at 1 hour and 6 hours postdose. Venous
`blood samples were collected for the analyses of
`plasma naloxone concentrations predose and at 2.5, 5,
`10, 15, 20, 30, 45, 60, 120, 180, 240, 300, 360, 480, and
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`720 minutes postdose using Vacutainer R(cid:2)
`tubes
`containing sodium heparin. The plasma was stored
`at –20°C until analyzed.
`Study Drugs. Naloxone HCl powder (cGMP grade,
`99.8% purity) was purchased from Mallinckrodt (St.
`Louis, Missouri); naloxone HCl for injection was man-
`ufactured by Hospira, Inc (Lake Forest, Illinois). Nasal
`devices (Aptar Unit-Dose device for liquids, Louve-
`ciennes, France) were supplied by Lightlake Ther-
`apeutics, Inc (New York, New York). The devices,
`containing naloxone HCl concentrations of 20 mg/mL
`and 40 mg/mL, were manufactured by DPT Labora-
`tories, Ltd (Lakewood, New Jersey) and delivered a
`volume of 0.1 mL.
`Analytical Methods. Plasma naloxone concentra-
`tions were determined using a validated liquid
`chromatography-tandem mass
`spectrometry (LC-
`MS/MS) assay. Plasma samples (0.2 mL) were added to
`individual wells of a 96-well plate along with 0.05 mL
`methanol:water (3:7) containing the internal standard
`(0.1 ng naloxone-d5) and 0.2 mL 1 M potassium
`phosphate (pH 7.2). After vortex mixing, the plate was
`loaded onto a preconditioned 96-well SPE plate and
`washed sequentially with 0.1% formic acid, acetonitrile,
`and dichloromethane:isopropanol
`(8:2). Naloxone
`was eluted with dichloromethane/isopropanol (8:2)
`containing 2% ammonium hydroxide to a new 96-well
`plate. After evaporation, the residue was reconstituted
`in 0.2 mL methanol:water (9:1) and submitted to
`LC-MS/MS analysis. Naloxone was analyzed using
`an AB MDS Sciex API-5000 LC-MS/MS system
`(Framingham, Massachusetts) with an atmospheric
`pressure chemical ionization source operated in the
`positive ion mode. The mobile phase consisted of
`a gradient
`increasing from 60% mobile phase A
`(0.04% ammonium hydroxide):40% mobile phase B
`(methanol:acetonitrile, 1:1) to 20% A/80% B with a flow
`rate of 0.4 mL/min through a 50×2.1 mm XBridge C18
`column. Naloxone eluted at approximately 2 minutes.
`Ions monitored were m/z 328.3 and 212.1 for naloxone
`and m/z 333.3 and 212.1 for the internal standard. The
`calibration curves (peak area ratios) were linear (r2 >
`0.980) over the concentration range of 10.0 pg/mL to
`10 ng/mL; the lower limit of quantitation (LLOQ) was
`10.0 pg/mL. The interday precision of the calibration
`curves and quality control samples ranged from 2.1%
`to 7.9%, and the accuracy ranged between –2.4% and
`3.8% during the analysis of the samples.
`Data Analyses. The safety population included all
`subjects who received at least 1 dose of naloxone; the
`PK population included all subjects who received at
`least 1 dose of naloxone with sufficient data to calcu-
`late meaningful PK parameters. PK parameters were
`calculated using standard noncompartmental methods
`
`and a validated installation of WinNonlin R(cid:2)
`Phoenix,
`version 6.3 (Pharsight Corp, St. Louis, Missouri).
`Values of peak plasma concentrations (Cmax) and the
`time to reach Cmax (tmax) were the observed values
`obtained directly from the concentration-time data.
`The terminal elimination half-life (t½) was estimated
`by linear regression analysis. The area under the
`concentration-time curve from time 0 to the last quan-
`tifiable concentration (AUC0-t) was determined by the
`linear trapezoidal method and extrapolated to infinity
`(AUC0-Ý) by adding the value of the last quantifiable
`concentration divided by the terminal rate constant
`(λz). The extrapolated percentage of AUC0-Ý was less
`than 20% for all concentration profiles; therefore, only
`AUC0-Ý is reported. The apparent total body clear-
`ance (CL/F) was calculated as the dose divided by
`AUC0-Ý. PK comparisons were performed using a
`mixed-effects model in which sequence, period, and
`treatment were independent factors. Dose proportion-
`ality for all IN doses of naloxone was accessed using
`Cmax and AUC0-Ý parameters. In this analysis the
`mixed-effects power model [ln(PK) = β0 + ηi + β1 ×
`ln(Dose) + εij] was used, and 90% confidence inter-
`vals (90%CI) were constructed for the ratio of the
`dose-normalized geometric mean values (Rdnm) of the
`parameters.17 All analyses of demographic and safety
`data were performed using SAS R(cid:2)
`statistical software,
`version 9.3 (SAS Institute, Inc, Cary, North Carolina).
`
`Human Factors and Usability Studies
`Study Participants. The study was reviewed and ap-
`proved by Concentrics Institutional Review Board
`(Indianapolis, Indiana); participants or a guardian
`reviewed and gave written informed consent before
`participation. The study was carried out in accordance
`with the Draft Guidance for Industry and Food and
`Drug Administration Staff: Applying Human Factors
`and Usability Engineering to Optimize Medical De-
`vice Design, June 22, 201118 and the Guidance for
`Industry—Label Comprehension Studies for Nonpre-
`scription Drug Products, August 2010.19
`Adolescents aged 12 to 17 years and adults 18 years
`of age or older participated in the 2 human use studies.
`The REALM test20 and REALM-Teen test21 were
`administered to the adults and adolescents, respectively,
`in order to screen literacy levels for information only
`in analyzing the population. The tests are based on a
`list of 66 words commonly found on medication labels.
`The subjects needed to be able to read, speak, and
`understand the nature of the study procedures. They
`were excluded if they had ever been trained or employed
`as a healthcare professional or had participated in any
`clinical trial, product label study, or market research
`study in the past 12 months.
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`Study Design. The study was conducted in rooms
`equipped with 1-way mirrors for observation. To
`simulate a real-life emergency, study participants were
`challenged with administering the medication to an un-
`conscious victim, simulated by a full-sized mannequin.
`No training on the use of the device was provided prior
`to the usability assessment.
`Intranasal devices (Aptar Unit-Dose device, Louve-
`ciennes, France) were filled with 0.1 mL of water and
`packed into a blister card. The blister card, along with
`a Quick Study Guide (QSG) and patient information
`section of the package insert were packed into a carton.
`Study A (2 devices) was slightly more complex and
`was conducted prior to study B (1 device) in order to
`determine if individuals were able to perform critical
`tasks without reviewing the QSG. The objective of
`the QSG was to provide clear and concise instructions
`(combined with pictures) for use in a crisis situation
`with limited time to interpret the directions (Figure 1).
`Subjects in study A were randomized to 1 of 2 arms:
`subjects in arm 1 were given an opportunity to read the
`QSG in advance of the simulation, whereas subjects in
`arm 2 did not review the QSG in advance. Subjects in
`study B (1 device) did not review the QSG in advance
`of the simulation.
`Subjects were presented with a scenario of an un-
`conscious overdose victim simulated by a life-sized
`mannequin similar to those used for cardiopulmonary
`resuscitation training. Subjects were given the product
`with labeling and asked to proceed as they would in
`a real-life emergency; no training or coaching was
`provided either prior to or during the simulation.
`Background noise, in the form of TV and radio, was in-
`troduced into the scenario to simulate voices and noise
`from onlookers. A trained observer (located behind a
`1-way mirror) documented the steps that the subject
`took during the simulation. Once the subject completed
`the simulation, an interview was conducted in a sepa-
`rate room to evaluate comprehension of key concepts
`in the patient information section of
`the package
`insert. After the comprehension interview, additional
`questions were asked about any incorrect actions that
`were observed during the human factors testing; this
`information was obtained in order to identify any
`potentially confusing sections of the labeling.
`Data Analyses. The primary endpoints for the critical
`tasks were (1) inserting the device nozzle into a nostril
`and (2) pressing the plunger to release a dose into the
`nose. Secondary endpoints included (3) checking for re-
`sponse, (4) calling 911, and (5) moving to a recovery po-
`sition after administering dose. Study A also included
`(6) waiting 2 to 3 minutes to assess the effectiveness of
`the first dose and (7) readministration using a new unit
`(if needed). As a subject interfaced with a mannequin
`rather than a person, the observer was able to make
`
`judgments on mitigating circumstances in which the
`subject was either restricted or confounded by the
`mannequin. This allows a response that is “not perfect
`or technically correct” to be considered as “correct”
`if the subject’s intent indicates that he or she either
`understood the correct action or that the apparent
`incorrect action has no safety risk. An example would
`be partial insertion into the mannequin’s nose because
`it lacked flexibility of a human nose. These were added
`to the final correct performance scores of primary and
`secondary tasks.
`The correct score and lower boundary of the 95%CI
`were calculated for each of the 2 human factors primary
`endpoints. The correct score was the point estimate
`for execution of both critical tasks, defined as the
`total number of subjects who correctly completed both
`critical tasks, divided by the number of subjects who
`performed the tasks, multiplied by 100. Success criteria
`for the combined primary endpoints had a lower bound
`threshold of at least 69% for the correct scores in
`study A (2 devices) or at least 73% for the correct
`scores in study B (1 device). This was based on sample
`size and CIs around a mean, a point estimate of the
`population mean. For all remaining human factors
`tasks and comprehension objectives, correct scores and
`2-sided 95%CIs were computed; however, no thresholds
`were established. Subgroup analyses were conducted
`to evaluate any potential differences between subjects
`with low literacy and adolescent subjects aged 12 to
`17 years. An error rate of 6% for each task was
`estimated based on preliminary qualitative work using
`untrained users completing each task. This led to a
`projected probability of completing both critical core
`tasks correctly for any particular subject to be at least
`88%. This estimate is consistent with rates accepted by
`the FDA for other approved products expected to be
`used by the lay public, including nasal sprays. With a
`sample size of 30 subjects per arm, the probability of
`having the lower bound of the 2-sided 95%CI (of the
`estimated proportion of subjects correctly completing
`all core tasks) above the predefined 69% threshold was
`87%, assuming the true correct demonstration of the
`core tasks rate was 88%. With a sample size of 50
`subjects, the probability of having the lower bound
`of the 2-sided 95%CI (of the estimated proportion of
`subjects correctly completing all core tasks) being above
`the predefined 73% threshold was 88%, assuming the
`true correct simulated use demonstration of the core
`tasks rate was 88%.
`
`Results
`Pharmacokinetic Study
`Subject Characteristics. Eighteen male and 12 female
`subjects (Table 1) received at least 1 dose of naloxone;
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`Figure 1. Quick Start Guide for use with 1 (left panel) and 2 (right panel) intranasal devices used in study B and study A, respectively.
`
`Table 1. Pharmacokinetics of Naloxone: Subject Demographics
`
`All
`
`Male
`
`Female
`
`30
`35.8 (22–55)
`
`18
`36.9 (22–55)
`
`12
`34.2 (24–46)
`
`7
`23
`
`2
`28
`
`3
`15
`
`2
`16
`
`4
`8
`
`0
`12
`
`80.2
`(56–102)
`26.5
`(19.6–29.8)
`
`86.2
`(56–102)
`26.8
`(19.6–29.8)
`
`71.3 (57–85)
`
`26.1
`(22.0–28.7)
`
`Number
`Mean age, years (range)
`Race
`White
`Black/African
`American
`Ethnicity
`Hispanic or Latino
`Not Hispanic or
`Latino
`Mean weight, kg
`(range)
`Mean BMI,a kg/m2
`(range)
`
`aBMI, body mass index.
`
`28 subjects completed the study. One male subject dis-
`continued the study after 1 treatment period (treatment
`C) due to a systolic blood pressure greater than 140 mm
`Hg prior to the start of the second period. This predose
`elevation in blood pressure was judged to be unrelated
`to drug treatment. One other male subject withdrew
`for personal reasons after completing 4 treatments; this
`individual did not receive treatment C.
`
`Pharmacokinetics. Naloxone plasma concentrations
`were above the lower limit of quantitation (10.0 pg/mL)
`at 2.5 minutes after IN administration,
`the first
`collection time point,
`in all but 1 (an individual
`receiving an 8-mg dose) of 114 samples collected;
`concentrations were measurable in 22 of 29 samples
`following IM injection (data not shown). The median
`tmax values after IN and IM doses ranged from 20
`minutes to 30 minutes, indicating that naloxone was ab-
`sorbed rapidly following either route of administration
`(Table 2; Figure 2). The mean Cmax values increased
`from 3.1 ng/mL to 10.3 ng/mL as the IN dose increased
`from 2 mg to 8 mg; the mean Cmax value following
`IM dosing was 0.9 ng/mL. AUC0-Ý increased from
`4.7 ng·h/mL to 15.8 ng·h/mL as the IN dose increased
`4-fold from 2 mg to 8 mg. The terminal elimination
`half-life of naloxone after all 4 IN regimens was ap-
`proximately 2 hours; it was 1.3 hours after the IM injec-
`tion. The geometric mean ratios of the dose-corrected
`Cmax values of the IN doses compared to the IM dose
`ranged between 55.1% and 70.8%, whereas the ratio
`was approximately half for AUC0-Ý (Table 3). Based
`on the actual and dose-corrected values of Cmax and
`AUC, the IM and IN doses were not equivalent. The
`pharmacokinetic properties of naloxone following IN
`administration were similar between male and female
`subjects for all 4 treatments (Figure 3, Table 4).
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`Table 2. Pharmacokinetics of IN and IM Naloxone
`
`Parameter (Units)a
`
`Nb
`Cmax (ng/mL)
`tmax (hours)
`AUC0-Ý(ng·h/mL)
`t½ (hours)
`CL/F (L/h)
`
`2 mg, 1 Spray
`20 mg/mL IN (A)
`
`4 mg, 2 Sprays
`20 mg/mL IN (B)
`
`4 mg, 1 Spray
`40 mg/mL IN (C)
`
`8 mg, 2 Sprays
`40 mg/mL IN (D)
`
`29
`3.1 (36.1)
`0.3 (0.3,1.0)
`4.7 (29.8)
`1.9 (34.6)
`452.5 (24.4)
`
`29
`6.5 (32.3)
`0.3 (0.2, 0.6)
`9.7 (26.7)
`2.4 (31.7)
`435.4 (22.3)
`
`29
`5.3 (44.6)
`0.5 (0.2, 1.0)
`8.5 (39.0)
`2.2 (29.1)
`534.7 (35.9)
`
`29
`10.3 (38.1)
`0.3 (0.2, 1.0)
`15.8 (23.1)
`2.2 (39.0)
`530.4 (22.0)
`
`0.4 mg IM
`(E)
`
`29
`0.9 (31.2)
`0.4 (0.1, 2.1)
`1.8 (22.7)
`1.3 (27.8)
`232.8 (22.4)
`
`aMean (%CV) for all except median (range) for Tmax. %CV, percent coefficient of variation; AUC0-inf, area under the plasma concentration-time curve from time
`zero to infinity CL/F, apparent clearance; Cmax, maximum plasma concentration; t½, terminal half-life; tmax, time to Cmax.
`bNumber of subjects receiving treatment.
`
`Figure 2. Plasma concentrations of naloxone following intranasal and intramuscular administration of naloxone HCl. Twenty-eight subjects were
`randomized in a 5-period, 5-treatment, 5-sequence crossover study, receiving 1 or 2 doses (0.1 mL per nostril) of a naloxone HCl formulation (20 and
`40 mg/mL) or an intramuscular injection of 0.4 mg. IN, intranasal; IM, intramuscular.
`
`Table 3. Naloxone Statistical Summary of Treatment Comparisons (Intranasal vs Intramuscular Administration)
`
`Parameter (Units)a
`
`Cmax/Dose
`(ng/mL/mg)
`
`AUC0-Ý /Dose
`(ng·h/[mL·mg])
`
`IN Administration
`(Test)
`
`2 mg IN (Trt A)
`
`4 mg IN (Trt B)
`4 mg IN (Trt C)
`8 mg IN (Trt D)
`2 mg IN (Trt A)
`
`4 mg IN (Trt B)
`4 mg IN (Trt C)
`8 mg IN (Trt D)
`
`Comparison
`
`Ratio (Test/Reference)
`of Adjusted Meansb
`
`90%CI for Ratio
`
`A vs E
`
`B vs E
`C vs E
`D vs E
`A vs E
`
`B vs E
`C vs E
`D vs E
`
`66.7
`
`70.8
`55.1
`55.3
`51.9
`
`53.5
`46.2
`43.9
`
`(59.5-74.7)
`
`(63.2-79.4)
`(49.2-61.8)
`(49.3-62.0)
`(48.3-55.8)
`
`(49.8-57.5)
`(43.0-49.8)
`(40.8-47.2)
`
`aAUC0-Ý/Dose,AUC per milligram naloxone administered;Cmax/Dose,Cmax per milligram naloxone administered;IM,intramuscular,IN,intranasal;Trt,treatment.
`bGeometric least-squares mean ratio between treatments, expressed as a percentage of IM administration (reference, treatment E); see Table 2 for additional
`detail.
`
`A power model was used to test for dose propor-
`tionality following IN naloxone.17 This was assessed
`by plotting the slope of the log dose and the log of
`Cmax and AUC0-Ý. A slope equal to 1.0 would indicate
`dose proportionality. The slope and 90%CI of the line
`for Cmax were 0.83 and 0.74 to 0.93. For AUC0-Ý, the
`slope and 90%CI of the line were 0.85 and 0.78 to
`
`0.91, indicating exposure to naloxone approached dose
`proportionality as the dose was increased from 2 mg to
`8 mg.
`
`Safety. There were no differences in the safety profile
`of IN naloxone compared to IM dosing. No significant
`erythema, edema, erosion, or other signs were observed
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`Krieter et al
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`7
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`Figure 3. Plasma concentrations of naloxone in male and female subjects following intranasal administration of 2, 4, and 8 mg naloxone HCl. Male
`and female subjects received either a single 0.1 mL intranasal dose (20 and 40 mg/mL) or 2 doses (1 in each nostril) of naloxone HCl (40 mg/mL).
`
`Table 4. Pharmacokinetics of Naloxone in Female and Male Subjects
`
`2 mg, 1 Spray
`20 mg/mL IN (A)
`
`4 mg, 2 Sprays
`20 mg/mL IN (B)
`
`4 mg, 1 Spray
`40 mg/mL IN (C)
`
`8 mg, 2 Sprays
`40 mg/mL IN (D)
`
`0.4 mg IM
`(E)
`
`Parameter (Units)a
`
`Female
`
`Male
`
`Female
`
`Male
`
`Female
`
`Male
`
`Female
`
`Male
`
`Female
`
`Male
`
`Nb
`Cmax (ng/mL)
`
`Tmax (h)
`AUC0-Ý (ng·h/mL)
`
`t½ (h)
`
`CL/F (L/h)
`
`12
`2.8
`(25.6)
`0.3
`(0.3, 0.8)
`4.6
`(31.3)
`1.7
`(33.6)
`463.5
`(25.3)
`
`17
`3.3
`(39.5)
`0.3
`(0.3, 1.0)
`4.8
`(29.5)
`2.1
`(33.7)
`447
`(24.3)
`
`12
`6.4
`(25.0)
`0.3
`(0.2, 0.6)
`9.6
`(19.3)
`2.5
`(35.4)
`432.6
`(22.0)
`
`17
`6.6
`(37.0)
`0.3
`(0.2, 0.5)
`9.8
`(31.4)
`2.3
`(28.8)
`437.4
`(23.2)
`
`12
`5.1
`(41.0)
`0.5
`(0.2, 0.8)
`7.8
`(39.3)
`2.4
`(33.1)
`571.1
`(33.1)
`
`17
`5.4
`(47.7)
`0.5
`(0.2, 1.0)
`8.9
`(38.9)
`2.0
`(23.7)
`509.0
`(38.4)
`
`12
`9.6
`(29.4)
`0.3
`(0.2, 0.8)
`14.6
`(22.6)
`2.4
`(49.1)
`572.2
`(21.9)
`
`17
`10.9
`(41.9)
`0.4
`(0.2, 1.0)
`16.7
`(22.5)
`2.1
`(26.5)
`501.0
`(20.6)
`
`12
`1.1
`(28.2)
`0.4
`(0.1, 0.8)
`1.8
`(20.6)
`1.1
`(20.7)
`226.5
`(21.0)
`
`17
`0.8
`(29.2)
`0.5
`(0.2, 2.1)
`1.8
`(24.7)
`1.4
`(27.9)
`237.3
`(23.7)
`
`aMean (%CV) for all except median (range) for Tmax; %CV, percent coefficient of variation; AUC0-Ý, area under the plasma concentration-time curve from time
`zero to infinity; CL/F, apparent clearance; Cmax, maximum plasma concentration; t½, terminal half-life; Tmax, time to Cmax.
`bNumber of subjects receiving treatment.
`
`Table 5. Nasal Mucosal Adverse Events Following IN Naloxone
`
`Treatment
`
`Erythemaa
`
`Edemaa
`
`Othera,b
`
`Totala
`
`with IN administration: 1 for nasal pain after the 2-mg
`dose and 1 for headache after the 8-mg dose.
`
`2 mg (20 mg/mL, 1 spray)
`4 mg (20 mg/mL, 2 sprays)
`4 mg (40 mg/mL, 1 spray)
`8 mg (40 mg/mL, 2 sprays)
`
`aAll AEs were grade 1.
`bNasal pain.
`
`3
`1
`1
`0
`
`3
`0
`2
`1
`
`1
`0
`0
`0
`
`7
`1
`3
`1
`
`in the nasal cavity prior to or after administration of
`IN naloxone. Few adverse events (AEs) associated with
`the nasal mucosa were reported; all were mild (grade 1),
`transient, and with no clear relationship to dose
`(Table 5). Vital signs, ECG, and clinical laboratory
`parameters did not reveal any clinically significant
`changes or evidence of QTcF prolongation after nalox-
`one administration. Two additional AEs were reported
`
`Human Factors and Usability
`Subject Characteristics. The human factors studies
`were conducted in a population of 116 participants
`(Table 6). Combined, 33 subjects were adolescents (aged
`12 to 17 years), and 83 were adults (aged 18 years or
`older). A total of 59 (50.9%) had low literacy, and 57
`(49.1%) had normal literacy.
`Subjects demonstrated the ability to correctly per-
`form both critical tasks, meeting the success threshold
`in studies using either 1 or 2 devices (Table 7). Using
`1 device, 90.6% of subjects (n = 48 of 53) were able
`to correctly perform both critical tasks. Similar results
`were obtained in the study using 2 devices: in arm
`1, which included a review of the QSG, 90.6% (n =
`29 of 32) of subjects correctly performed both critical
`tasks, while in arm 2, 90.3% (n = 28 of 31) of subjects
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`8
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`The Journal of Clinical Pharmacology / Vol 00 No 0 2016
`
`correctly performed both critical tasks without review-
`ing the QSG. In all cases the lower bound of the 95%CI
`was exceeded. Five secondary human factors tasks
`(Table 7) were also evaluated with correct performance
`ranging from 37.7% to 93.8% depending on whether
`1 or 2 devices was used and whether or not the QSG
`was reviewed in advance. Among the secondary tasks
`evaluated, 70% to 80% of subjects correctly adminis-
`tered a second IN dose, although fewer than 60% were
`able to correctly administer this second dose within 2
`to 3 minutes of the first dose (Table 7). Among other
`secondary tasks evaluated, the lowest scoring items
`included moving the victim to a recovery position and
`waiting 2 to 3 minutes before administering a second
`dose (Table 7). Comprehension was also evaluated
`on 9 communication objectives found in the patient
`information section of the package insert to insure that
`the general population could understand key messages.
`Overall, the scores were high, ranging from 70% to
`100%, with most scores in the 90% to 100% range
`(Table 8).
`
`Discussion
`Here, we demonstrate that IN administration of a
`naloxone HCl (2 to 8 mg) formulation in low volume
`(0.1 to 0.2 mL) results in PK parameters that either
`equal or exceed those observed following the IM dose
`of naloxone (0.4 mg) that is approved for the treatment
`of opioid overdose. The time to peak naloxone plasma
`concentration following IN administration was inde-
`pendent of dose and ranged from 0.3 hour to 0.5 hour
`compared with 0.4 hour following IM injection (Table
`4). The maximum plasma concentration obtained be-
`tween 2 mg and 8 mg approached dose proportionality,
`exceeded the maximum concentration produced by the
`0.4 mg IM dose of naloxone, and was independent of
`delivery to either 1 or both nostrils (Table 2, Figure 2).
`Moreover, at the earliest time sampled (2.5 minutes),
`plasma naloxone concentrations after IN administra-
`tion of 2 mg to 8 mg were higher than following
`the 0.4-mg IM dose; this rapid rise may be advan-
`tageous for reversing respiratory depression in opioid
`overdose.
`The high plasma concentrations of naloxone fol-
`lowing IN administration reported here (Figure 2,
`Table 2) may be viewed as surprising based on a study
`reporting an absolute bioavailability of 4% after IN
`administration.22 In that study, naloxone (0.8 and 2 mg)
`was administered in volumes of 1 and 2.5 mL/nostril
`with a mucosal atomizing device. Optimal delivery vol-
`umes for IN drug administration are ࣘ0.2 mL/nostril.23
`This low bioavailability was attributed to the delivery
`of relatively large volumes to healthy, awake volunteers
`who swallowed significant amounts of drug that pooled
`
`Table 6. Human Factors and Usability Study Demographics
`
`Study A
`(N = 63)
`
`Study B
`(N = 53)
`
`Characte