`
`
` ||||
`
`Cinical efficacy of midazolam for the induction of
`sedation, reduction of anxiety, and induction of
`amnesia is well documentedafter intravenous? and
`oral’ administration. Despite the advantages ofrapid
`sedative effects, there are disadvantages associated
`with intravenous administration, primarily the ne-
`
`: Department of PharmacyPractice and Science, Pharmacokinet-
`Fre,
`CS anu Biopharmaceutics Laboratory, University of Maryland at Balti
`Tere, Baltimore, Maryland (Dr. Burstein), the Department of Dental Medi-
`Sine (Drs. Modica and Hatton) the Division of Neuropharmacology (Dr.
`Gengo}, 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
`Or. Gengo}, The State University of New York at Buffalo, Buffato, New
`fork (Ors. Gengo and Forrest). Submitted for publication February 27,
`1997. accepted in revised form April 28, 1997, Address for reprints:
`Ag.
`+ Burstein, PharmD, Department of Pharmacy Practice and Sci:
`2h
`versity of Maryland at Baltimore, 100 Penn Street, Suite 340,
`3a. wre, MD 21201.
`,
`
`/ Clin Pharmacol 1997:37:711-718
`
`cessity of an injection. In patients with a fear of nee-
`dies 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-
`ics 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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`PV cs
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`
`Pharmacokinetics and Pharmacodynamics
`of Midazolam After Intranasal
`Administration
`
`Aaron H. Burstein, PharmD, BCPS, Rosanne Modica, DDS, Michael Hatton, DDS, FADSA,
`Alan Forrest, PharmD, and Fran M. Gengo, PharmD, FCP
`
`This study aimed to characterize the pharmacokinetics and pharmacodynamics ofmi-
`dazolam after intranasal administration to healthy volunteers. Eight participants were
`
`given0:25
`mg/Keintranasally and 2 img intravenously in a randomized, crossoverfash-
`ion. Blood samplesfor determination ofplasma concentrations ofmidazolam and mea-
`sures of cognitive function (using the digit symbol substitution test} were obtained at
`baseline and 5, 10, 20, 30, 45, 60, 90, 120, 180, 240, and 360 minutes after administration
`ofstudymedications. Plasma samples were analyzed bygas chromatography (% coeffi-
`cient of variation <10%}. Pharmacokinetic data were fitted using iterative two-stage
`analysis to a two-compartment model. Pharmacodynamic data werefitted by a baseline
`subtraction Hill-type model. The mean {SD}for total clearance, distributional clearance,
`volume ofdistribution in the central comPariment, volume ofdistribution 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/kg, 0.67 (0.11) L/kg, 2.46 (1.72) hr',
`
`0%.(13%}, and 3,1 (0.84) hours, respectively. The:mean-(SD)-for.the,concentration at
`
`Witch the effect is half maximal {ECs,} and the maximal effect or the maximal change
`in effect measure from baseline (Enax} weres63,1 (21.2) ng/mL and.52:8 (21.1) correct
`
`substitutions, respectively. After intranasal administration, midazolam concentrations
`rapidly achieve values considered sufficient to induce conscious sedation and produce
`predictable changes in digit symbol substitution score.
`eee
`
`n, Clin Pha
`
`

`

`
`
`NY}. Before enrollment, all volunteers gave written
`informed consent.
`Healthy male and nonpregnantfemale nonsmokers
`were considered eligible for inclusion in the study if
`they were atleast 18 years old. Potential participants
`were excludedif 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 daysbefore thefirst study day, participants
`were oriented to the tests of cognitive function to be
`used(i.e, 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 overnightfast. They
`were continuedto 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.
`Anintravenouscatheter 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-mLsaline
`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,.vol-
`unteers were administered two.sprays.of-4%-tepical
`lidocainé“intoeach
`nostril. Doses of study medica-
`
`tion administered intranasally consisted of a single
`0.25-mg/kg dose of midazolam. The study medica-
`tion was drawnup, immediately before. administra-
`tion, intosyringe of theappropriate volume from a
`stocksolutionconsisting of the-intravenous5=my/
`Iterative two-stage analysis using the computer soft
`mL:concentration solution. The needle was removed
`ware package Adapt® (Biomedical Simulations Rt
`from the syringe, and_.an.intravenous.cannula was
`source, University of Southern California, L
`
`attached, allowingaflexible tube to be-inserted into
`Angeles, CA) was performedto fit candidate pharma
`the naresforadministration. The intranasal dose was
`cokinetic and pharmacodynamic models
`to
`administered at.a.rate.of.1.mL/min, with administra-
`plasma concentration-time and pharmacodynamil
`tion alternated between nostrils in 1-mL increments.
`data. An explanation of this technique is provided
`Volunteers were instructed to inhale with each ad-
`elsewhere.” Model discrimination was performed by
`
`712 © 4 Clin Pharmacol 1997:37:711-718
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`MtAeon.Bondeeo
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`BURSTEIN ET AL
`
`
`ministration and to refrain from swallowingfg
`4
`long as comfortably possible.
`After administration of study medication
`
`hours), blood samples (5 mL) were collected ff
`the intravenous catheter ints K,-EDTA Vacutg
`
`tubes (Becton-Dickinson Vacutainer Systems, F
`lin Lakes, NJ) at 5, 10, 20, 30, 45, 60, 90, 120,
`240, and 360 minutes. Samples were centrifuged:
`mediately for 10 minutes, and plasma was harves
`
`and frozen at —20°C until analyzed for midazol
`concentration.
`:
`Digit symbol substitution tests were performed
`baseline and 10, 30, 60, 90, 120, 180, 240, and
`
`minutesafter infusion of the study medications
`numberof correct substitutions during each 90
`ondtesting interval were counted. Different versj
`
`of the DSST were administered at each measuremi
`time.
`
`
`
`Assay of Samples
`
`Plasma samples were analyzed for midazolam ct
`centrations using a slightly modified version of
`gas chromatography methodof De Kroon etal.* St
`dard curves were prepared over the range of 10
`mL to 300 ng/mL. Aliquots of patient plasma samp
`were treated with 250 uL of water and 20 wL of a Sf
`ng/mL diazepam internal standard solution. Sol
`phase extraction was performed using 100-mg
`cartridges. Benzodiazepines were eluted with 500
`of methanol. After evaporation under Nz at 50°C,
`residue was reconstituted with 50 uL of toluenéf
`methanol/acetone (85/15/5). Aliquots of these reco
`stituted solutions were injected onto a Varian {Vari
`Chromatograph Systems, Walnut Creek, CA) 341
`GC using an Alltech (Alltech Associates Inc., De
`field, IL) 6 meter by */,-inch OV17 columnwith ni ng
`gen as the carrier gas. The sensitivity of the assay
`with 1 wL of sample was 10 ng/mL,and was lineéf
`over the range of 10 ng/mL to 300 ng/mL. Over
`_
`the % coefficients of variation of the assay welt.
`9.9%, 4.5%, and 9.6% at concentrations of 15
`mL, 80 ng/mL, and 260 ng/mL, respectively.
`
`Pharmacokinetic/Pharmacodynamic Modeling
`
`
`
`
`436Re
`
`
`

`

`
`
`MIDAZOLAM PK AND PD AFTER INTHANASAL ADMINISTRATION
`
` ition. Soli CS
`100-mg Gygee4
`
`wie
`nputer soft:
`ilations Re-.
`fornia, Los
`ate pharma-”
`lels
`to the’
`icodynarmG
`is provide
`formed by
`
`inspection of residuals and Akaike’s information cri-
`rion.
`rep!
`:ma concentration time data after the intranasal
`anc ...cavenous doses were simultaneouslyfitted us-
`ing a linear, two-compartment intravenous injection
`and nasal absorption model. Modeling incorporated
`aresidual variance model in which the standard de-
`yiations of the observations were related linearly to
`the fitted values. The parameters estimated for mida-
`golam included the volumeof distribution in the
`central compartment (V,), volumeofdistribution in
`the peripheral compartment {V,), distributional
`clea->nce {Cly) for both intranasal and intravenous
`ad:
`....stration and total clearance (Cl), absorption
`rate constant (K,), and bioavailability (F) for intrana-
`sal administration. Initial modelling allowed V,, V,,
`and Cl, to differ between intranasal and intravenous
`administration, with Cl assumedto be similar.
`Pharmacokinetic parameter estimates obtained
`from the initial modeling process werefixed in each
`volunteer, and pharmacodynamic measures were
`subsequently modeled. Plasma concentration DSST
`effe-* data were Otted by the following baseline sub-
`tra. -n Hill-type equation:
`
`Enyax* CY
`B+io=—c
`ECG3, + GC”
`
`where E, is the baseline effect, E,.., is the maximal
`effect or the maximal change in effect measure from
`baseline, EC., is the concentration at whichthe effect
`is '/, maximal, C is the plasma concentration of mida-
`zolam, and T 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 simultaneouslyfitted by the
`pharmacokinetic and pharmacodynamic models.
`
`RESULTS
`
`Ei” - healthy volunteers were enrolled in this inves-
`tic
`on. Of these, six were men and two were
`women, The mean (SD) age and weight of partici-
`Pants were 29.5 (5.2) years and 77.9 (16.6) kg, respec-
`‘ively, A summary of the demographic characteris-
`lics of participants is provided in Table I. Treatment
`vas well tolerated by all volunteers except subject
`ho. 5. Within 10 minutes of administration of the
`‘Ntranasal dose {on study day 2), this volunteer be-
`Came lethargic, difficult to arouse, and hypotensive.
`‘azenil at 2-mg was administered intravenously
`“prompt reversal of the lethargy and improve-
`Mat in blood pressure. Pharmacodynamic data for
`
`
`TABLE |
`
`Subject Demographic Information
`
`Subject
`No.
`
`1
`2
`3
`4
`5
`6
`7
`8
`Mean
`SD
`
`Age
`tyr}
`
`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,* however, the concentration—time data
`for this volunteer was included in the pharmacoki-
`netic analysis.
`Plots of midazolam plasma concentration—time
`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) minutesafter 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 wasstatis-
`tically superior for describing the data in all but sub-
`ject no. 3. The concentration—timeprofile 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, Cig, V., V,, K,, and
`half-life (t,,.) 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, 2.46 (1.72)
`hr-', and 3.1 (0.84) hours, respectively. Mean (SD}
`values of 50% (13%) of the dose were absorbed after
`intranasal administration. A summary of parameter
`values for individual participants is provided in Ta-
`ble HU.
`Plots of DSST score-versus-time curvesfor intrana-
`sal administration are shown in Figure 4. Lmpair-
`ment of participants’ performances was evident early
`
`PHARMACOKINETICS AND PHARMACODYNAMICS
`
`713
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`
`
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`
`
`after administration, with maximal impairmen
`
`curring 30 minutes (range, 15—120 minutes) after
`ministration of the intranasal dose. The maxima
`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 ECs, and Ey, were 63.1 (21.2) ng/mL and 5
`{21.1) correct substitutions, respectively. A sumn
`
`of individual values is provided in TableIII.
`
`The intranasalroute of administration for midazolg
`may represent an attractive alternative to the con
`
`tional intravenous and oral routes of administrati
`for inducing conscious sedation. A large group’
`including those with mental disabili
`patients,
`
`and violent and combative patients, often posed
`
`culties when medications are administered to indi
`sedation before procedures such as dental work
`these patients, the anxiety associated with the prod
`
`8
`:
`,
`
`dure is often exacerbated by the fear and anticipatg
`pain of receiving aninjection. At the authors’instiff
`
`tion, these patients often require general anesthes}
`and the use of an operating room suite to sedatethe
`
`
`
`
`
`Concentration(ng/ml)
`
`
`
`BURSTEIN ET AL
`
`Eoe
`
`£© 2£c 8e9O
`
`o
`
`100
`
`250
`200
`150
`Timea (minutes)
`
`300 360400
`
`Figure 1. Plasma concentration-time profiles of midazolam
`afterintranasal administration ofa 0.25-mg/kg dose. Each point
`{O) represents the mean value; error bars represent standard
`errors.
`
`
`
`Concentration(ng/ml)
`
`DISCUSSION
`
`
`
`oao
`
`oa
`
`fea
`
`
`
`100 «6350=400«150 «6-200 «250 300
`
`
`
`
`100
`Time (minutes) 150 200 280 300 350 400 4
`
`
`
`
`
`
`Time (minutes)
`
`Figure 2. Plasma concentration—time profile of midazolam after
`fatravenous administration of a 2-mg fixed dose. Each point {O}
`represents the ineun value; error burs represent standard errors.
`
`“
`Figure 3. Plasma concentration-time profile of midazolam afté.
`#.
`intranasal administration in subject ne. 3.
`
`4 B
`
`y *
`
`714 © J Clin Pharmacol 1997;37:711-718
`
`.
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`|
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`AQUESTIVE EXHIBIT 1129 Page 00048
`AQUESTIVE EXHIBIT 1129 Page 0004
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`
`t
`
`

`

`
`
`
`
`
`
`
`
`
`=weo
`
`ad3
`aaad
`aa
`Ay
`a
`i"
`
`~9QhLaao
`
`eQa
`
`t—
`bEitp)pT
`a
`
`a=
`
`2 2>2aaa 33p
`
`ao*+ 3na
`
`a0
`
`lao
`
`130
`
`Concentration (ng-ml)
`100
`#150
`200
`250
`300
`360
`400
`a500«400
`Time (minutes)
`
`dazolam after
`
`re 4, Digit symbol substitution test (DSST} score during each
`‘cond testing session. Bach point {QO} represents the mean
`value; error bars represent standard errors,
`
`Figure 5. Representative true {®) and predicted (solid line} digit
`symbol substitution test (DSST} score versus the plasma concen-
`tration curve for midazolam for subject no. 4.The DSST score is
`the aumber of correct substitutions completed during the 90-sec-
`ond testing session,
`
`PHARMACOKINETICS AND PHARMACODYNAMICS
`
`715
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`
`
`pairmentSame
`erSSSoySSSSficy
`FABLE I!
`ttes} aftergrmme
`—ANryper
`
`Summary of Pharmacokinetic Parameters of Midazoiam after Intranasal Administration
`
`MIDAZOLAM PK AND PD AFTER INTRANASAL ADMINISTRATION
`
`Subject
`No.
`
`]
`2
`3
`4
`5
`6
`7
`
`Mean
`SD
`
`Ve
`(L/kg}
`
`0.021
`0.39
`0.25
`0.19
`0.27
`0.20
`0.34
`0.46
`0.27
`0.14
`
`Vp
`(L/kg)
`
`0.66
`0.65
`0.81
`0.73
`0.79
`0.47
`0.57
`0.67
`0.67
`0.11
`
`Cid
`(L/nr/kg}
`
`Cit
`(L/nr/kg)
`
`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
`
`tie
`(hr}
`
`3.0
`2.5
`3.4
`4,4
`42
`2.3
`2.5
`2.5
`3.1
`0.84
`
`Ka
`(hr-"}
`
`1.5
`1.4
`18
`4.3
`1.4
`48
`2.7
`L.7
`2.5
`1.7
`
`F
`
`0.53
`0.46
`0.49
`0.41
`0.76
`0.44
`0.33
`0.56
`0.50
`0.13
`
`Vc, volume ofdistribution in central compartment; Vp, volumeofdistribution in peripheral compartment; Cid, distributional
`clearance; CH, total clearance; ty2, halHife; Ka, absorption rate constant; F, bioavailability.
`eSSSreaipaeR
`
`ge group
`disabilitf
`|
`1 pose di
`
`successfully to allow performanceofthe dental pro-
`ce"ires. Clearly, any alternative that induces seda-
`t.... effectively while avoiding the use of general an-
`esthesia and operating room timehassignificant im-
`plications not only for patient safety but also for the
`cost of routine dental surgical procedures.
`To the authors’ knowledge,this study is thefirst to
`
`model the disposition of midazolam aiter intranasal
`administration to adults. Previously, Walbergh et al’
`studied the concentration—timeprofile of both intra-
`venous and intranasal midazolam after administra-
`tion to pediatric patients. However, in this study,
`only maximal concentrations and the timeto attain
`these concentrations were determined. Theirfinding
`of a mean {+ SD) peak concentration of 72.2 (+ 27.3)
`ng/mL and time to peak concentration of 10.2 {+ 2)
`minutes suggests that rapid attainmentofsignificant
`
`

`

`BURSTEIN ET AL
`
`Summary of Pharmacodynamic Parameters of
`Midazotam after Intranasal Administration
`
`E
`
`Subject
`Eo
`(change from
`ECso
`No.
`(baseline no.}*
`baseline}t
`{ng/mL}
`G
`
`
`
`
`
`
`ecla
`
`the present study is consistent with obsery
`TABLEill
`after oral'® and intramuscular’ administration
`availability in the present study (50 + 13%) is sir
`
`to values obtained after oral administration (4
`17%)."* Intranasal administration of medicatio
`
`ditionally has been thought to be associated
`several advantages over oral administration,inclff
`
`ing avoidance of hepatic first-pass metabolism
`wall metabolism, and destruction of medication
`2.54
`75.5
`44.4
`69.3
`1
`
`2.74
`62.3
`33.9
`66.0
`2
`gastrointestinal fluids.” However, the nasal mu
`4.15
`29.5
`29.7
`83.5
`3
`may serve as a barrier to the entry of medicatj
`
`3.48
`41.3
`72.7
`100.0
`4
`into the systemic circulation. Cytochrome P-450
`NAT
`Nat
`NAt
`NAT
`5
`zymes, at concentrations 5% of those found in ff
`
`2.40
`86.1
`79.5
`73.6
`6
`liver, have been identified within the human n:
`
`0.90
`83.3
`72.0
`74.4
`7
`mucosa.” A potential explanation for the less
`3.89
`63.8
`37.3
`84.0
`8
`complete bioavailability after intranasal administR
`2.87
`63.1
`52.8
`78.7
`Mean
`
`tion may be potential metabolism of midazolamif
`1.10
`21.2
`21.1
`11.5
`SD
`rene
`
`cytochrome P-450 onits passage across the nasal ne
`
`* Baseline number of correct substitutions.
`cosa.
`t Change from baseline in the number of correct substitutions.
`
`Intranasal administration of midazolam for ind
`t Pharmacodynamic data unavailable due to flumazenil administration.
`
`Eo, baseline effect; Emax, Maximum effect or maximum change in effect; ECso,
`tion of conscious sedation has been used succe¥
`concentration at which effect is 4. maximal: NA, not available.
`fully in adult patients for phlebotomy in an agitaté
`
`yyaAier
`and frightened patient,” for managementof claus
`phobia during magnetic resonance imaging," and fa
`
`dental surgery.''’* Doses administered in these
`ports have varied from a weight-based dose rangiti
`
`from 0.2 mg/kg to 0.25 mg/kg*'" to a fixed-dog
`administration of 0.5 mg repeated onceif ineffectiv
`
`In the present study, doses of 0.25 mg/kg wereuse¢
`resulting in a relatively large volumeof solution bé
`
`ing instilled into the nares (4—5 mL). Despite th
`
`maximal volume of the nares of approximately 2
`mL,” the larger administered volume made swa
`lowing of solution more likely. Despite the use @
`
`what wasbelieved to be a sufficiently slow admi
`tration rate in this study, it was likely that some of8
`
`the participants swallowed medication. The delaye
`time to reach maximum concentration (tpa,} is COU
`
`sistent with values reported after oral administray?
`tion’® and may represent not only nasal absorpt
`
`but also concomitant gastrointestinal absorptiong:,
`
`The plasma concentration—timeprofile after intrana;,.
`sal administration in subject no. 3 supports this noy.
`
`tion. The dual peaks occurring at 20 and 120 minutes,
`after administration are consistent with anticipated:
`
`maximal concentrations resulting from nasa! absorp-
`
`tion followed by oral absorption. During administraz,
`
`tion of the intranasal study dose, this participant iny,
`
`dicated that he believed he was swallowing medica
`
`tion. The second peak, occurring at 120 minutes;
`
`coincides with the ingestion of the 2-hour light,
`
`breakfast given after administration. Associated with,
`this second peak was impairmentoftheparticipant's”
`cognitive performance as measured by DSST score.”
`The commercially available preparation of midazo-
`
`plasma concentrations may beobtained after intrana-
`sal administration of 0.1 mg/kg. Similarly, Rey et al"*
`conducted a comparative pharmacokinetic study of
`intravenous and intranasal midazolam administra-
`tion to pediatric patients. Mean time to achieve a
`mean (+ SD) maximal concentration of 104 (+ 32)
`ug/L was 12 (+ 4) minutes after a dose of 0.2 mg/kg.
`Additionaily, the investigators found higher appar-
`ent plasma clearances and volumesof 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 consciou sedation-is-40-ng/mL.5~
`-'” Evaluation of the mean intranasal plasma concen-
`tration—timeprofile shows that participants attained
`concentrations exceeding this threshold..concentra-
`tion..as...early...as..10°minutes after administration.
`Mean plasma concentrationwas sustained above this
`thresholdconcentration for'90to 180-minutes (range,
`90—360 minutesin 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 ofintranasal midazolam in
`
`716 © J Clin Pharmacol 1997;37:711-718
`
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`MIDAZOLAM PK AND PD AFTER INTRANASAL ADMINISTRATION_.
`
`3%) is si
`
`1
`i
`
`|
`
`
`
`
`lam exists in a hydrophilic form at the formulated
`istered medications must cross the blood—brainbar-
`H of 2. After oral ingestion, midazolam was main-
`tier to induce impairmentof cognitive performance
`taired ina low pH environment, thereby preventing
`or alterations in electroencephalographic measures,
`th
`-nversion of midazolam to the ring open, lipo-
`The lack of hysteresis in the present study may be
`plilic form. The ingestion offood, withits buffering
`related specifically to the intranasal! route of adminis-
`| ociated
`of the gastric acidity and subsequent conversion of
`tration. It has been suggested that communications
`tion, inc];
`midazolamtoits lipophilic structure, may havefacil-
`exist between the subarachnoid space andnasalcavi-
`abolism, g
`itated the absorption of the orally administered frac-
`ties, cranial and nasal cavities, and the perineural
`‘dications
`tion of the intranasal dose.
`sheaths in the olfactory nerve and the nasal mu-
`asal mucg
`Previous experienceof the authors’ groupin dental
`cosa.”° It may be hypothesized that these communi-
`patients and that reported inaletter by Lugo et al?”
`medicatio
`cations represent a route for the rapid and direct
`indicate that the administration of the undiluted in-
`ae P-450 a
`entry of intranasally administered midazolam into
`ound in
`jectable formulation of midazolam is associated with
`the central nervous system. If this hypothesis was
`luman nas.
`ja
`ation, burning; irritation;-and general discom-
`valid, one would expect a rapid onset ofeffect and
`he less tha
`fo.t-ior~patients: The discomfort evident inthe au-
`lack of hysteresis on effect—concentration plots, due
`administr
`thors: previous..experiences--was. such. that patients
`to the circumvention of the blood—brain barrier. As
`dazolam b
`whopreviouslyhad desired an:alternative.to injec-
`pharmacodynamic measures associated with the in-
`1e nasal mij
`tionslater indicatedthey wouldprefertheinjection
`travenous dose were not determined in this study,
`over intranasal” drops. Lidocaine was therefore ad-
`effect—concentration profiles and pharmacodynamic
`n for indud
`ministered as a topical nasal spray before administra-
`parameter values could not be compared to support
`ed succesg
`tion of the intranasal dose of midazolam to minimize
`or refute this hypothesis,
`an agitate
`the occurrenceofthese side effects. Each spray deliv-
`
`Problems associated with intranasal administra-
`of claustr¢
`ered approximately 0.05 mLor 2 mg/spray; therefore,
`tion.ofmidazolam include thepreadministration use
`1g,'° andfo
`tt
`tal dose received by participants was 8 mg.
`of intranasal--lidocaine and the potential for swal-
`Aithoughit ispossible thatthe administration of top-
`n these
`
`lowing. Use of administration methods such as atom-
`ical lidocaine may haveinduced. local changes in
`ase rangi
`izers to reducé the administered particle size or
`fixed-dos¢
`the nasal mucosa thereby affecting absorption, the
`
`slower administration rates via injection may mini-
`method used represents the anticipated administra-
`ineffective:
`mize the swallowing of medication seen with admin-
`
`tion techniquein clinical practice.
`- were used.
`istration at 1 mL/min using a syringe. Despite the
`‘olution be:
`The DSST was used to evaluate the pharmacody-
`disadvantages, this route represents a viable alterna-
`-Jespite tha
`namic response to the intranasal dose of midazolam.
`
`tive for patients in whom intravenous administration
`This test was chosen based onits simplicity, ease
`
`is not feasible. Intranasal administration of midazo-
`of siministration, and documented sensitivity as a
`lam at a dose of 0.25 mg/kg resulted in predictable
`m ..ure of benzodiazepine-induced alterations in
`effects on cognitive performance and concentration
`
`cognitive performance.”* The DSSTis a measure pri-
`profiles anticipated to provide adequate conscious
`marily of cognitive and psychomotorskill: however,
`
`sedation for minor surgical and diagnostic proce-
`both a sedation visual analog scale and an observer's
`dures. Further investigations are necessary to evalu-
`assessment of alertness/sedation scale have been
`
`ate the comparative pharmacodynamicsafter intra-
`shown to correlate with the DSST test when used
`nasal and intravenous administration to support or
`
`after intravenous administration of midazolam.‘ Al-
`refute the hypothesis regarding direct transport be-
`
`thoughit was not specifically evaluated in this inves-
`tween the nasal mucosa and subarachnoid space.
`
`tigation,
`it may be hypothesized that changes in
`
`+
`['.8'T score evident after intranasal administration
`REFERENCES
`.O minutes *
`C
`_dazolam would berepresentative of changes in
`nticipated ...4level of sedation,
`1. Barker [, Butchart DGM, Gibson J, Lawson HIM, Mackenzie N:
`‘al absorp-
`No time-dependent relationship between plasma
`IV. sedation for conservative dentistry: a comparison of midazo-
`Iministra- ~
`Micszolam concentrations and pharmacodynamic
`lain and diazepam. Br J Anaesth 1986;58:371—377.
`cipantin-
`response was seen. This finding is in contrastto re-
`2. Clark MS, Silverstone LM, Coke JM, Hicks J: Midazolam,diaze-
`g medica- ©
`sults of other investigators, who describe hysteresis
`pam and placeboas intravenous sedatives for dental surgery. Oral
`minutes,
`in both DSST** and electroencephalogram® pharma-
`Surg Oral Med Oral Pathol 1987:63:127-131.
`- our light
`codynamic measures associated with midazolam
`3. Rodrigo MRC, Cheung LK: Oral midazolam sedation in third
`ated with
`plasma concentrationsafter intravenous administra-
`molar surgery. {nt { Oral Maxillofac Surg 1987:16:333—337.
`~-ticipant’s
`( -. The apparent delay between plasma concentra-
`4. De Kroon IF, Langedijk PN, De Goede PN: Simultaneous deter-
`ST score.
`and pharmacodynamiceffect has a physiologic
`mination of midazolam and its three hydroxy metabolites in hu-
`man plasma hy electron-capture gas chromatography without de-
`* midazo-
`*..8 whenit is considered that systemically admin-
`rivatization. / Chromatogr 1989:491:107-116.
`
`PHARMACOKINETICS AND PHARMACODYNAMICS
`
`717
`
`AQUESTIVE EXHIBIT 1129 Page 0007
`AQUESTIVE EXHIBIT 1129 Page 0007
`
`
`

`

`
`
`
`BURSTEIN ET AL
`
`5. D’Argenio DZ, Schumitzky A: Adapt If Users Guide. Biomedi-
`cal Simulatians Resource. Los Angeles: University of Southern
`California, 1992.
`6. Forrest A, Ballow CH, Nix DE, Birmingham MC, Schentag JJ:
`Developmentof a population pharmacokinetic model and optimal
`sampling strategies for
`intravenous ciprofloxacin. Antimicrob
`Agents Chemother 1993:37:1065-1072.
`7. Akaike H: An informationcriterion (AIC). Math Sei 1976:14:5—
`9.
`
`8. Breimer LTM, Burm AGL, Danhof M, Hennis PJ, Vletter AA,
`de Voogt JWH, et al: Pharmacokinetic-pharmacodynamic model-
`ing of the interaction between Aumazenil and midazolam in vol-
`unteers
`by
`aperiodic EEC analysis. Clin Pharmacokinet
`1991; 20:497—508.
`9. Cheng ACK:Intranasal midazolam forrapidly sedating an adult
`patient. Anesth Analg 1993: 76;904,
`10. Moss ML, Buongiorno PA, Clancy VA:Intranasal midazolam
`for claustrophobia in MRI. { Comput Assist Tomogr 1993; 17:991-
`992.
`
`11, Fukuta O, Braham RL, Yanase H, Atsumi N, Kurosu K: The
`sedative effect of intranasal midazolam administration in the den-
`tal treatment of patients with mentaldisabilities Part 1: the effect
`of a 0.2 mg/kg dose. | Clin Pediatr Dent 1993;17:231-237.
`12. Kaufman E, Davidson E, Sheinkman Z, Magora F: Comparison
`between intranasal and intravenous midazolam sedation (with or
`without patient control) in a dental phobia clinic. J Oral MaxiHo-
`fae Surg 1994;52:840-843.
`13. Walbergh EJ, Wills RJ, Eckhert J: Plasma concentrations of
`midazolam in children following intranasal administration. Anes-
`thesiology 1991;74:233~235.
`14, Rey E, Delaunay L, Pons G, Murat [, Richard MO, Saint-Mau-
`rice C, Olive G: Pharmacokinetics of midazolam in children: com-
`parative study of intranasal and intravenous administration. Eur
`/ Clin Pharmacol 1991;41:355—357.
`
`/
`
`
`15. Allonen H,Ziegler G, Klotz U: Midazolam kinetics,
`maco! Ther 1981;30:653-661.
`16. Crevoisier C, Ziegler WH, Eckert M, HeizmannP: Relat;
`
`between plasma concentration and effect of midazolam af
`and intravenous administration. Br J Clin Pharmacol 4
`
`(suppl):51S-618.
`4
`
`17. Persson MP, Nilsson A, Hartvig P: Relation of seda:
`amnesia to plasma concentrations of midazolam in s
`tients. Clin Pharmacol Ther 1988;43:324—-331.
`
`18. Avram MJ, Fragen RJ, Caldwell NJ: Dose-finding and p
`cokinetics study of intramuscular midazolam. j Clin Pho
`1987; 27:314-317.
`
`19, Chien YW, Chang SF: Intranasal drug delivery for ayst
`medications, Crit Rev Ther Drug Carrier Syst 1987;4(2):67-4@4
`20. Gervasi PG, Longo V, Naldi F, Panattoni G, Ursino F: Xex
`otic-metabolizing enzymes in human respiratory nasal muz
`Biochem Pharmacol 1991;41:177-184.
`:
`
`21, Sarkar MA; Drug metabolism in the nasal