Acta Neurol Scand 2009: 120: 353—357 DOI: 10.1111/j. 1600-0404.2009.01170.x
`
`Copyright © 2009 The Authors
`Journal compilation © 2009 Blackwell Munksgaard
`ACTA NEUROLOGICA
`SCANDINAVICA
`
`Clinical Commentary
`
`Pharmacokinetics and tolerability of
`intranasal diazepam and midazolam in
`healthy adult volunteers
`
`Ivaturi VD, Riss JR, Kriel RL, Cloyd JC. Pharmacokinetics and
`tolerability of intranasal diazepam and midazolam in healthy adult
`volunteers.
`Acta Neurol Scand 2009: 120: 353—357.
`© 2009 The Authors Journal compilation © 2009 Blackwell Munksgaard.
`
`V. D. lvaturim, J. R. Riss‘,
`n. L. Kriei”, J. c. Cloyd”
`‘Center for Orphan Drug Research and 2Department of
`Experimental and Clinical Pharmacology, University of
`Minnesota, Minneapolis, MN, USA
`
`Objective — The purpose of this pilot study was to determine the
`pharmacokinetics and tolerability of an investigational diazepam
`(DZP) formulation and a parenteral midazolam (MDZ) formulation
`following intranasal (in) administration for the efficient treatment of
`seizure emergencies. Methods — Each subject received 5 mg of DZP
`and MDZ via both in. and intravenous routes in a four-way,
`randomized crossover trial. Blood samples were collected over 48 h.
`DZP and MDZ concentrations were measured using HPLC. Using
`analog scales, subjects rated tolerability (O = no change from
`normal; 10 = maximum intolerability) and pain (0 = no pain;
`4 = extreme pain) prior to and 0, 5, 15, 60 min, and 8 h after
`administration. Results — The Cmax and Tmax values for in DZP and
`MDZ were 179.2 ng/ml and 28.8 min vs 62.8 ng/ml and 21.6 min,
`respectively. Immediately following in. administration, subjects
`reported tolerability scores of 6.75 and 6.0, and identical pain scores,
`3.2, for DZP and MDZ, respectively. Conclusion — Both formulations
`were rapidly absorbed following in administration with transient
`discomfort. DZP had a longer half-life, which may result in an
`extended duration of action. Further studies in large patient
`populations to evaluate the safety after long term use, efficacy and
`pharmacokinetics of in. DZP are warranted.
`
`Key words: diazepam; intranasal; midazolam;
`pharmacokinetics; tolerability
`
`Vijay D. lvaturi, Center for Orphan Drug Research,
`Rm 4206, McGuire Translational Research Facility.
`2001 6th St. SE, College of Pharmacy, University of
`Minnesota, Minneapolis. MN 55455, USA
`Tel: 612 524 1851
`Fax: 612 626 9985
`e-mall: ivatu001@umn.edu
`
`Presented as a poster at the American Academy of
`Neurology, April 2005, ‘Bioavailability and tolerability of
`a novel intranasal diazepam formulation in healthy
`volunteers‘.
`
`Accepted for publication January 5, 2009
`
`Introduction
`
`Individuals with uncontrolled epilepsy represent
`one of the greatest challenges in the management
`of this disorder (1, 2). These patients are particu-
`larly prone to status epilepticus (SE) as well as
`prolonged or cluster seizures which are in them-
`selves serious conditions that can evolve into SE
`
`Intravenously administered benzodiazepines
`(3).
`(BZDs) are widely used for the treatment of seizure
`emergencies. When given within 30 min of seizure
`onset, intravenous (i.v.) BZDs are effective in more
`than 80% of patients (3, 4). However, i.v. admin-
`istration requires skilled personnel and transport to
`a medical
`facility which can delay initiation of
`
`therapy (5). Treatment delay is associated with
`longer seizure duration, greater difficulty in termi-
`nating the
`seizure, prolonged hospitalization,
`higher mortality, and reduced quality of life (3, 6).
`Administration of BZDs by other routes could
`permit earlier
`initiation of therapy outside of
`medical facilities. Rectal administration of diaze-
`
`pam (DZP) for the treatment of seizure emergen-
`cies is safe and effective, reduces medical costs, and
`improves quality of life, but many patients and
`their caretakers are reluctant to consider this mode
`
`is in a
`of therapy especially when the patient
`location which is socially embarrassing (7—10).
`The availability of a fast-acting intranasal (in)
`treatment that can be easily administered by the
`
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`Ivaturi et al.
`
`patient or a caregiver would greatly improve the
`management of seizure disorders. Essential Char-
`acteristics for an i.n. drug delivery system in the
`treatment of seizure emergencies include: patients
`must be able to tolerate the formulation; admin-
`istration volume of 0.5 ml or less; rapid, consistent
`absorption; and easy administration by non—med-
`ical caregivers and patients.
`The purpose of this study was to evaluate the
`pharmacokinetics and tolerability of i.n. adminis—
`tered DZP and midazolam (MDZ) in healthy adult
`volunteers.
`
`Methods
`
`The study was approved by the Institutional
`Review Boards at
`the University of Minnesota
`and Hennepin County Medical Center. Four
`healthy, non—pregnant women aged 20—24 years
`participated in the
`study. Subjects provided
`informed consent and were compensated for par-
`ticipation. Subjects were excluded if they were in
`poor health, unwilling or unable to receive i.n. or
`i.v. medications, pregnant, smokers, allergic to
`DZP or MDZ, or had narrow-angle glaucoma.
`Subjects’
`treatment
`sequence was
`randomly
`assigned using a latin-square design. The study
`consisted of a four-way, randomized, single-blind,
`crossover design in which subjects received 5 mg
`doses of i.n. DZP,
`i.n. MDZ, i.v. DZP and i.v.
`MDZ. Subjects were admitted to the clinical
`research unit located at Hennepin County Medical
`Center and remained there for 8 h on four separate
`occasions after a minimum 1-week washout period.
`Commercial
`formulations were used for
`i.v.
`administration of DZP and MDZ. The i.n. DZP
`
`formulation consisted of an investigational super-
`saturated solution containing 40 mg/ml of DZP,
`glycofurol and water. The injectable MDZ formu-
`lation (5mg/ml) was also used for i.n. administra-
`tion. The i.n. doses of 5 mg were administered
`using a 1.0 ml syringe such that 0.125 ml of the
`DZP solution and 1 ml of the MDZ solution were
`
`dripped slowly into either one of the nostrils.
`Intranasal administration of normal saline (0.5 ml)
`given with a 1.0 ml dropper served as a control to
`compare tolerability of the drugs. Using a 10-point
`Global Tolerability Analog Scale, each subject
`rated overall
`tolerability of the i.n.
`(drug and
`normal saline) and iv. doses (drug only) at 5 min
`prior to and 0, 5, 15, 60 min and 8 h after drug
`administration. A score of 10 was considered the
`
`least tolerable. This scale is analogous to Visual
`Analog Scales and has been adapted from a
`previous study evaluating the tolerability of a
`nasal formulation (11). Subjects also completed
`
`354
`
`a pain and subjective discomfort questionnaire for
`the i.n. administrations. Using a 4 point analog
`scale with 4 representing extreme pain or discom-
`fort, subjects rated specific pain characteristics:
`burning, stinging, and throbbing at —15, 0, 5, and
`15 min.
`
`for pharmacokinetic
`Blood samples of 5 ml
`analysis were collected, by means of a catheter
`inserted into a forearm vein,
`into glass tubes
`containing ethylenediamine tetraacetic acid as
`anticoagulant at —5, 0,
`l, 5, 10, 20, 30, 60 min
`and 8 h. For DZP, additional
`samples were
`obtained at 24 and 48 h. Within 15 min of collec-
`tion, the blood samples were spun in a centrifuge,
`and plasma was carefully separated. Plasma sam-
`ples were stored at ~80°C pending analysis.
`
`Drug assay
`
`Plasma samples were analyzed for MDZ and DZP
`concentrations using an Agilent 1100 series HPLC
`system (Agilent Technologies, Palo Alto, CA,
`USA) with a C4 column. The mobile phase for
`the system consisted of 40% acetonitrile and 60%
`phosphate buffer (pH-6.0). The flow rate of the
`mobile phase was 0.5 ml/min and the injection
`volume was 50 ul. Standard curves were prepared
`over the range of 5—500 ng/ml and quality control
`samples containing 15 (low), 50 (medium) and
`250 ng/ml (high) of DZP and MDZ were prepared
`separately with blank human plasma.
`An aliquot of 0.2 ml of the plasma was added to a
`12 x 75 mm glass tube. A sample of NaOH (200 pl)
`and the internal standard lorazepam (200 pl) were
`added and the solution was mixed well. A 2 ml
`volume of ether was poured in the tube as an
`extracting solvent and vortex mixed for l min and
`then centrifuged for 10 min at 769 g. A sample of
`the organic layer was collected and evaporated until
`dry with nitrogen at 34°C, and then 200 pl of
`the HPLC mobile phase was added to dissolve the
`residue. After 30 s of vortex mixing, 50 ul of the
`sample solution was injected into the HPLC system.
`The standards for DZP and MDZ were analyzed
`on separate days and the mean coefficients of
`variation were 5.6% and 5.0%, respectively. The
`mean coefficients of variation for the intraday
`variation of DZP and MDZ quality control
`samples were 8.6% and 7.5%, respectively.
`
`Pharmacokinetic analysis
`
`Concentration—time data of DZP and MDZ were
`
`examined using non—compartmental pharmacoki-
`netics analysis with WinNonLin software (version
`5.2; Pharsight Corporation, Mountain View, CA,
`
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`‘ Table 1 Mean (3:80) pharmacokinetic parameters of diazepam (DZP) and mi.
`dazolam (MDZ) in healthy volunteers following intravenous (iv) and intranasal (in)
`administration of 5 mg dose
`
` PK parameter i.v. DZP in. DZP i.v. MDZ i.n. MDZ
`
`
`
`
`
`
`
`
`
`Intranasal diazepam and midazolam
`
`IN DZP (n = 3)
`
`O
`
`4o 720 g
`01..
`
`.
`
`o
`
`30',
`70
`
`
`1
`5
`10
`15
`20
`30
`60
`Tlme (mm)
`
`IN MDZ(n=3)
`
`00
`
`(ng/ml)NWkVI01{-2O ,4 o
`Concentration
`
`‘9
`
`0
`
`1
`
`I
`
`S
`
`15
`10
`Tlme (min)
`
`20
`
`30
`
`60
`
`Figure 2. Concentration time profiles (M0 min) of individual
`subjects (n = 3) for intranasal midazolam and diazepam.
`
`21.8 i: 7.63
`—
`28.8 d: 20.95
`—
`Tmax (min)
`62.8 d: 14.51
`155.2 :1: 96.42‘
`179.2 :1: 8.85
`344.0 :1: 9281‘
`Cmax (ng/ml)
`
`
`
`
`59.1 :t 7.76 22.4 :1: 3.45 0.9 i 0.50Half-life (h) 3.0 i 0.74
`
`‘Cuncentration 5 min after injection.
`
`250
`
`200
`
`+|N MDZ(n=3)
`41» IN 02? in = 3)
`
`E150
`:
`:3 100
`
`5
`
`‘5-
`
`/
`
`L~~1ib~-wj whit
`,/1 i
`I”
`1
`
`I
`,2"; l
`
`.2”
`
`SD o
`
`20
`
`so
`
`so
`
`1
`
`s
`
`15
`10
`Tlme (min)
`
`Figure 1. Comparison of mean intranasal diazepam and
`midazolam concentration vs time profile.
`
`USA). The terminal rate constant ()VZ) was deter-
`mined from the slope of the terminal
`log-linear
`portion of the plasma—concentration—time curve,
`and the terminal half—life (ll/2) was calculated as
`ln2/(ltz). Maximum plasma concentrations (Cmax)
`and time to maximum concentration (Tmax) were
`determined by direct observation of the data.
`Means and standard deviations for the parameters
`were also obtained using the descriptive statistics
`tool in WinNonlin version 5.2.
`
`Scores
`
`Global tolerability scores
`
` I IN DZP
`
`9 IN MDZ
`
`Baseline
`
`0 min
`
`15 min
`5 min
`Time (mln)
`
`60 min
`
`Results
`
`Four women, aged 20—24 years entered the study.
`One subject dropped out due to travel conflicts after
`completing the in. DZP arm and was excluded from
`all group analyses. The pharmacokinetic parameters
`for the three subjects are summarized in Table 1. The
`mean concentration—time profiles are shown in
`Fig.
`1 and the individual subject’s concentration
`time profiles for both in DZP and MDZ are shown
`in Fig. 2. The average in. DZP Cmx and Tmax were
`179.2 :1: 8.8 ng/ml and 28.8 :1: 20.9 min,
`respec-
`tively. The average in MDZ Cmax and Tmax were
`62.8 :L- 14.5 ng/ml and 21.6 i 7.6 min,
`respec-
`tively. The Cmax and Tmax of the subject who dropped
`out of the study were 109.48 ng/ml and 20 min,
`respectively following in. DZP administration.
`
`Figure 3. Comparison of mean global tolerability scores after
`intranasal administration (n = 3).
`
`Immediately following in. administration, sub-
`jects reported an average global tolerability score
`of 6.75 and 6.0 for DZP and MDZ, respectively,
`which were statistically not different (P > 0.05)
`(Fig. 3). Within 15 min, scores decreased to 3.3
`and 1.5, respectively, which eventually returned to
`baseline (Fig. 3).
`Subjects rated both formulations as causing
`considerable pain with a maximum score of 3.2
`immediately following nasal administration. Fifteen
`minutes later, the mean pain score for both drugs
`was 1.2. Posterior nasal drainage and watery eyes
`were reported by all subjects.
`
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`Ivaturi et al.
`
`Discussion
`
`Using PubMed with key terms ‘intranasal midazo-
`lam and diazepam’, we found no published reports
`directly comparing i.n. DZP and i.n. MDZ.
`Various MDZ formulations given i.n. have been
`investigated with most studies using the commer-
`cially available injectable MDZ solution (12, 13).
`These
`studies with doses between
`10—20 mg
`(2—4 ml) reported Cmax and Tmax values in the
`range of 147—192 ng/ml and 14—25 min, respec-
`tively. The absorptive area of the nose limits the
`volume administered to approximately 0.1-0.3 ml
`per nostril although smaller volumes are preferable
`(14). When the commercially available injectable
`MDZ solution is given i.n., volumes exceeding
`0.20 ml are required in order to administer a
`clinically relevant dose (12). This could affect both
`bioavailability and Cmax. Highly concentrated
`investigational nasal MDZ formulations, including
`a water and propylene glycol admixture (pH 4)
`(15),
`and a
`solution containing 14% (w/v)
`sulfobutylether B—cyclodextrin (pH 4.3) (16) have
`also been studied in humans. Although these
`formulations permit administration of smaller
`volumes (0.2—0.3 ml), there was no distinguishable
`difference in the values of Cmax and Tmax.
`Three previous studies have investigated i.n. DZP
`in humans. Gizurarson et al. compared an i.n. 2 mg
`dose of a 20 mg/ml DZP solution dissolved in 5%
`glycofurol in polyethylene glycol 200 with the same
`dose given iv. (17). Blood samples were collected
`for 5 h following drug administration. The mean
`bioavailability was 50.4 :t: 23.3% with a time to
`peak concentration of 18 :1: 11min. All subjects
`complained of nasal discomfort immediately fol-
`lowing drug administration, but
`the discomfort
`resolved within 30 min. Lindhardt et al. evaluated
`an i.n. formulation of DZP in polyethylene glycol
`300 in seven healthy volunteers. Using a crossover
`design, they compared 4 and 7 mg i.n. closes with a
`5 mg i.v. dose and collected blood samples for
`60 min after drug administration. The i.n. formula-
`tion had a relative bioavailability of 45% and 42%, a
`Cmx of 99 and 179 ng/ml and a Tmax of 18 and
`42 min for the 4 and 7 mg doses, respectively (18).
`Given that the half-life of DZP ranges from 24 to
`48 h, their bioavailability values are likely an under-
`estimate of the actual extent of absorption. Lau and
`Slattery, using a 10 mg dose of DZP dissolved in
`Cremophor EL, reported a bioavailability of 78%
`with a Cmax of 175 ng/ml and a Tmax ofl h (19). A
`recent study by Cloyd et al. (20) determined the
`pharmacokinetics and dose proportionality of 5 and
`10 mg doses of an i.n. administered DZP formula-
`tion compared with i.v. administration in eight
`
`356
`
`healthy volunteers using a crossover design. The
`formulation used was a 40 mg/ml supersaturated
`solution of DZP in glycofural~water cosolvent
`mixture. Each subject received two i.n. and one i.v.
`dose of DZP and blood samples were collected up to
`48 h after dosing. The mean Cmax, Tmax and I. /2
`were
`134.3 :l:61.9 ng/ml,
`55.6 i 60.3 min, and
`49.1 at: 20.4 h for the 5 mg dose, and 247.0 :1:
`60.9 ng/ml, 39.3 :J: 38.1 min, and 57.0 i: 28.0 h
`for the 10 mg dose. Using analog scales, subjects
`rated tolerability (0 = no change from normal;
`10 = maximum intolerability) prior to and 0, 5, 15,
`60 min, and 8 h after administration. The mean
`tolerability scores observed were 4.4 and 4.7 for the 5
`and 10 mg doses. Both these scores dropped down to 3
`and 2.5, 15 min post-dose and to 1, 60 min post—dose.
`The pharmacokinetic parameters for i.v. DZP
`and iv. MDZ shown in Table 1 are comparable
`to those reported in the literature (21). The rela-
`tionship between DZP pharmacokinetics
`and
`pharmacodynamics is complex. Following rapid
`i.v. administration,
`relatively high plasma DZP
`concentrations occur prior to distribution to vari-
`ous body compartments including the central ner-
`vous system (CNS). This makes correlation of DZP
`levels with seizure control difficult. In contrast, the
`
`absorption of DZP following rectal or nasal admin-
`istration, although relatively rapid, does permit
`equilibration of DZP concentrations between
`plasma and the CNS. Milligan et al. rectally admin-
`istered a 20 mg dose ofDZP solution or placebo to
`10 adults with epilepsy and then observed spike
`wave activity and measured plasma concentrations.
`Rectal DZP significantly reduced EEG spike fre-
`quencies within 20 min at a mean serum DZP level
`of 210 ng/ml. The mean Cmax of DZP was
`413 ng/ml and the mean Tmax was 32 min (22).
`Based on these results, subsequent controlled clin-
`ical
`trials using similar doses, and presumably
`similar plasma DZP concentrations, have demon-
`strated that rectal DZP is effective in treating acute
`repetitive seizures (8).
`Although we administered 5 mg DZP i.n. in this
`study, doubling the dose to 10 mg by giving 5 mg
`DZP into each nostril should result in concen-
`
`trations >200 ng/ml
`5—10 min.
`
`that are attained within
`
`is unclear whether prolonged serum DZP
`It
`concentrations are needed to achieve and maintain
`seizure control. The longer elimination half-life of
`DZP compared with MDZ as shown in the results
`conveys a theoretical advantage in preventing
`subsequent seizure recurrence. In controlled inves-
`tigations DZP is effective in treatment of seizure
`emergencies (8, 23). Such studies have yet to be
`conducted with MDZ.
`
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`

`All subjects reported moderate discomfort with
`both formulations. This is a major
`limitation
`of both the injectable MDZ solution and the
`investigational DZP formulation.
`Measures to improve comfort level or tolerabil-
`ity are needed for greater patient acceptance.
`Nonetheless, some patients and caretakers would
`prefer the transient discomfort of the present in
`formulations to rectal administration of medica—
`tion in public settings. Similar views have been
`expressed in a comparative study of in. MDZ and
`rectal DZP (10). Intranasal DZP may be useful in
`the treatment of seizure emergencies. However, this
`was a small study of healthy volunteers which
`precludes generalization to clinical use and further
`research is needed to improve tolerability of the
`formulation and to characterize the appropriate
`dose.
`
`Acknowledgements
`
`We thank Dennis Weller for helping with the HPLC analysis.
`Funding for this Study was generously provided by Parents
`Against Childhood Epilepsy (PACE) and the Epilepsy Foun-
`dation.
`
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