`
`ased on 1:
`doer, He in"
`
`Administration
`
`Aaron” H. Burstein, PharmD. BCPS, Rosanne Modica, DDS, Michael Hutton, DDS, FADSA,
`Alan Forrest, PharmD, and Fran M. Gengo. PharmD, FCP
`
`MM
`This study aimed to characterize the pharmacokinetics and pharmacodynamics ofmi—
`dazolam after intranasal administration to healthy volunteers. Eight participants were
`git/spit}?
`
`. M
`ngg‘intranasally and 2 mg intravenously in a randomized. crossoverfash-
`ion. Blood samples for determination ofplasma concentrations ofmidazolam and mea-
`sures of cognitive function Iusing the digit symbol substitution test} were obtained at
`baseline and 5, I 0. 20. 30. 45, 6'0, .90. I20, 180, 240, and 360 minutes after administration
`of study medications. Plasma samples were analyzed by gas chromatography {% coeffi-
`cient of variation (10%]. Pharmacolcinetic data were fitted using iterative two-stage
`analysis to a two-compartment model. Pharmacodynamic data were fitted by a baseline
`subtraction Hill-type model. The mean (SD}for total clearance. distributional clearance,
`volume ofdistribution in the central compartment, volume of distribution in the periph-
`eral compartment, absorption rate constant, bioavailability,
`and half-life were 0.57
`{0.26} L/hr/kg. 0.31 (0.29) L/hr/kg. 0.27 {0.14} L/ g,
`0.67 (0.11} L/kg, 2.46 {1.72) hr",
`09/ {13%}, and 3.1 (0.84} hours. respectively.
`ThermeanzslrSDJ-for:,the..concentration at
`which the effect is half maximal [ECsol and the maximal efiect or the maximal change
`
` --.-8 (21.1} correct
`in efi‘ect measure from baseline (Rum) weretbfll (21.2} ng/mL and;
`substitutions. respectively. After intranasal administration. midazolam concentrations
`rapidly achieve values considered sufi‘i‘cient to induce conscious sedati
`on and produce
`predictable changes in digit symbol substitution score.
`
`
`
`
`
`M
`
`
`
`
`
`Clinical efficacy of midazolam for the induction of
`sedation, reduction of anxiety, and induction of
`amnesia is Well documented after intravenous“2 and
`oral3 administration. Despite the advantages of rapid
`sedative effects, there are disadvantages associated
`With intravenous administration, primarily the ne—
`
`I
`
`: Department of Pharmacy Practice and Science. Phaimacokinet—
`FrC.
`ICE and Biopharmaceutics Laboratory, University of Maryland at Balti~
`more, Baltimore. Maryland (Dr. Bursteinl, the Department of Dental Medi-
`une (Dis. Modica and Hatton) the Division of Neuropharmacology (Dr.
`Ge"Eel. Dent Neurologic Institute, Buffalo, New York. the Clinical Pharma-
`Cokinetics Laboratory (Dr. Forrest). Millard Fillmore Hospital. Buffalo,
`New York, and' the Departments of Pharmacy Practice and Neurology
`f Dr. Gengo). The State University of New .York at Buffalo. Buffalo. New
`{Wk (Drs. Gengo and Forrest). Submitted for publication February 27,
`19‘37: accepted in revised form April 28. 1997. Address for reprints:
`Aa'
`‘
`‘. Burstein, PharmD, Department of Pharmacy Practice and Scil
`l
`3’“
`iiversity of Maryland at Baltimore. 100 Penn Street. Suite 540.
`3a.. ore. MD 21201.
`'
`
`'
`
`cessity of an injection. In patients with a fear of nee-
`dles and injections, this route of administration may
`precipitate fear and anxiety. In an attempt to reduce
`anxiety, while obviating the use of anxiety-potentiat-
`ing injections. intranasal administration has been
`used, primarily in pediatric patients, for the induc—
`tion of conscious sedation. Although a limited
`amount of intranasal pharmacokinetic data is avail-
`able in pediatric patients, no information is available
`regarding the plasma concentration profile and phar-
`macokinetics of midazolam after intranasal adminis—
`tration of midazolam to adults. The purpose of this
`study. therefore. was to evaluate the pharmacokinet-
`ice and pharmacodynamics of midazolam after intra-
`nasal administration to adult volunteers.
`
`METHODS
`
`Study Conduct
`
`The study was approved by the institutional Review
`Board of Millard Fillmore Health Systems (Buffalo.
`
`711
`
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`BURSTEIN ET AL
`
`
`
`ministration and to refrain from swallowing f.'
`long as comfortably possible.
`]
`After administration of study medication.
`.
`
`hours), blood samples [5 mL) were collected .'
`the intravenous catheter into Ka-EDTA Vacut.
`
`tubes {Becton-Dickinson Vacutainer Systems, F
`lin Lakes, NI] at 5, 10, 20, 30, 45, 60, 90, 120,
`240, and 360 minutes. Samples were centrifuge ‘
`mediately for 10 minutes, and plasma was harve"
`
`and frozen at —20°C until analyzed for midazo“
`concentration.
`7,
`Digit symbol substitution tests were performs“
`baseline and 10, 30, 50, 90, 120, 180, 240, and
`
`minutes after infusion of the study medications
`
`number of correct substitutions during each 90
`ond testing interval were counted. Different versi'
`
`
`
`NY}. Before enrollment, all volunteers gave written
`informed consent.
`Healthy male and nonpregnant female nonsmokers
`were considered eligible for inclusion in the study if
`they were at least 18 years old. Potential participants
`were excluded if there existed a history of hepatitis;
`renal, respiratory, cardiovascular, or psychiatric dis—
`ease; sensitivity to benzodiazepines or lidocaine;
`drug or ethanol abuse; or if women were not practic-
`ing a medically approved method of contraception.
`Eight volunteers (six men, two women} were en-
`rolled in the nonblind, randomized, crossover study.
`Within 4 days before the first study day, participants
`were oriented to the tests of cognitive function to be
`used He, digit symbol cognitive function substitu-
`tion test [DSST]]. Administration of practice tests
`was repeated until stable baseline test scores were
`achieved. Volunteers were assigned randomly to
`groups regarding the order of administration of the
`intranasal and intravenous doses of midazolam.
`Volunteers reported to the study unit at 7:00 AM
`each study day after an 8—hour overnight fast. They
`were continued to fast until 2 hours after administra-
`tion of the study drug, at which time they were pro-
`vided with a light breakfast [juice and muffin]. Caf-
`feine-containing foods and beverages were avoided.
`An intravenous catheter was placed into a peripheral
`vein in the nondominant arm. Baseline blood sam'
`ples were obtained, and the DSST was administered.
`Doses of study medication were then administered.
`Doses administered as intravenous injections con-
`sisted of a single 2-mg dose of midazolam adminis-
`tered as intravenous bolus doses through a heparin
`lock over 2 minutes. After administration, the hepa-
`rin lock was flushed with two separate 10~mL saline
`flushes. After a minimum 4-day washout period, par-
`ticipants Were crossed over to the remaining treat-
`ment. Vital signs, including heart rate, blood pres-
`sure and oxygen saturation, were monitored continu-
`ously throughout each study day.
`_
`Five minutes before intranasal administration,r._vol:
`upteers were_administeredtwosprays-oi14%-:»topical
`
`headers” {01.631
`nostril. Doses of study medica-
`tion administered intranasally consisted of a single
`0.25-mg/kg dose of midazolam. The study medica-
`tion was drawn up, immediately before. administra-
`tion, into___s_y_ringe of the..appropriate volume from a
`stodk“solution."icon/aiming of the intravenous '5'—'m'g/
`nib-concentrationsolution. The needle was removed
`from the syringe, an.d._.an,intrayenqufifiannnla. was
`attached, allowing a ‘ eigible tube ,tobe-inserted into
`the nares'forladlf'ninislr_ation.The intranasal dose was
`administered git a..rate...o.f .1...m-Lr/min. with administra-
`tion alternated between nostrils in 1-mL increments.
`Volunteers were instructed to inhale with each ad-
`
`712 0 J Clin Pharmacot 1997;37:711-718
`
`Assay of Samples
`
`
`
`
`
`Plasma samples were analyzed for midazolam c’
`centrations using a slightly modified version of
`gas chromatography method of De Kroon et al.‘1 St
`dard curves were prepared over the range of 10
`mL to 300 ng/mL. Aliquots of patient plasma samp
`were treated with 250 pl. of water and 20 JuL ofa 5_
`
`ng/mL diazeparn internal standard solution. 80'
`phase extraction was performed using loo-mg
`cartridges. Benzodiazepines were eluted with 500'
`of methanol. After evaporation under N; at 50°C,
`residue was reconstituted with 50 ,uL of toluen _
`methanol/acetone [85/15/5]. Aliquots of these reco
`stituted solutions were injected onto a Varian {Vari
`Chromatograph Systems, Walnut Creek, CA) 34
`GO using an Alltech (Alltech Associates Inc., D
`field, IL] 6 meter by 1/.,-inch OV17 column with hi I‘-'
`gen as the carrier gas. The sensitivity of the assfi
`
`with 1 uL of sample was 10 ng/mL,and was line‘s":
`over the range of 10 ng/mL to 300 ng/mL. Overflfi;
`
`the 0/o coefficients of variation of the assay were.
`9.9%, 4.5%, and 9.6% at concentrations of 15 nél
`mL, 80 ng/mL, and 260 ng/mL, respectively.
`%
`Pharmacokinetic/Pharmacodynamic Modeling
`g. I
`"it
`Iterative two-stage analysis using the computer soft;
`ware package Adapts [Biomedical Simulations R
`source, University of Southern California. L“,
`Angeles. CA] was performed to fit candidate pharmfl;
`cokinetic and pharmacodynamic models
`to 3%
`plasma concentration—time and pharmacodynnml
`data. An explanation of this technique is provideg
`elsewhere.” Model discrimination was performed byg
`
`
`
`
`
`
`
`:4':*.:55.,...1¢..m-ui
`
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`MIDAZOLAM PK AND PD AFTER INTRANASAL ADMINISTRATION
`f____—._.__w._____._________—_____—____
`
`cations.
`each 90
`
`inspection of residuals and Akaike’s information cri~
`rion.
`ta 131
`-:ma concentration time data after the intranasal
`ant"
`ravenous doses were simultaneously fitted us-
`ing a linear, two-compartment intravenous injection
`and nasal absorption model. Modeling incorporated
`a residual variance model in which the standard de—
`viations of the observations were related linearly to
`the fitted values. The parameters estimated for mida—
`zolam included the volume of distribution in the
`central compartment [Vc], volume of distribution in
`the peripheral compartment
`[VP], distributional
`clearance [Cld] for both intranasal and intravenous
`ad:
`;,,.stration and total clearance [Cl], absorption
`rate constant [K3], and bioavailability [F] for intrana—
`sal administration. Initial modelling allowed VG, VP,
`and C1,; to differ between intranasal and intravenous
`administration, with Cl assumed to be similar.
`Pharmacokinetic parameter estimates obtained
`from the initial modeling process were fixed in each
`volunteer. and pharmacodynamic measures were
`subsequently modeled. Plasma concentration DSST
`effer‘ data were fitted by the following baseline sub-
`tra
`. :n Hill-type equation:
`
`“E Ew-cr
`”EC;,,+ c7
`
`Ition. 8011'.)—
`IOU-mg F.-
`
`-
`
`
`
`where E0 is the baseline effect, Emax is the maximal
`effect or the maximal change in effect measure from
`baseline, ECSO is the concentration at which the effect
`is 1/2 maximal, C is the plasma concentration of mida-
`zolam. and F is the slope term. Despite the assump-
`tic. hat the learning curve was complete before
`study, it was decided to model the baseline effect.
`On determining the appropriate pharmacodynamic
`model, both plasma concentrations and pharmaco-
`dynamic measures were simultaneously fitted by the
`
`pharmacokinetic and pharmacodynamic models.
`
`
`' healthy volunteers were enrolled in this inves-
`E31
`on. Of these. six were men and two were
`Ug
`Women. The mean [SD] age and weight of partici—
`
`pants were 29.5 [5.2] years and 77.9 [16.6] kg, respec-
`tively. A summary of the demographic characteris—
`nputer sofij
`llcs of participants is provided in Table 1. Treatment
`ilations Ref;-
`Was Well tolerated by all volunteers except subject
`fornia, Los
`{10. 5. Within 10 minutes of administration of the
`' ate pharmaj‘“
`lTltranasal dose {on study day 2], this volunteer be-
`lels
`to fill?
`Ciflme lethargic, difficult to arouse, and hypotensive.
`lCOCl menu“.
`F
`‘azenil at 2-mg was administered intravenously
`is ptihvided
`3‘
`prompt reversal of the lethargy and improve-
`:rformed by
`mm: in blood pressure. Pharmacodynamic data for
`
`RESULTS
`
`‘
`
`
`TABLE 1
`
`Subject Demographic Information
`
`Subject
`No.
`
`1
`2
`3
`4
`5
`6
`7
`8
`Mean
`SD
`
`Age
`{yr}
`
`28
`31
`30
`24
`26
`29
`41
`27
`29.5
`5.2
`
`Weight
`(kg)
`
`82.7
`72.7
`109
`93.2
`72.3
`72.3
`60.0
`60.9
`77.9
`16.6
`
`Gender
`
`M
`M
`M
`M
`M
`M
`F
`F
`
`M, male: F, female.
`
`
`subject no. 5 was subsequently considered uninter-
`pretable for analysis. As flumazenil has been shown
`to have no significant effect on midazolam pharma-
`cokinetics,‘3 however, the concentration—time data
`for this volunteer was included in the pharmacoki-
`netic analysis.
`Plots of midazolam plasma concentration-dime
`curves for intranasal and intravenous administration
`
`are shown in Figures 1 and 2, respectively. Midazo—
`lam was absorbed rapidly after intranasal adminis-
`tration, with maximal concentrations achieved with
`a mean [range] of 25 [10—48] minutes after the initia-
`tion of administration. Maximal concentrations were
`
`variable with mean [range] values of 147 [91.3-—
`224.3] ng/mL. A two-compartment model was statis—
`tically superior for describing the data in all but sub-
`ject no. 3. The concentration-time profile for subject
`no. 3 exhibited dual peaks, with the first peak oc-
`curring 20 minutes after administration and the sec-
`ond peak occurring 120 minutes after administration
`{Figure 3]. To describe the dual peak phenomenon
`adequately in this volunteer, modeling incorporated
`both intranasal and oral absorption components with
`a lag time to the onset of oral absorption.
`The mean [SD] values for Cl, Cid, Va. VP, K,“ and
`half—life [tm] were 0.57 [0.26] L/hr/kg, 0.31 [0.29] L/
`hr/kg, 0.27 [0.14] L/kg, 0.67 {0.11) L/kg, 2.45 {1.72}
`hr". and 3.1 [0.84] hours, respectively. Mean [SD]
`values 0f50% [13%] of the dose were absorbed after
`intranasal administration. A summary of parameter
`values for individual participants is provided in Ta-
`ble II.
`Plots of DSST score-versus-time curves for intrana-
`
`sal administration are shown in Figure 4. impair-
`ment of participants' performances was evident early
`
`PHARMACOKINETlCS AND PHARMACODYNAMICS
`
`713
`
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`

`BURSTEIN ET AL
`
`
`
`
`after administration, with maximal impairmen
`
`curring 30 minutes (range, 15—120 minutes) afte'
`ministration of the intranasal dose. The maxim.
`duction in DSST score was variable, with per
`
`reductions ranging from 33% to 97%.
`A representative plot of the midazolam pla
`
`concentration—effect profile for subject no.
`shown in Figure 5. No hysteresis loops were id
`
`fied in any of the volunteers. The mean (SD) val
`
`for ECso and Emax were 63.1 [21.2) ng/mL and 5
`{21.1} correct substitutions, resPectively. A sum.
`
`of individual values is provided in Table III.
`
`
`
`DISCUSSION
`
`The intranasal route of administration for midazo _._
`may represent an attractive alternative to the con
`tional intravenous and oral routes of administrati
`for inducing conscious sedation. A large grou '
`patients,
`including those with mental disabili
`
`and violent and combative patients, often pose .
`
`culties when medications are administered to indu
`Sedation before procedures SUCh as dental work
`
`these patients the anxiety associated With the pm
`.
`’
`.
`.
`'
`dure lS often exacerbated by the fear and antimpat
`pain of receiving an injection. At the authors' insti'
`tion, these patients often require general anesthe "
`and the use of an operating room suite to sedate th .
`
`
`
`
`_nvb-D
`
`.1 MO
`
`100
`
`a!O
`
`O!0
`
`hD
`
`E‘a.
`
`5 Sa
`
`EC
`8C
`
`O0
`
`1”“
`
`25°
`20°
`15°
`Tm (minutes)
`
`3°“
`
`35°
`
`‘00
`
`Figure 1. Plasma concentration-time profiles Of midazolam
`afterintranasal administration ofa 0.25-mg/kg dose. Each point
`[0} represents the mean value; error bars represent standard
`ermm
`
`
`
`
`
`Concentratlon(nglml) 3D
`
`(nglml)
`
`
` _.- MD
`
` Concentration
`
`100
`
`150
`
`200
`
`250
`
`Time (minutes)
`
`
`
`“ir-
`Figure 3. Plasma concentration—time profile of midazolam HIT“.
`inimnasal administration in subject no. 3.
`*1
`
`
`300
`350
`
`
`
`
`
`
`100
`
`250
`200
`150
`Time (minutes)
`
`300
`
`350
`
`400
`
`Figure 2. Plasma concentration—time profile of midazolam after
`intravenous administration ofa 2-mg fixed dose. Each point {0)
`represents the mean value: error bars represent standard errors.
`
`714 0 J Clin Pharmacol 1997;37:711-718
`
`_____.___,
`
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`

`MIDAZOLAM PK AND PD AFTER INTRANASAL ADMINISTRATION
`
`W S
`m T
`
`ABLE I!
`
`ummary of Pharmacokinetic Parameters of Midazoiam after lntranasal Administration
`_WW
`Subject
`Vc
`Vp
`Cld
`Clt
`tm
`Ka
`_No.
`(L/kg:
`tL/kg)
`(L/hr/ksl
`lLflIr/kel
`1hr}
`(hr-‘1
`
`F
`
`1
`2
`3
`4
`5
`6
`7
`
`Mean
`so
`
`0.021
`0.39
`0.25
`0.19
`0.27
`0.20
`0.34
`0.46
`0.27
`0.14
`
`0.66
`0.65
`0.81
`0.73
`0.79
`0.47
`0.57
`0.67
`0.67
`0.11
`
`0.39
`0.38
`0.43
`0.71
`0.97
`0.91
`0.42'
`0.33
`0.57
`0.26
`
`0.26
`0.45
`0.31
`0.17
`0.19
`0.23
`0.35
`0.55
`0.31
`0.29
`
`3.0
`2.5
`3.4
`4.4
`4.2
`2.3
`2.5
`2.5
`3.1
`0.34
`
`1.5
`1.4
`. 1.3
`4.3
`1.4
`4.8
`2.7
`1.7
`2.5
`1.7
`
`0.53
`0.46
`0.49
`0.41
`0.76
`0.44
`0.33
`0.56
`0.50
`0.13
`
`c, volume of distribution in central compartment; Vp. volume of distribution in peripheral compartment; Cid, distributional
`clearance; Cit, total clearance: 13,2, hart-lite; Ka, absorption rate constant; F. bioavailability.
`m
`
`successfully to allow performance of the dental pro-
`cedures. Clearly, any alternative that induces seda-
`t:3.. effectively while avoiding the use of general an-
`esthesia and operating room time has significant im-
`plications not only for patient safety but also for the
`cost of routine dental surgical procedures.
`To the authors’ knowledge, this study is the first to
`
`model the disposition of midazolarn after intranasal
`administration to adults. Previously, Walbergh et a113
`studied the concentration—time profile of both intra-
`venous and intranasal midazolam after administra—
`tion to pediatric patients. However, in this study,
`only maximal concentrations and the time to attain
`these concentrations were determined. Their finding
`ofa mean (1- SD] peak concentration of 72.2 (t 27.3]
`ng/mL and time to peak concentration of 10.2 (i 2]
`minutes suggests that rapid attainment of significant
`
`50
`
`IDO
`
`1:10
`
`Concentrann (mg/HM)
`
`,5
`
`wcO
`
`.m+
`jd-l
`Im
`.D
`5
`Cf)
`-u-’
`
`UuhL
`
`OUu
`
`.0a
`
`s‘1
`Ed(I!in
`D
`
`O
`
`50
`
`100
`
`150
`
`200
`
`250
`
`300
`
`350
`
`400
`
`Time (minutes)
`
` M V
`
`
`
`mG
`
`ifc
`
`E Eawz:u E 5;oup
`
`.3n
`D
`
`
`
`3
`=
`
`
`
`
`pairmentlp'. ‘2.
`ites] after-'10
`
`maximal
`Nith per
`
`3
`)lam plas '
`ct no. 4
`.
`were 1de
`"313) val
`
`
`
`
`-_.
`
`
`
`
`
`
`l anesthe'_
`sedate the4
`
`anticipa
`101:5 1nst1
`
`I
`
`dozolam afier
`
`re 4. Digit symbol substitution test (0887") score during each
`«acond testing session. Each point {0) represents the mean
`Wine: error bars represent standard errors.
`
`Figure 5. Representative true (Cl and predicted {solid line} digit
`symbol substitution test {DSSTJ‘ score versus the plasma concen-
`trotion curve for rnidnzolam for subject no. 4.The DSST score is
`the number of correct substitutions completed during the {NJ-sec-
`ond testing session.
`
`PHARMACOKINETICS AND PHARMACODYNAMICS
`
`715
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`

`BUHSTEIN ET AL
`
`
`
`
`
`'l—I—I—I-q—u“
`TABLE ill
`
`Summary of Pharmacodynamic Parameters of
`Midazotam after lntranasal Administration
`
`Emu
`Subject
`Eo
`(change from
`E050
`
`No.
`(baseline no.l*
`baseline}?
`{ng/mL)
`G
`
`2.54
`75.5
`44.4
`69.3
`1
`2.74
`62.3
`33.9
`66.0
`2
`4.15
`29.5
`29.7
`83.5
`3
`3.48
`41.3
`72.7
`100.0
`4
`NA:
`NA:
`NA:
`NAI
`5
`2.40
`86.1
`79.5
`73.6
`6
`0.90
`83.3
`72.0
`74.4
`7
`3.89
`63.8
`37.3
`84.0
`8
`2.87
`63.1
`52.8
`78.7
`Mean
`_...._________________m___
`SD
`11.5
`21.1
`21.2
`1.10
`' Baseline number of correct substitutions.
`t Change from baseline in the number of correct substitutions.
`1: Pharmaccciynamic data unavailable due to flumazenil administration.
`E0, baseline effect; Em, maximum effect or maximum change in effect; E050,
`concentration at which effect is 1/2 maximal; NA, not available.
`—“-—IIIIII—I—I-———*
`
`plasma concentrations may be obtained after intrane-
`sal administration of 0.1 mg/kg. Similarly, Rey et a1“
`conducted a comparative pharmacokinetic study of
`intravenous and intranasal midazolarn administra—
`tion to pediatric patients. Mean time to achieve a
`mean [1 SD] maximal concentration of 104 (t 32}
`,ug/ L was 12 (i 4) minutes after a dose of 0.2 mg/kg.
`Additionally, the investigators found higher appar-
`ent plasma clearances and volumes of distribution
`after intranasal administration.
`Maximal concentrations in the present investiga-
`tion were attained a mean [range] of 25 [10—48) min—'
`utes after the intranasal administration of midazo-
`lam. Although this time is longer than those pre-
`viously reported in pediatric patients,”'“ the results
`'-are of limited clinical significance. It has been re-
`ported previously that the threshold concentration
`for induction of conscign ,_sedation».is-407-ng/mL.15“
`- ‘7 Evaluation of the mean ntranasal plasma concen—
`tration—time profile shows that participants attained
`concentrations exceeding this th=reshold...concen-tra—
`tion.,..as..early ..as» 1.10-"minutes after administration.
`Mean plasma concentrationwas sustained above this
`thresthFl.contentration retinitis 'I'1:80"minutes (range,
`90—360 minutes in individual volunteers). Although
`maximal effects would not be expected until 25 min-
`utes after administration, adequate conscious seda-
`tion of sufficient duration for performance of short
`procedures would be anticipated.
`The rapid absorption of intranasal midazolam in
`
`716 0 J Clin Pharmacol 1997;37:711-718
`
`
`the present study is consistent with observ
`after oral15 and intramuscularm administration
`
`availability in the present study [50 1 13%) is s .,
`
`to values obtained after oral administration ['7
`17%).“ Intranasal administration of medicatio
`
`ditionally has been thought to be associated
`several advantages over oral administration, inc {.5
`
`ing avoidance of hepatic first-pass metabolism
`wall metabolism, and destruction of medication
`
`gastrointestinal fluids.lg However, the nasal mu
`may serve as a barrier to the entry of medicati
`
`into the systemic circulation. Cytochrome P450
`zymes, at concentrations 5% of those found in it
`
`liver, have been identified within the human 11
`
`mucosa.20 A potential explanation for the less
`
`complete bioavailability after intranasal adminis.
`tion may be potential metabolism of midazolam-u
`
`cytochrome P—450 on its passage across the nasal In _
`cosa.
`
`
`Intranasal administration of midazolam for ind
`
`tion of conscious sedation has been used succe
`fully in adult patients for phlebotomy in an agitat-
`
`and frightened patient,9 for management of claus
`phobia during magnetic resonance imaging,“| and .
`
`dental surgery.”12 Doses administered in these _‘
`ports have varied from a weight-based dose rang'u‘
`
`from 0.2 rug/kg to 0.25 mgl'kgim"z to a fixed-do
`administration of 0.5 mg repeated once if ineffectiv.
`
`In the present study, doses of 0.25 mg/kg were use}
`resulting in a relatively large volume of solution in
`
`ing instilled into the nares [4—5 mL]. Despite I_
`maximal volume of the nares of approximately 2
`
`mL,21 the larger administered volume made sw'
`lowing of solution more likely. Deepite the use a
`
`what was believed to be a sufficiently slow admi
`tration rate in this study, it was likely that some 0 '
`
`the participants swallowed medication. The delays
`time to reach maximum concentration (t,,,.,,,) is co-
`
`sistent with values reported after oral administra
`tion15 and may represent not only nasal absorpt
`
`
`but also concomitant gastrointestinal absorption -
`
`The plasma concentration—time profile after intrana-i,
`sal administration in subiect no. 3 supports this noii
`tion. The dual peaks occurring at 20 and 120 minuted:
`after administration are consistent with anticipate 13"
`maximal concentrations resulting from nasal absorp-f; -
`tion followed by oral absorption. During administraiié
`tion of the intranasal study dose, this participant ill-i.
`dicated that he believed he was swallowing medics-:3
`tion. The second peak, occurring at 120 minutesf
`coincides with the ingestion of the Z-hour light&
`breakfast given after administration. Associated with;-
`this second peak was impairment of the participant's:
`cognitive performance as measured by DSST score:
`The commercially available preparation of midazo-
`
`
`
`
`
`
`
`
`
`
`
`
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`stration. B
`:%Jissi
`'
`
`:
`
`lam exists in a hydrophilic form at the formulated
`PH of 2. After oral ingestion, midazolam was main-
`taivnd in a low pH environment, thereby preventing
`th
`unversion of midazolam to the ring open, lipo-
`plnlic form. The ingestion of food, with its buffering
`of the gastric acidity and subsequent conversion of
`midazolam to its lipophilic structure, may have facil-
`itated the absorption of the orally administered frac-
`tion of the intranasal dose.
`Previous experience of the authors’ group in dental
`patients and that reported in a letter by Lugo et a]22
`indicate that the administration of the undiluted in-
`jeclable formulation of midazolam is associated with
`is
`.1ati'on'; burning; "irri-tation;--and general discom—
`fo.rL‘:-t'or --pati'e'iits3.- The discomfort evident in the au-
`thors-3: previous experiences was such that patients
`who previously had desired an- alternative to injec-
`treasurer indicated they would prefer'the'injection
`over"intranas'aldi‘ops. Lidocaine was therefore ad-
`ministered as a topical nasal spray before administra-
`tion of the intranasal dose of midazolam to minimize
`the occurrence of these side effects. Each spray deliv-
`an agitate
`
`ered approximately 0.05 mL or 2 mg/spray; therefore,
`of Claus
`.'
`
`13,10 and f."
`th
`ital dose received by participants was 8 mg.
`‘
`n these
`Although it repossrble that the administration of top-
`
`953 rang'
`ical lidocaine may have___i__nduced local changes in
`
`
`fixed—dog:
`the nasal mucosa'thereby affecting absorption, the
`
`ineffectivé
`method used represents the anticipated administra-
`
`. Were used‘
`tion technique in clinical practice.
`
`olution b-'
`The DSST was used to evaluate the pharmacody-
`
`-. )espite th.
`namic response to the intranasal dose of midazolam.
`
`imately 2|
`This test was chosen based on its simplicity, ease
`.
`
`of ailministration, and documented sensitivity as a
`‘
`
`IT.-
`.. .ure of benzodiazepine—induced alterations in
`
`cognitive performance.23 The DSST is a measure pri-
`
`marily of cognitive and psychomotor skill; however,
`‘ Lie delays '7
`both a sedation visual analog scale and an observer's
`
`ml is con
`assessment of alertness/sedation scale have been
`
`Shown to correlate with the DSST test when used
`
`after intravenous administration of midazolam.24 Al—
`
`though it was not specifically evaluated in this inves-
`
`ligation,
`it may be hypothesized that changes in
`
`I 4*“? score evident after intranasal administration
`t
`.0 minutes :
`C
`dazolam would be representative of changes in
`nticipated I.
`level of sedation.
`:al absorp-
`No time-dependent relationship between plasma
`lministra- '
`mldazolam concentrations and pharmacodynamic
`cipant in’
`I‘eSponse was seen. This finding is in contrast to re-
`g medica- ‘
`_Sults of other investigators, who describe hysteresis
`minutes.
`In both DSST” and electroencephalograma pharma-
`1 our light
`CDdynamic measures associated with midazolam
`ated with
`Plasma concentrations after intravenous administra—
`ticipant’s
`l
`The apparent delay between plasma concentra-
`ST score-
`l
`ind pharmacodynamic effect has a physiologic
`f midazo-
`l». as when it is considered that systemically admin-
`
`
`
`
`i-
`
`‘
`
`
`
`.MIDAZOLAM PK AND PD AFTER INTRANASAL ADMINISTRATION .M
`
`
`
`istered medications must cross the blood—brain bar-
`rier to induce impairment of cognitive performance
`or alterations in electroencephalographic measures.
`The lack of hysteresis in the present study may be
`related specifically to the intranasal route of adminis-
`tration. It has been suggested that communications
`exist between the subarachnoid space and nasal cavi-
`ties, cranial and nasal cavities, and the perineural
`sheaths in the olfactory nerve and the nasal mu-
`case.26 It may be hypothesized that these communi-
`cations represent a route for the rapid and direct
`entry of intranasally administered midazolam into
`the central nervous system. If this hypothesis was
`valid, one would expect a rapid onset of effect and
`lack of hysteresis on effect—concentration plots, due
`to the circumvention of the blood—brain barrier. As
`pharmacodynamic measures associated with the in-
`travenous dose were not determined in this study.
`effect—concentration profiles and pharmacodynamic
`parameter values could not be compared to support
`or refute this hypothesis.
`Problems associated with intranasal administra-
`tion._o.f__midazolam include thepreadministration use
`of intranasial- --lidocaine and the potential for swal-
`lowing. Use'of administration methods such as atom—
`izers to reduce”the administered particle size or
`slower administration rates via injection may mini-
`mize the swallowing of medication seen with admin-
`istration at 1 mL/min using a syringe. Despite the
`disadvantages, this route represents a viable alterna-
`tive for patients in whom intravenous administration
`is not feasible. Intranasal administration of midazo-
`lam at a dose of 0.25 mg/kg resulted in predictable
`effects on cognitive performance and concentration
`profiles anticipated to provide adequate conscious
`sedation for minor surgical and diagnostic proce-
`dures. Further investigations are necessary to evalu-
`ate the comparative pharmacodynamics after intra-
`nasal and intravenous administration to support or
`refute the hypothesis regarding direct tranSport be-
`twaen the nasal mucosa and subarachnoid space.
`
`REFERENCES
`
`1. Barker 1. Butchart DGM. Gibson I. Lawson HM. Mackenzie N:
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`2. Clark MS. Silverstone LM. Coke IM. Hicks]: Midazoiam, diaze-
`parn and placebo as intravenous sedatives for dental surgery. Oral
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`3. Rodrigo MRC. Clieung LK: Oral midazolam satiation in third
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`717
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`
`BURSTEIN ET AL
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`5. D‘Argenio DZ. Schumitzky A: Adapt H Users Guide. Biomedi-
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`
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`16. Crevoisier C, Ziegler WH, Eckert M, Heizmann P: Rela .'
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