Pharmacokinetics and pharmacodynamics of midazolam administered
`as a concentrated intranasal spray. A study in healthy volunteers
`
`P. D. Knoester,1 D. M. Jonker,2 R. T. M. van der Hoeven,1 T. A. C. Vermeij,3 P. M. Edelbroek,3
`G. J. Brekelmans3 & G. J. de Haan3
`1Stichting Apotheek der Haarlemse Ziekenhuizen (hospital pharmacy), Boerhaavelaan 24, 2035 RC Haarlem, 2Department of Physiology, University of
`Leiden, Wassenaarseweg 62, 2300 RC Leiden and 3Stichting Epilepsie Instellingen Nederland (tertiary epilepsy treament centre), Achterweg 5, 2103 SW
`Heemstede, The Netherlands
`
`Aims To investigate the pharmacokinetic and pharmacodynamic profile of
`midazolam administered as a concentrated intranasal spray, compared with intravenous
`midazolam, in healthy adult subjects.
`Methods Subjects were administered single doses of 5 mg midazolam intranasally
`and intravenously in a cross-over design with washout period of 1 week. The total
`plasma concentrations of midazolam and the metabolite 1-hydroxymidazolam after
`both intranasal and intravenous administration were described with a single pharmaco-
`kinetic model. b-band EEG activity was recorded and related to midazolam plasma
`concentrations using an exponential pharmacokinetic/pharmacodynamic model.
`Results Administration of the intranasal spray led to some degree of temporary
`irritation in all
`six subjects, who nevertheless
`found intranasal administration
`acceptable and not painful. The mean (ts.d.) peak plasma concentration of
`midazolam of 71 (t25 ng mlx1) was reached after 14 (t5 min). Mean bioavail-
`ability following intranasal administration was 0.83t0.19. After intravenous and
`intranasal administration, the pharmacokinetic estimates of midazolam were: mean
`volume of distribution at steady state 1.11t0.25 l kgx1, mean systemic clearance
`16.1t4.1 ml minx1 kgx1 and harmonic mean initial and terminal half lives 8.4t2.4
`and 79t30 min, respectively. Formation of the 1-hydroxymetabolite after intranasal
`administration did not exceed that after intravenous administration.
`Conclusions In this study in healthy volunteers a concentrated midazolam nasal
`spray was easily administered and well tolerated. No serious complications of the
`mode of administration or the drug itself were reported. Rapid uptake and high
`bioavailability were demonstrated. The potential of midazolam given via a nasal spray
`in the acute treatment of status epilepticus and other seizure disruptions should be
`evaluated.
`
`intravenous, midazolam, modelling, pharmaco-
`intranasal,
`Keywords: formulation,
`kinetics pharmacodynamics, PK-PD
`
`Introduction
`
`The benzodiazepine diazepam is a standard treatment in
`the acute management of all types of seizures in both adults
`and children. However,
`it does have disadvantages
`including a short duration of action and a tendency to
`accumulate if repeated doses are given. For acute seizures
`
`Correspondence: P. D. Knoester, Hospital pharmacist at UMC Nijmegen,
`PO Box 9101, 6500 HB Nijmegen, The Netherlands. E-mail: p.knoester@
`klinfarm@azn.nl
`
`Received 22 February 2001, accepted 17 December 2001.
`
`diazepam must be applied either intravenously or rectally
`in order to reach an effective blood concentration as
`soon as possible. Non-professional carers may be reluctant
`to administer midazolam by these routes [1, 2].
`The use of the water soluble benzodiazepine midazolam
`hydrochloride is well established as a premedicant,
`anxiolytic and anaesthetic induction agent [3]. Its safety
`and efficacy in the acute treatment of seizure exacerbations
`is well documented [4]. The efficacy of
`intranasal
`midazolam as premedication and sedative prompted its
`potential use in the management of acute seizures [1, 5–8].
`The nasopharyngeal mucosal surface is relatively large
`
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`P. D. Knoester et al.
`
`and well vascularized, allowing for a rapid absorption of
`midazolam. Nasal absorption also avoids the high first-pass
`metabolism of midazolam after oral administration [9].
`The dose of intranasal midazolam for treating seizure
`activity is based on body weight. It is 0.2 mg kgx1 for
`children, 5 mg for adults under 50 kg, and 10 mg of
`midazolam for adults weighing more than 50 kg. In most
`studies on intranasal midazolam,
`the undiluted, com-
`mercially available parenteral fluid containing 5 mg mlx1
`midazolam has been used. This requires a relative large
`volume, 1–2 ml in adult patients, to be applied, which
`may account for the lacrimation, burning and general
`discomfort that is associated with intranasal midazolam
`[10, 11]. A significant amount of
`the fluid can be
`swallowed and absorbed from the gastrointestinal tract,
`which decreases bioavailability and therefore reduces
`efficacy [10]. Furthermore, treatment failure may occur
`due to poor technique in delivering an adequate volume of
`midazolam liquid [8].
`These disadvantages might possibly be overcome by
`increasing the concentration of midazolam,
`thereby
`reducing the total volume of fluid to be delivered. In
`the present study we have investigated a concentrated
`intranasal
`formulation of midazolam. The aim was to
`compare the pharmacokinetic and EEG pharmacodynamic
`parameters after intranasal and intravenous administration
`of midazolam to healthy volunteers.
`
`Methods
`
`Midazolam formulations
`
`The study medications were prepared by the Apotheek der
`Haarlemse Ziekenhuizen Hospital Pharmacy. Intravenous
`midazolam 5 mg mlx1 (pH 3.3) was formulated using
`midazolam hydrochloride (Spruyt Hillen, IJsselstein, The
`Netherlands). The intranasal midazolam formulation
`contained midazolam hydrochloride in a mixture of
`water and propylene glycol (pH 4). Benzyl alcohol 1%
`v/v was added as an antimicrobial preservative.
`The intranasal device used (Spruyt Hillen) delivered
`an equivalent dose of 2.5 mg midazolam with each 90 ml
`spray. The stability of both formulations was investigated
`using a validated h.p.l.c. analytical method. During a
`6 month test period at ambient temperature no significant
`changes in pH or midazolam concentration occurred.
`Kept
`in the dark,
`the solutions remained clear and
`colourless.
`
`Subjects
`
`the Leiden University
`The Ethics Review Board of
`Medical Centre approved the investigational protocol for
`this study. Six nonsmoking volunteers (two female, four
`
`male) provided informed consent and participated in the
`study. Their mean age was 40t9 years
`(meants.d.,
`range: 27–47), and mean weight was 74t5 kg (range:
`66–80). None had a history of cardiac or neurological
`disease. They were not allowed to take any medication on
`a regular basis or benzodiazepines in the week before the
`study days. All subjects were healthy as assessed by medical
`history and physical examination,
`including ECG and
`blood pressure, and clinical chemical laboratory tests. The
`background EEG was normal.
`
`Study design
`
`The study was an open, crossover trial. On the two study
`days
`the subjects
`fasted and refrained from caffeine-
`containing
`beverages
`until
`2 h
`after midazolam
`administration. Alcoholic beverages were avoided from
`the day prior to the study until completion of the study
`day. All subjects received a single dose of 5 mg midazolam
`either intravenously or intranasally, in random order with
`a 7 day washout period between treatments.
`Intravenous midazolam was given as a bolus injection
`over 30 s
`into a peripheral vein of
`the lower arm.
`Intranasal midazolam was self-administered by one spray in
`each nostril. Subjects remained supine for the first 2 h of
`study. Blood samples were collected from a forearm vein in
`heparinized tubes. In addition to a pre-dose sample, blood
`was collected at 2, 5, 10, 15, 20, 30 and 60 min and 2, 3, 4, 5,
`6, 7, and 8 h postdose. The blood samples were kept
`on ice for a maximum of 2 h until centrifuged. Plasma
`samples were stored frozen at x20u C until assayed.
`
`Analysis of midazolam and 1-hydroxymidazolam
`
`Plasma concentrations of both compounds were deter-
`mined using a specific h.p.l.c. method with u.v. detection
`at 220 nm. Plasma aliquots of 1 ml were mixed with
`40 ng of the internal standard chlordesmethyldiazepam
`(Hoffman-La Roche, Basel, Switzerland) and 0.5 ml
`sodium hydroxide
`(0.1 M). Following
`liquid-liquid
`extraction with
`5 ml
`cyclohexane–dichloromethane
`(55–45
`v/v),
`the organic
`layer was
`evaporated.
`The residue was dissolved in 250 ml water-acetonitrile
`(95–5 v/v) and 200 ml were injected onto the chromato-
`graph. Separation was achieved on a custom-made
`column (15r0.46 cm) packed with Inertsil ODS-3
`C-18 (Varian Chrompack, Houten, The Netherlands)
`with an isocratic mobile phase of 0.1 M phosphate buffer
`pH 7.0-acetonitrile (65–35 v/v).
`range
`the
`Calibration curves were
`linear over
`of 0–400 ng mlx1
`(r2>0.99).
`Inter-
`and intra-day
`coefficients of variation were less
`than 7%. The
`limit of quantification for both compounds was
`0.5 ng mlx1.
`
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`EEG recordings
`
`Ten silver-silver chloride electrodes were placed on
`the skull of
`the subjects at positions
`following the
`International 10–20 system of electrode placement. EEG
`was recorded using a 32 channel digital EEG (Vickers
`Medelec DG32) with a bandwidth of 0.5–50 Hz, gain
`7 mV mmx1, sample frequency 240 Hz. The EEG data
`were filtered, electrical noise reduced, digitized and stored
`on optical disks for later analysis. In addition, during
`acquisition the raw data were examined visually for
`artefacts.
`Two-minute EEG-time epochs were analysed from
`5 min before and 5, 10, 15, 20, 30, 45, 60, 75, 90, and
`120 min after midazolam administration. During EEG
`recording, subjects closed their eyes. The EEG signals
`were quantified by use of fast Fourier transformation.
`The averaged amplitudes (square root of power (mV2)) in
`the 14–40 Hz beta frequency band were calculated and
`used as the EEG effect measure.
`
`Safety and tolerability assessment
`
`After administration of midazolam, subjects were periodi-
`cally questioned and monitored for any unusual symptoms.
`They were asked specifically to record any sensation (bitter
`taste, burning sensation, pain) experienced after intranasal
`administration.
`
`Pharmacokinetic analysis
`
`The time course of midazolam concentrations was
`described by a two-compartment model, whereas for
`1-hydroxymidazolam, a one-compartment model was
`used. In the model development process, discrimination
`was based on visual inspection of the plasma profiles and
`the residuals, and on Akaike’s information criterion [12].
`The concentration data were weighted using iterative
`reweighting (WinNonlin version 3.1). The model con-
`sisted of
`the following differential equations, each
`describing the amounts of the parent compound midaz-
`olam (AP) in the central and peripheral compartment
`denoted by the subscripts 1 and 2, respectively:
`¼ kA . F . D . e
`.t k10 . AP1 k12 . AP1
`þ k21 . AP2 kM . AP1
`
`dAP1
`dt
`
`kA
`
`ð1Þ
`
`Midazolam as an intranasal spray
`
`for intravenous administration and when t<tlag. kM is the
`first-order rate constant for the conversion of midazolam
`to 1-hydroxymidazolam.
`The amount of the active metabolite 1-hydroxymidaz-
`olam in the central compartment (AM) was described by:
`¼ kM . AP1 k10OH . AM
`ð3Þ
`
`dAM
`dt
`
`the elimination rate constant of
`
`here k10OH denotes
`1-hydroxymidazolam.
`of
`distribution
`of
`volume
`Estimation
`of
`the
`1-hydroxymidazolam was not possible because inclu-
`sion of this parameter causes of the model. To solve
`this problem,
`the amounts of midazolam and of
`1-hydroxymidazolam were related to the observed con-
`centrations by dividing by the volume of distribution of
`midazolam (VC). Previously, the volumes of distribution of
`midazolam and the metabolite were shown not to differ
`from each other [9]. Nevertheless, estimates of k10, kM and
`k10OH would be affected if these volumes did differ.
`Therefore calculation of the clearance (CL) and half-life
`(t1/2) of midazolam was based on the sum of k10 and kM, and
`were calculated using standard equations [13]. Equations 1
`and 2 cannot be solved algebraically to obtain explicit
`equations
`for the maximum plasma concentration of
`midazolam (Cmax) and time to maximum concentration
`(tmax). Therefore,
`these parameters were determined
`manually from the curve fitted to the concentration-time
`data. The areas under the concentration curves (AUC)
`were calculated by the linear trapezoidal rule. Extrapola-
`tion to infinite time was achieved by dividing the last
`concentration by the terminal rate constant lb. The AUC
`values obtained from the midazolam curves after i.v.
`and i.n. administration were used to calculate absolute
`bioavailability (FAUC) using the standard equation [13]:
`ð4Þ
`
`FAUC ¼ AUCi:n:  Di:v:
`AUCi:v:  Di:n:
`
`Pharmacodynamics analysis
`
`The EEG activity in the b-band (14–40 Hz) was related to
`the midazolam plasma concentration using an exponential
`model:
`
`EðCÞ ¼ E0 þ bn . Cn
`
`ð5Þ
`
`in which E(C) is the observed effect at concentration
`C, E0 is the baseline effect value, and b and n are
`parameters determining the curvature of the exponential
`function.
`
`Statistical analysis
`
`The Student’s one tailed t-test with a 5% level of
`significance was used to test the difference of tlag and F
`
`dAP2
`dt
`
`¼ k12 . AP1 k21 . AP2
`
`ð2Þ
`
`in which F and D denote the bioavailability and dose,
`respectively. Absorption of midazolam from the nasal
`mucosa was described with a first order absorption-rate
`constant (kA) and a lagtime (tlag). kA was reduced to zero
`
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`

`0
`
`60
`
`120 180 240 300 360 420 480 540
`Time (min)
`
`1000
`
`100
`
`10
`
`1
`
`0.1
`
`Concentration (µg l–1)
`
`Figure 1 Fit of the composite model to the concentration vs
`time data for midazolam and 1-hydroxymidazolam in one
`volunteer. Solid lines indicate the time course of midazolam
`concentrations (&) and 1-hydroxymidazolam concentrations (2)
`after intravenous administration. Dotted lines indicate the time
`course of midazolam concentrations (m) and
`1-hydroxymidazolam concentrations (.) after intranasal
`administration.
`
`0
`
`60
`
`120 180 240 300 360 420 480 540
`Time (min)
`
`1000
`
`100
`
`10
`
`1
`
`0.1
`
`Concentration (µg l–1)
`
`Figure 2 Individual plasma concentration vs time curves for
`midazolam (solid lines) and 1-hydroxymidazolam (broken lines)
`after intranasal administration of 5 mg midazolam. The bold
`curves represent the mean pharmacokinetic model fit to the data.
`
`indicates that there is no appreciable difference in the
`extent of metabolism after
`intranasal
`administration
`compared with intravenous administration.
`
`Pharmacodynamics
`
`In one subject, no reliable EEG registration was obtained
`due to technical difficulties and the pharmacodynamic
`analysis was performed in the remaining five subjects.
`EEG activity vs midazolam plasma concentration data
`in individual subjects are shown in Figure 3. In all indi-
`viduals the intraindividual basal EEG-activity after intra-
`venous and intranasal administration was comparable.
`After intranasal administration, observable changes in EEG
`activity were observed in only one subject. Comparison
`of
`the pharmacodynamic parameter
`estimates
`after
`intravenous and intranasal administration would not be
`possible if the data were fitted to the model separately.
`Thus, the intravenous and intranasal EEG data of each
`subject were fitted to the pharmacodynamic model
`
`P. D. Knoester et al.
`
`from zero and one, respectively. The nonparametric
`Spearman correlation was calculated and tested for
`deviation from zero using GraphPad Instat version 2.05a
`software. All data are presented as the meants.d., unless
`indicated otherwise.
`
`Results
`
`Safety and tolerability
`
`No relevant changes were observed in blood pressure,
`heart rate or respiration after administration of midazolam.
`Within 2 min after intravenous administration, all subjects
`felt
`sedated, and two of
`them fell asleep. Intranasal
`administration led to some degree of nasal irritation in
`all subjects. Some subjects complained of teary eyes, a
`slightly bitter taste and a raw throat. The symptoms
`disappeared within 10 min in all but one subject, in whom
`intranasal irritation lasted for 25 min All subjects tolerated
`intranasal administration well and none found it to be
`painful.
`
`Pharmacokinetics
`
`of midazolam and
`concentrations
`plasma
`The
`1-hydroxymidazolam were evaluated in all six volunteers
`using the composite model described above. An example
`of the curves fitted to the concentration data from one
`individual is given in Figure 1. The individual plasma
`concentrations after both intravenous and intranasal
`administration are shown in Figure 2. The pharmaco-
`kinetic parameters obtained using an integrated model
`for both midazolam and 1-hydroxymidazolam are
`summarized in Table 1. The model described the data
`adequately with the residuals being distributed satis-
`factorily and with a
`low correlation between the
`parameters. In two subjects, inclusion of the lagtime did
`not improve the fit to the data as determined by the
`Akaike criterion, and in these subjects the lagtime was
`constrained to 0 min.
`intranasal
`Midazolam was
`rapidly absorbed after
`administration, with a mean peak concentration of
`71t25 ng mlx1 reached after 14t5 min. The mean
`lagtime for the appearance of midazolam and its metabolite
`after intranasal administration was 0.87t0.74 min, which
`from 0 (P=0.02). Mean
`was
`significantly different
`bioavailability was high (0.83t0.19), but was significantly
`different from 1.0 (P=0.04; C.I. 0.68, 0.98). Mean FAUC,
`calculated
`from noncompartmental
`analysis, was
`0.80t0.19 (Table 2). The mean ratio AUCi.n./AUCi.v.
`for 1-hydroxymidazolam, a measure for
`the relative
`amount of metabolite formed, was 0.79t0.41.
`In
`addition, a moderate but significant correlation between
`this ratio and FAUC was found (rs=0.81, P=0.01). This
`
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`Midazolam as an intranasal spray
`
`Table 3 Pharmacodynamic parameter estimates following intravenous
`and intranasal administration of 5 mg midazolam. The EEG data were
`fitted simultaneously to the model (equation 5) because the data
`obtained after intranasal administration did not allow separate estimation
`of the parameters. Values are meants.d.
`
`Estimate
`
`0.044t0.015
`0.0027t0.0027
`2.3t2.1
`
`25
`75 100
`50
`Predicted midazolam concentration (µg l–1)
`
`200
`
`Parameter
`
`E0 (mV2)
`B
`n
`
`0.30
`0.25
`0.20
`0.15
`0.10
`0.05
`0.00
`10
`
`Power of EEG in b-band (µV2)
`
`Figure 3 Individual EEG effect vs predicted plasma midazolam
`concentration after i.v. (solid lines) and i.n. (broken lines)
`administration of the drug. The bold curve represents the mean
`pharmacodynamic model fit.
`
`distribution to a second compartment could not be
`identified in this data set due to the first order formation
`rate of the metabolite. In the case of the parent compound,
`distribution to a second compartment was characterized
`from the concentration-time data
`after
`intravenous
`administration.
`In the composite model used, the formation rate of
`1-hydroxymidazolam was assumed to be equal for the two
`routes of administration. Under this assumption, a good fit
`to both the midazolam and the 1-hydroxymidazolam data
`was obtained, indicating no difference in the extent of
`metabolism between the two routes. This was further
`confirmed by noncompartmental analysis. The mean ratio
`AUCi.n./AUCi.v. of 1-hydroxymidazolam was virtually
`identical to the mean value of FAUC, which rules out the
`possibility that
`intranasal metabolism by cytochrome
`P450 metabolizing enzymes on the nasal mucosa
`contributes substantially to the observed concentration
`time profiles. In addition, the similarity of these AUC
`values indicates that very little of the concentrated spray
`used in this study is swallowed. After oral administration
`to adults, midazolam has been reported to be subject to
`saturable first-pass metabolism, with reported bioavail-
`abilities
`in the range of 0.24–0.5 [15, 16]. The
`bioavailability reported in the present study corresponds
`well with the value of 0.83t0.15 reported in a study
`
`Table 1 Pharmacokinetic measurements after intravenous and
`intranasal administration of midazolam obtained using a composite
`pharmacokinetic model (see text).
`
`Parameter
`
`F
`kA (minx1)
`tlag (min)
`VC (l kgx1)
`VSS (l kgx1)
`CL (l minx1 kgx1)
`t1/2, l1 (min)*
`(min)*
`t1/2, lz
`kM (minx1)
`Cmax (mg lx1)
`tmax (min)
`
`Estimatets.d.
`
`0.83t0.19
`0.168t0.053
`0.87t0.74
`0.46t0.14
`1.11t0.25
`0.0161t0.0041
`8.4t2.4
`79t30
`0.0036t0.0015
`71t25
`14t5
`
`F: intranasal bioavailability, kA: absorption rate constant, tlag: lag-time,
`VC: volume of the central compartment, VSS: volume of distribu-
`tion at steady state, CL: midazolam clearance, t1/2, l1: equilibration
`formation rate constant of
`t1/2, lz: terminal half-life, kM:
`half-life,
`1-hydroxymidazolam, Cmax: maximum concentration after intranasal
`administration, tmax: time to maximum concentration after intranasal
`administration. Values are meants.d. *Half-lives are expressed as
`harmonic means.
`
`Table 2 Estimates of the mean areas under the curve of the intravenous
`and intranasal formulations and mean bioavailability of the intranasal
`formulation from noncompartmental analysis for midazolam and
`1-hydroxymidazolam. Values are meants.d.
`
`Parameter
`
`Midazolam
`
`1-Hydroxymidazolam
`
`AUCi.v. (mg lx1 min)
`AUCi.n. (mg lx1 min)
`FAUC
`
`13.0t4.7
`10.2t3.3
`0.80t0.19
`
`1.76t0.61
`1.27t0.43
`0.79t0.41
`
`simultaneously with the average parameter estimates
`reported in Table 3. Since only small changes in EEG
`activity were observed, the model parameters could not be
`estimated reliably.
`
`Discussion
`
`adequately
`pharmacokinetic model
`integrated
`An
`described the concentration profiles of midazolam and
`its active metabolite 1-hydroxymidazolam after intra-
`venous and intranasal administration. Using this model,
`the mean bioavailability of midazolam administered by
`nasal spray was estimated to be 0.83t0.19, corresponding
`well with a mean FAUC value of 0.80t0.19 calculated
`from noncompartmental analysis.
`The formation of 1-hydroxymidazolam was best
`described by a one-compartment model. Although it has
`been shown that 1-hydroxy-midazolam is distributed
`into two compartments in both man and rat [9, 14],
`
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`P. D. Knoester et al.
`
`where midazolam was administered intranasally [17]. In
`another study in adults, a bioavailability of 0.50t0.13 was
`reported [10], when 3.9 ml of a 5 mg mlx1 solution of
`midazolam was instilled alternating between nostrils in
`1 ml increments. It is quite possible that a considerable
`amount of the solution was swallowed. In the study by
`Bjo¨ rkman et al. spilling and swallowing of the 5 mg mlx1
`solution was minimized by slow and careful spraying of
`0.1 ml aliquots into the nostrils [17], but the method was
`time consuming. In the present study, a high bioavail-
`ability was achieved with a single 90 ml spray in each
`nostril, using a more concentrated solution of midazolam.
`After
`intravenous administration, changes
`in EEG
`activity seemed to be midazolam concentration dependent
`within each individual. However, considerable inter- and
`intra-subject variability in EEG activity was observed
`(Figure 3). The data were described by a reduced form
`of the sigmoid Emax equation, which is useful in cases
`where the maximum response cannot be estimated from
`the data [18]. When bn is made equal to Emax/EC50
`n,
`the sigmoid Emax equation appears under the condi-
`tion that c%EC50, where EC50 is the concentration at
`half maximal effect. The pharmacodynamic analysis was
`hampered by the small changes in EEG activity after
`intranasal administration. Judging from the intravenous
`concentration-effect data, this was due to the slightly
`lower peak concentrations of midazolam after intranasal
`administration (Figures 2 and 3). It is for this reason
`that the EEG activity after intravenous and intranasal
`administration superimpose and that conclusions regard-
`ing the pharmacodynamic characteristics of intravenous
`vs
`intranasal midazolam cannot be drawn based on
`these data.
`that
`vivo,
`in
`It has been shown in humans
`1-hydroxymidazolam has a potency and intrinsic activity
`similar to the parent compound midazolam [9]. Further-
`more, after oral administration to volunteers, the forma-
`tion of the active metabolite significantly contributes to
`the sedative effect [19]. Differences in the extent of
`metabolite formation between intravenous and intranasal
`administration are likely to complicate the pharmaco-
`dynamic analysis in the sense that a pharmacodynamic
`interaction model would be needed to describe the
`concentration-effect
`relationship. A mechanism-based
`model
`assuming a competitive interaction between
`midazolam and 1-hydroxymidazolam has been validated
`in rats [14]. However, in the present study, fitting both a
`composite parametric model and a non-parametric model
`to the concentration data showed that no differences in
`the extent of metabolite formation occurred between
`formulations. Therefore, the 1-hydroxymidazolam con-
`centration data were not
`taken into account
`in the
`pharmacodynamic analysis. Although formation of the
`active metabolite 1-hydroxymidazolam is very likely to
`
`the
`the shape of
`contribute to the effect on EEG,
`concentration-effect curve based on midazolam concen-
`trations is not expected to differ between the routes of
`administration.
`Intranasal midazolam has proved to be effective and safe
`in the treatment of acute seizure exacerbations [1, 5–8].
`The more concentrated intranasal spray used in the present
`study was well
`tolerated, although all volunteers
`felt
`some degree of
`irritation directly after administration.
`This disappeared within 25 min for all subjects. Benzyl
`alcohol, which has weak anaesthetic properties, may have
`contributed to the decline of the irritation.
`This concentrated intranasal midazolam spray com-
`bines ease of administration with good tolerability and
`a favourable pharmacokinetic profile, all
`regarded as
`essential requirements for ‘on demand’ administration in
`acute situations [20]. The potential of midazolam nasal
`spray in status epilepticus or other
`acute seizure
`dysregulations should be further evaluated.
`
`The authors gratefully acknowledge the valuable comments
`Professor Dr M. Danhof made on this manuscript.
`
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