The Journal of Clinical
`Pharmacology
`
`http://www.jclinpharm.org
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`Bioavailability and pharmacokinetics of lorazepam after intranasal, intravenous, and intramuscular
`administration
`
`DP Wermeling, JL Miller, SM Archer, JM Manaligod and AC Rudy
` 2001; 41; 1225
`J. Clin. Pharmacol.
`
`
`The online version of this article can be found at:
`http://www.jclinpharm.org/cgi/content/abstract/41/11/1225
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`
`
`WERMELING ET ALBIOAVAILABILITY AND PK OF LORAZEPAMPHARMACOKINETICS AND PHARMACODYNAMICS
`
`Bioavailability and Pharmacokinetics
`of Lorazepam after Intranasal, Intravenous,
`and Intramuscular Administration
`
`Daniel Paul H. Wermeling, PharmD, Jodi Lynn Miller, PharmD,
`Sanford Mitchell Archer, MD, Jose M. Manaligod, MD, and Anita C. Rudy, PhD
`
`The purpose of this study was to evaluate the pharmacokinetic
`profile of intranasal lorazepam in comparison to currently es-
`tablished administration routes. Eleven healthy volunteers
`completed this randomized crossover study. On three occa-
`sions, each separated by a 1-week washout, subjects received
`a 2 mg dose of lorazepam via the intranasal, intravenous, or
`intramuscular route. Blood samples were collected serially
`from 0 to 36 hours. Noncompartmental methods were used to
`determine pharmacokinetic parameters. Lorazepam was
`well absorbed following intranasal administration with a
`mean (%CV) bioavailability of 77.7 (11.1). Intranasal admin-
`istration resulted in a faster absorption rate than intramuscu-
`
`lar administration. Elimination profiles were comparable be-
`tween all three routes. The concentration-time profile for
`intranasal delivery demonstrated evidence of a double peak
`in several subjects, suggesting partial oral absorption. Fe-
`males were found to have significantly higher AUC values
`than males for all three delivery routes. Overall, this study
`demonstrated favorable pharmacokinetics of intranasal
`lorazepam in relation to standard administration methods.
`Intranasal delivery could provide an alternative, noninvasive
`delivery route for lorazepam.
`Journal of Clinical Pharmacology, 2001;41:1225-1231
`©2001 the American College of Clinical Pharmacology
`
`Lorazepam, a benzodiazepine, is available both
`
`orally and parenterally.1 It is used clinically as an
`anxiolytic, as a treatment for status epilepticus, preop-
`eratively, and as an adjunct for nausea management,
`and it has recently been studied for its potential use in
`acute psychotic situations.1-5 In many of these cases, it
`is necessary to administer lorazepam via the intrave-
`nous (IV) or intramuscular (IM) route for rapid onset of
`action and assured dose bioavailability.
`An alternative route of administration, one that
`would avoid the use of needles while continuing to
`provide rapid effect, should prove extremely useful in
`a variety of clinical settings. In particular, it would be
`highly beneficial in the pediatric setting. Alternative
`
`From the Drug Product Evaluation Unit of the University of Kentucky College
`of Pharmacy (Dr. Wermeling, Dr. Miller, Dr. Rudy) and the Division of Oto-
`laryngology—Head and Neck Surgery, University of Kentucky Chandler
`Medical Center (Dr. Archer, Dr. Manaligod). This study was financially sup-
`ported by Intranasal Technology, Inc., Pomona, New York. Submitted for
`publication December 6, 2000; revised version accepted July 2, 2001.
`Address for reprints: Daniel Paul H. Wermeling, PharmD, University of Ken-
`tucky, College of Pharmacy, 800 Rose Street, C-117, Lexington, KY
`40536-0093.
`
`J Clin Pharmacol 2001;41:1225-1231
`
`routes of delivery include rectal or intranasal (IN) ad-
`ministration. The rectal route has been evaluated for
`lorazepam but was found to have a slow absorption rate
`in humans6 and was found to undergo extensive
`first-pass metabolism in dogs.7 The IN route has been
`studied previously in humans as well.8 It was found to
`have a moderate concentration profile, as evidenced by
`its 51% absolute bioavailability. Other benzodiazepines,
`such as midazolam9,10 and diazepam,8,11 have also been
`examined intranasally in humans with promising
`results.
`The purpose of this study was to determine whether
`IN administration would provide comparable
`bioavailability and pharmacokinetic profiles with re-
`spect to intravascular and intramuscular delivery.
`
`MATERIALS AND METHODS
`
`Subjects
`
`Twelve (6 male, 6 female) healthy volunteers (Table I)
`within the age range of 18 to 35 years were eligible for
`enrollment in this study. The screening evaluation con-
`
`1225
`AQUESTIVE EXHIBIT 1134 Page 0002
`
`
`Downloaded from at UNIV OF KENTUCKY on January 23, 2008 http://www.jclinpharm.org
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` © 2001 American College of Clinical Pharmacology. All rights reserved. Not for commercial use or unauthorized distribution.
`
`
`
`

`

`WERMELING ET AL
`
`Table I Subject Demographics and Administration Sequence
`
`Dosing Sequence
`
`Subject
`
`Age (years)
`
`Weight (kg)
`
`Gender
`
`Ethnicity
`
`Period 1
`
`Period 2
`
`Period 3
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`
`58.6
`25
`56.8
`20
`NAa
`NAa
`75.2
`22
`65.9
`20
`67.7
`20
`62.7
`20
`72.3
`21
`79.8
`26
`80.4
`21
`77.5
`26
`79.5
`21
`IV, intravenous; IM, intramuscular; IN, intranasal.
`a. NA, not applicable. Subject 3 dropped from the study following the first dosing period.
`
`Caucasian
`Caucasian
`Caucasian
`Caucasian
`Caucasian
`Caucasian
`Caucasian
`Caucasian
`Asian
`Caucasian
`Caucasian
`Caucasian
`
`F
`F
`F
`F
`F
`F
`M
`M
`M
`M
`M
`M
`
`IV
`IN
`IM
`IM
`IV
`IN
`IM
`IN
`IV
`IM
`IN
`IV
`
`IM
`IV
`NAa
`IV
`IN
`IM
`IV
`IM
`IN
`IN
`IV
`IM
`
`IN
`IM
`NAa
`IN
`IM
`IV
`IN
`IV
`IM
`IV
`IM
`IN
`
`sisted of a medical history, physical and nasal examina-
`tions, and clinical laboratory tests. Subjects were ex-
`cluded from participation based on the presence of any
`clinically significant laboratory values or disease
`states, including acute or chronic nasal symptoms and
`physical abnormalities of the nasal passage. Subjects
`were also excluded for tobacco use within the past 2
`years, presence of alcohol or substance abuse within
`the past 5 years, and pregnancy or if not willing to ab-
`stain or use barrier methods of birth control during the
`study period. Written informed consent was obtained.
`The institutional review board of the University of
`Kentucky approved this study.
`
`Study Procedures
`
`This was a randomized, three-way crossover, single-
`dose study with each treatment separated by a washout
`period of 1 week. All 12 subjects reported to the study
`center at 18:00 the night prior to the study day and re-
`mained in the center until the last blood draw was ob-
`tained, approximately 36 hours after dosing. During
`each experiment period, subjects were administered
`the study drug via either the IV, IM, or IN route as deter-
`mined by a previously constructed randomization
`schedule (Table I).
`Drug administration occurred at approximately
`08:00 on each study day. Except for water ad libitum or
`a caffeine-free drink or juice, subjects underwent an
`overnight fast of at least 8 hours. No fluids were al-
`lowed 1 hour prior to or after dosing. Standardized
`meals were provided at 12:00 and 18:00 each day and
`breakfast at 08:00 on day 2 of each study period. No
`
`1226
`
`J Clin Pharmacol 2001;41:1225-1231
`
`xanthine-containing foods or beverages were allowed
`for 48 hours prior to dosing and until the last blood
`sample was collected for each study period. No medi-
`cations known to affect lorazepam pharmacokinetics
`were allowed within 7 days prior to each study period
`or during any study period.
`Vital signs consisting of blood pressure, respiratory
`rate, and pulse rate were measured at selected preset
`times throughout the study. Pulse oximetry monitoring
`was available for any volunteer who remained overly
`sedated for longer than 8 hours. Adverse events were
`recorded as they occurred. Subjects were specifically
`questioned about adverse events while vital signs were
`recorded. Nasal examinations to detect any local ad-
`verse reactions were performed by an otolaryngologist
`prior to study drug administration, 2 to 4 hours after ad-
`ministration, and at the poststudy evaluation.
`Venous blood samples (10 ml) were collected from
`an indwelling catheter placed solely for study pur-
`poses. Samples were obtained at 0 (predose), 5, 15, 30,
`and 45 minutes and 1, 2, 3, 4, 8, 12, 18, 24, and 36 hours
`after lorazepam administration was completed. The
`samples, directly collected in Vacutainer® tubes con-
`taining sodium heparin, were separated into their re-
`spective plasma and cell components by a refrigerated
`centrifuge (4°C). The plasma was transferred to poly-
`propylene tubes and stored at approximately –70°C.
`
`Dose Administration
`
`A standard 2.0 mg dose of lorazepam was used for all
`routes of administration. Subjects remained seated in
`bed at a 30- to 45-degree angle for 2 hours following
`
`
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` © 2001 American College of Clinical Pharmacology. All rights reserved. Not for commercial use or unauthorized distribution.
`
`
`
`AQUESTIVE EXHIBIT 1134 Page 0003
`
`

`

`BIOAVAILABILITY AND PK OF LORAZEPAM
`
`each drug administration. For IV administration, 2.0
`mg in 2.0 ml sterile solution was given at a rate of 0.5
`ml/min over 4 minutes followed by 2.0 ml normal sa-
`line at a rate of 0.5 ml/15 seconds to flush the port. This
`resulted in a total infusion time of 5 minutes. The IV
`dose was administered in the arm contralateral to
`where the catheter was placed for blood withdrawal.
`IM lorazepam, 2.0 mg in 1.0 ml sterile solution, was ad-
`ministered as a single deep muscle injection into the
`frontal thigh area using standard techniques. Before IN
`administration, subjects gently blew their nose. Using
`the Pfeiffer unit dose spray pump (Pfeiffer of America,
`Princeton, NJ), a single spray of lorazepam (1.0 mg/100
`µl) was administered to the lateral nasal wall of each
`nostril. Subjects were not allowed to blow their nose
`for 60 minutes following administration.
`
`Assay of Samples
`
`Sample analysis was conducted using a liquid chroma-
`tography/mass spectrometry/mass spectroscopy assay.
`The internal standard was deuterated lorazepam.
`Using 1.0 ml of human plasma, the lower limit of sensi-
`tivity was 0.10 ng/ml. The upper limit of detection was
`25.0 ng/ml. Samples with concentrations greater than
`25.0 ng/ml were diluted to a concentration between
`0.10 and 25.0 ng/ml and reanalyzed. Coefficients of
`variation for within- and between-batch analysis were
`0.0% to 11.1% and 4% to 10%, respectively. Accuracy
`was 90.0% to 110.0%.
`
`Pharmacokinetic
`Analysis
`
`Pharmacokinetic parameters were determined using
`standard noncompartmental methods with log-linear
`least squares regression analysis to determine the elim-
`ination rate constants (WinNonlin, Pharsight Corp.,
`Palo Alto, CA). The areas under the concentration ver-
`sus time curves from time zero to infinity (AUC0-∞) were
`calculated by a combination of the linear and logarith-
`mic trapezoidal rules, with extrapolation to infinity by
`dividing the last measurable serum concentration by
`the elimination rate constant (λ
`z).12 Values for the maxi-
`mum concentration (Cmax) and time to Cmax (tmax) were
`determined by visual inspection of concentration ver-
`sus time data for each subject. The elimination half-life
`was determined from 0.693/λ
`z. The absolute
`bioavailability (F) for the IN and IM dosage forms, as-
`suming equal 2 mg doses, was determined by F =
`AUC I N , 0 - ∞/AUC I V, 0 - ∞ for the IN dose and F =
`AUCIM,0-∞/AUCIV,0-∞ for the IM dose. Clearance (CL for IV
`and CL/F for IN and IM doses) was determined by di-
`
`PHARMACOKINETICS AND PHARMACODYNAMICS
`
`viding the dose by AUC0-∞. Volume of distribution at
`steady state and for elimination (Vss and Vz) were deter-
`mined by moment curves.13
`
`Statistical
`Considerations
`
`Sample size was determined by clinical feasibility
`rather than standard calculations using alpha and
`power estimates. Posteriori statistical analysis was per-
`formed using an ANOVA model to evaluate sequence,
`subject (sequence), treatment, and period for carryover
`effects. Gender effects were also evaluated in the
`model. Log-transformed AUC and Cmax values were
`used to calculate ratios and 90% confidence intervals
`(CI) for the three delivery routes. A p-value of < 0.05
`was considered significant.
`
`RESULTS
`
`A total of 11 volunteers completed all study periods.
`Subject demographics are listed in Table I. Subject
`number 3 dropped out after the first dosing period due
`to personal reasons not related to the experimental pro-
`cedures and subsequently was not included in any
`mean or pharmacokinetic calculations. The mean (SD)
`weight of the 11 completing subjects was 70.4 (8.7) kg.
`The age of subjects ranged from 20 to 26 years, with a
`mean of 22.0 years. All, except 1 subject, were
`Caucasian.
`No significant adverse events occurred throughout
`the three study periods. A complete listing of side ef-
`fects for each respective delivery route is provided in
`Table II. Overall, drowsiness/sleepiness was the most
`commonly reported effect. Pain at site of injection,
`“heavy” feeling, and blurred vision were also fre-
`quently noted during the study. Adverse events associ-
`ated specifically with IN delivery included bad taste,
`cool feeling in the nose and throat, and a burning sensa-
`tion. No local adverse reactions were detected in the
`nasal passage by the otolaryngologist. No clinically sig-
`nificant vital sign changes were observed during the
`entire study course.
`The mean pharmacokinetic parameters for the IV,
`IM, and IN administrations are listed in Table III. The
`median tmax achieved for IM delivery was six times the
`tmax for IN delivery. The resulting Cmax attained via IV
`administration was more than twofold greater than the
`Cmax following IM or IN administration. The AUC0-t and
`AUC0-∞ were both found to be larger for IV and IM deliv-
`ery in comparison with the IN route. A mean
`bioavailability of 77.7% was observed for IN adminis-
`tration compared with the other routes (~100%).
`
`1227
`AQUESTIVE EXHIBIT 1134 Page 0004
`
`
`Downloaded from at UNIV OF KENTUCKY on January 23, 2008 http://www.jclinpharm.org
`
` © 2001 American College of Clinical Pharmacology. All rights reserved. Not for commercial use or unauthorized distribution.
`
`
`
`

`

`WERMELING ET AL
`
`Table II
`
`Incidence of Adverse Events
`
`Adverse Event
`
`Number of Subjects
`with Complaint
`
`IV
`
`IM
`
`IN
`
`rapidly in the bloodstream initially after IN dosing.
`Within a time range of approximately 1 to 3.5 hours of
`the initial plasma concentration rise, another slight in-
`crease was observed. This is shown for 1 selected sub-
`ject in whom the trend was well pronounced (Figure 2).
`The latter increase is most likely attributed to oral ab-
`sorption from drug that passed into the pharynx area
`and was consequently ingested.
`As determined by the ANOVA model, carryover ef-
`fects for AUC0-t, AUC0-∞, and Cmax were found to be in-
`significant. No significant gender differences were ob-
`served in Cmax, but females were found to have
`significantly higher AUC0-t (p = 0.0001) and AUC0-∞ (p =
`0.0001) values compared with males for all delivery
`routes. The ratios and 90% CI for IM/IV and IN/IV Cmax
`parameters were very similar (Table IV). This was also
`reflected in the direct comparison of IN to IM, which re-
`sulted in CI of 0.72 to 1.24. AUC values for IN to both IV
`and IM ranged from 74% to 77% with low data vari-
`ability, as evidenced by the relatively tight CI.
`
`DISCUSSION
`
`Pharmacokinetic parameters attained in the present
`study are comparable to values in the literature follow-
`ing administration of IV or IM lorazepam at an equiva-
`lent dose.14-17 To our knowledge, only one other study
`has been conducted using IN lorazepam.8 Lau and
`Slattery8 administered a total lorazepam dose of 4 mg
`using a solution concentrated at 4 mg/100 µl. The dose
`was delivered via a pipette and was divided between
`each nostril. Their resultant parameters (mean [SD])
`were as follows: Cmax 18.7 (5.9), tmax range 0.5 to 4.0
`hours, and bioavailability 51% (11.9). The parameters
`in the present study (Table III) are more favorable than
`previously reported. The Cmax values observed from
`both studies are comparable even though the dose used
`by Lau and Slattery was twice the dose presently ad-
`ministered. In addition, their solution was four times
`more concentrated, and only half the volume was used
`for administration. Their bioavailability was approxi-
`mately 24% lower, and the tmax range was much larger,
`suggesting slower, decreased uptake. In comparison,
`the present formulation and delivery device appear to
`provide faster, increased drug absorption.
`Observation of the plasma concentration plots and
`calculated parameters indicate that IN delivery seems
`to primarily parallel IM delivery with exception to tmax
`and bioavailability. IN lorazepam reaches its maximum
`concentration at least two times faster than IM. How-
`ever, IN has a bioavailability of approximately 78%,
`while IM bioavailability is practically 100%. The rela-
`tively small variation present in the pharmacokinetic
`
`3
`
`1
`
`1
`1
`1
`4
`10
`1
`1
`
`Back pain
`Bad taste
`Blurred vision
`Burning/coolness in nose
`Burning/coolness in throat
`Ceiling moving
`Chemical smell
`Dazed/confused
`Diarrhea
`Disconnected/incoherent
`Dizziness/lightheaded
`Drowsiness/sleepiness
`Euphoria/giddiness
`Eyes heavy
`Eyes watery
`Floating sensation
`Flu/cold-like symptoms
`Groggy/heavy feeling
`Headache
`Hiccups
`Muscle tension/soreness
`Nausea
`Pain at injection site
`Pallor
`Phlegm in throat
`Postnasal drainage
`Pulse elevated
`Relaxed
`Slow response time
`Thirsty
`Warm
`IV, intravenous; IM, intramuscular; IN, intranasal.
`
`1
`
`3
`1
`
`2
`
`1
`
`1
`
`1
`6
`1
`8
`7
`
`1
`1
`
`1
`2
`10
`2
`
`11
`
`1
`3
`
`2
`1
`1
`
`1
`
`2
`1
`
`1
`3
`10
`
`2
`
`6
`1
`2
`2
`5
`1
`
`1
`1
`2
`1
`
`1
`
`The average lorazepam concentration-time plots
`from 0 to 4 hours and 0 to 36 hours are shown in Figure
`1. The plots for all three routes appear similar from 3 to
`36 hours, suggesting the major differences occur during
`the first hours of administration. The rise in lorazepam
`plasma concentrations during the first hour is espe-
`cially distinctive, with IV as the most rapid followed by
`IN and IM, respectively. The latter portion of the graph
`shows that IV and IM are fairly comparable in concen-
`tration magnitude while IN remains at a slightly lower
`level.
`Following IN administration, a second absorption
`phase was detected in 5 subjects. Lorazepam appeared
`
`1228
`
`J Clin Pharmacol 2001;41:1225-1231
`
`
`Downloaded from at UNIV OF KENTUCKY on January 23, 2008 http://www.jclinpharm.org
`
` © 2001 American College of Clinical Pharmacology. All rights reserved. Not for commercial use or unauthorized distribution.
`
`
`
`AQUESTIVE EXHIBIT 1134 Page 0005
`
`

`

`BIOAVAILABILITY AND PK OF LORAZEPAM
`
`Parameter
`
`2 mg IV
`
`2 mg IM
`
`Table III Pharmacokinetic Parameters of Lorazepam
`
`tmax (h)a
`(0.083-1.017)
`0.1
`(57.8)
`47.6
`Cmax (ng/ml)
`(27.3)
`16.6
`t1/2 (h)
`(19.4)
`386.8
`AUC0-t (ng(cid:127)h/ml)
`(30.8)
`500.8
`AUC0-∞ (ng(cid:127)h/ml)
`(27.0)
`4.3
`CL or CL/F (L/h)
`(11.9)
`93.2
`Vss (L)
`99.2
`(15.2)
`97.8
`Vz or Vz/F (L)
`100.9
`Assume 100%
`F (%)
`Values are presented as mean (%CV); n = 11. IV, intravenous; IM, intramuscular; IN, intranasal.
`a. Median and range given for tmax.
`
`3
`22.6
`17.4
`372.8
`506.2
`4.3
`
`—
`
`(0.5-8.017)
`(28.9)
`(38.1)
`(16.4)
`(33.7)
`(28.5)
`
`(10.8)
`(10.2)
`
`2 mg IN
`
`0.5
`21.4
`18.5
`288.0
`393.5
`5.7
`
`140.1
`77.7
`
`(0.25-2)
`(24.3)
`(28.3)
`(25.4)
`(38.0)
`(31.8)
`
`(16.8)
`(11.1)
`
`—
`
`2
`
`4
`
`Time (h)
`
`6
`
`8
`
`40
`
`30
`
`20
`
`10
`
`0
`
`0
`
`Concentration (ng/mL)
`
`Figure 2. Plasma concentration-time profile of lorazepam after a 2
`mg intranasal dose in subject 2.
`
`were not included in the study design, based on the
`concentration versus time profiles (Figure 1), IN would
`be expected to have a pharmacological profile resem-
`bling IM delivery. In addition, a faster onset of action
`would be anticipated with IN delivery. Rapid onset, yet
`avoidance of invasive administration using needles,
`would be advantageous in a variety of clinical settings.
`The diminished IN bioavailability leads to several
`possible explanations. Some of the drug may simply
`not have been absorbed through the nasal mucosa and
`was subsequently cleared from the nose via normal
`physiologic mechanisms. These processes occur at an
`average rate of approximately 5 to 6 mm/min, resulting
`in clearance of the nasal passage every 20 to 30 min-
`utes.18 Another explanation for lower bioavailability is
`metabolism by phase II enzymes present in the nasal
`mucosa.19 The major metabolite of lorazepam is
`lorazepam glucuronide. Once conjugated, the metabo-
`lite is renally excreted.20,21 Active glucuronyl
`
`1229
`AQUESTIVE EXHIBIT 1134 Page 0006
`
`0
`
`1
`
`2
`
`3
`
`4
`
`100
`
`80
`
`60
`
`40
`
`20
`
`0
`
`Concentration (ng/mL)
`
`60
`
`50
`
`40
`
`30
`
`20
`
`10
`
`0
`
`Concentration (ng/mL)
`
`0
`
`6
`
`12
`
`18
`
`24
`
`30
`
`36
`
`Time (h)
`
`Figure 1. Mean plasma concentration-time profiles from 0 to 4
`hours (top) and 0 to 36 hours (bottom) for lorazepam after a single 2
`), intramuscular (
`), or
`mg dose administered via the intravenous (
`) route. Error bars represent standard deviation.
`intranasal (
`
`parameters (Tables III and IV) did not differ between
`the three administration routes, suggesting no greater
`subject variability results from IN delivery.
`Clinical significance of pharmacokinetic differences
`between these administration routes was not deter-
`mined. Even though pharmacodynamic assessments
`
`PHARMACOKINETICS AND PHARMACODYNAMICS
`
`
`Downloaded from at UNIV OF KENTUCKY on January 23, 2008 http://www.jclinpharm.org
`
` © 2001 American College of Clinical Pharmacology. All rights reserved. Not for commercial use or unauthorized distribution.
`
`
`
`

`

`WERMELING ET AL
`
`Table IV Ratios and 90% Confidence Intervals (CI) for Pharmacokinetic Parameters
`
`Parameter
`
`IV
`
`Meana
`IM
`
`487.46
`484.1
`Log (AUC0-∞)
`369.63
`380.54
`Log (AUC0-t)
`22.29
`42.14
`Log (Cmax)
`IV, intravenous; IM, intramuscular; IN, intranasal.
`a. Values reflect the least squares geometric means.
`
`IN
`
`373.72
`279.75
`21.09
`
`IM/IV (90% CI)
`
`IN/IV (90% CI)
`
`IN/IM (90% CI)
`
`1.01
`0.97
`0.53
`
`(0.95-1.07)
`(0.91-1.04)
`(0.40-0.69)
`
`0.77 (0.73-0.82)
`0.74 (0.69-0.79)
`0.5
`(0.38-0.65)
`
`0.77
`0.76
`0.95
`
`(0.72-0.82)
`(0.71-0.81)
`(0.72-1.24)
`
`transferase (GT) enzymes have been detected in the na-
`sal mucosa.19,22,23 One study did not find any evidence
`of GT activity in the human nasal mucosa. However,
`this enzyme exists in multiple forms, only one of which
`was analyzed in that particular study.24 Last, as evi-
`denced by the second peak (Figure 2), partial oral ab-
`sorption of the dose could have played a role in the
`bioavailability, especially if nasal clearance took place.
`Considering oral bioavailability is about 90% and any
`first-pass effect
`is considered minimal
`for
`lorazepam,20,25 it is not probable that this would ac-
`count for approximately 20% of the dose. Therefore,
`the decreased bioavailability is assumed to result from
`a combination of events.
`Midazolam and diazepam, two other benzo-
`diazepines, have also been studied intranasally.9-11
`Björkman et al10 and Burstein et al9 found IN
`midazolam to have a mean (SD) bioavailability of 83
`(15) and 50 (13), respectively. Gizurarson et al11 found
`IN diazepam bioavailability to be 50.4% ± 23.3%.
`These reported values, in addition to the present study,
`suggest that the maximum bioavailability expected
`from IN benzodiazepine delivery can be estimated at
`80%.
`The second peak phenomenon is most likely attrib-
`uted to oral absorption. Maximum concentration fol-
`lowing oral lorazepam occurs approximately 0.5 to 3
`hours after dose administration.21,25 The second peak in
`the present study occurred within this time frame, sug-
`gesting that the rise in concentration was in fact due to
`ingestion. This phenomenon has been observed with
`other IN drug formulations,9,26 as well as several oral
`medications.27 One study28 of particular interest ad-
`dresses the occurrence of double peaks in plasma con-
`centrations following oral administration of a benzo-
`diazepine, alprazolam, to rats. The suggested
`mechanism is a reduction in gastric motility resulting
`from the muscle-relaxant properties of alprazolam.
`This mechanism may explain why further absorption
`in subjects 1 and 12 (data not shown) did not occur un-
`til approximately 3 to 4 hours after dose administra-
`
`1230
`
`J Clin Pharmacol 2001;41:1225-1231
`
`tion. Lorazepam absorbed intranasally may have de-
`creased gastric motility, therefore delaying subsequent
`oral absorption from the gastrointestinal tract.
`Gender differences in benzodiazepine pharma-
`cokinetic profiles have been studied previously. Sev-
`eral of
`these studies found no significant
`pharmacokinetic differences between genders.29-31 Al-
`ternatively, Yonkers et al32 conducted a literature re-
`view and concluded that young women may require
`lower doses of benzodiazepines. In this review, they
`also suggested that benzodiazepines that undergo
`conjugative metabolism have a slower elimination in
`women than men. Kristjánsson and Torsteinsson33
`found that females had a significantly higher elimina-
`tion rate constant for oral alprazolam. In the same
`study, significant gender differences were also noted in
`the clearance, which was found to be significantly
`faster in females. The present study found statistically
`significant gender differences in AUC values, with fe-
`males having higher AUC0-t and AUC0-∞ than males.
`This study was not designed to determine clinical sig-
`nificance of this difference. It should be noted, how-
`ever, that these present data were not body weight nor-
`malized for analysis. This could potentially affect the
`observed gender difference. The conflicting reports in
`the medical literature on this topic suggest that it may
`be an area of interest for future studies.
`In conclusion, lorazepam appears to be well ab-
`sorbed via the IN administration route. It has a faster
`absorption rate than IM and comparable elimination
`profiles with IV and IM delivery. No significant adverse
`effects were noted with any of the administration
`routes in this study. The concentration versus time
`profile for IN lorazepam suggests it may provide an
`alternate, noninvasive delivery route. Further
`pharmacodynamic and efficacy studies need to be con-
`ducted to determine its relevance in clinical situations.
`Despite the relatively small number of subjects, this
`study has demonstrated favorable pharmacokinetics of
`IN lorazepam in relation to existing standard adminis-
`tration methods.
`
`
`Downloaded from at UNIV OF KENTUCKY on January 23, 2008 http://www.jclinpharm.org
`
` © 2001 American College of Clinical Pharmacology. All rights reserved. Not for commercial use or unauthorized distribution.
`
`
`
`AQUESTIVE EXHIBIT 1134 Page 0007
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`

`

`BIOAVAILABILITY AND PK OF LORAZEPAM
`
`REFERENCES
`
`1. McEvoy GK, Litvak K, Welsh OH, Snow EK (eds.): American Hos-
`pital Formulary Service Drug Information. Bethesda, MD: American
`Society of Health-System Pharmacists, 1999.
`2. Ativan® (lorazepam) tablets product information. Philadelphia:
`Wyeth Laboratories, 1999.
`3. Ativan® (lorazepam) injection product information. Philadelphia:
`Wyeth Laboratories, 1999.
`4. Battaglia J, Moss S, Rush J, Kang J, Mendoza R, Leedom L, et al:
`Haloperidol, lorazepam, or both for psychotic agitation? A
`multicenter, prospective, double-blind, emergency department
`study. Am J Emerg Med 1997;15:335-340.
`5. Foster S, Kessel J, Berman ME, Simpson GM: Efficacy of lorazepam
`and haloperidol for rapid tranquilization in a psychiatric emergency
`room setting. Int Clin Psychopharmacol 1997;12:175-179.
`6. Graves NM, Kriel RL, Jones-Saete C: Bioavailability of rectally ad-
`ministered lorazepam. Clin Neuropharmacol 1987;10:555-559.
`7. Podell M, Wagner SO, Sams RA: Lorazepam concentrations in
`plasma following its intravenous and rectal administration in dogs. J
`Vet Pharmacol Ther 1998;21:158-160.
`8. Lau SWJ, Slattery JT: Absorption of diazepam and lorazepam fol-
`lowing intranasal administration. Int J Pharmaceutics
`1989;54:171-174.
`9. Burstein AH, Modica R, Hatton M, Forrest A, Gengo FM:
`Pharmacokinetics and pharmacodynamics of midazolam after
`intranasal administration. J Clin Pharmacol 1997;37:711-718.
`10. Björkman S, Rigemar G, Idvall J: Pharmacokinetics of midazolam
`given as an intranasal spray to adult surgical patients. Br J Anaesth
`1997;79:575-580.
`11. Gizurarson S, Gudbrandsson FK, Jonsson H, Bechgaard E:
`Intranasal administration of diazepam aiming at the treatment of
`acute seizures: clinical trials in healthy volunteers. Biol Pharm Bull
`1999;22:425-427.
`12. Proost JH: Wagner’s exact Loo-Riegelman equation: the need for a
`criterion to choose between the linear and logarithmic trapezoidal
`rule. J Pharm Sci 1985;74:793-794.
`13. Gibaldi M, Perrier D: Pharmacokinetics. New York: Marcel
`Dekker, 1982.
`14. Kraus JW, Desmond PV, Marshall JP, Johnson RF, Schenker S,
`Wilkinson GR: Effects of aging and liver disease on disposition of
`lorazepam. Clin Pharmacol Ther 1978;24:411-419.
`15. Patwardhan RV, Yarborough GW, Desmond PV, Johnson RF,
`Schenker S, Speeg KV: Cimetidine spares the glucuronidation of
`lorazepam and oxazepam. Gastroenterology 1980;79:912-916.
`16. Nielsen-Kudsk F, Jensen TS, Magnussen I, Jakobsen P, Jensen PB,
`Mondrup K, Petersen T: Pharmacokinetics and bioavailability of in-
`travenous and intramuscular lorazepam with an adjunct test of the
`inattention effect in humans. Acta Pharmacol Et Toxicol
`1983;52:121-127.
`17. Greenblatt DJ, Shader RI, Franke K, MacLaughlin DS, Harmatz JS,
`Allen MD, Werner A, et al: Pharmacokinetics and bioavailability of
`
`intravenous, intramuscular, and oral lorazepam in humans. J Pharm
`Sci 1979;68:57-63.
`18. Chien YW, Su KSE, Chang S (eds.): Nasal Systemic Drug Delivery.
`New York: Marcel Dekker, 1989.
`19. Longo V, Citti L, Gervasi PG: Biotransformation enzymes in nasal
`mucosa and liver of Sprague-Dawley rats. Toxicol Lett
`1988;44:289-297.
`20. Kyriakopoulos AA, Greenblatt DJ, Shader RI: Clinical
`pharmacokinetics of lorazepam: a review. J Clin Psychiatry
`1978;39:16-23.
`21. Greenblatt DJ: Clinical pharmacokinetics of oxazepam and
`lorazepam. Clin Pharmacokinet 1981;6:89-105.
`22. Bond JA: Some biotransformation enzymes responsible for
`polycyclic aromatic hydrocarbon metabolism in rat nasal turbinates:
`effects on enzyme activities on in vitro modifiers and intraperitoneal
`and inhalation exposure of rats to inducing agents. Cancer Res
`1983;43:4805-4811.
`23. Bond JA, Harkema JR, Russel VI: Regional distribution of
`xenobiotic metabolizing enzymes in respiratory airways of dogs.
`Drug Metab Dispos 1988;16:116-124.
`24. Gervasi PG, Longo V, Naldi F, Panattoni G, Ursino F:
`Xenobiotic-metabolizing enzymes in human respiratory nasal mu-
`cosa. Biochem Pharmacol 1991;41:177-184.
`25. Hutchison TA, Shaham DR, Anderson ML (eds.): DRUGDEX®
`System. Englewood, CO: MICROMEDEX, Inc. (Edition expires
`12/2000).
`26. Duquesnoy C, Marnet JP, Sumner D, Fuseau E: Comparative clini-
`cal pharmacokinetics of single doses of sumatriptan following subcu-
`taneous, oral, rectal and IN administration. Eur J Pharm Sci
`1998;6:99-104.
`27. Suttle AB, Pollack GM, Brouwer KLR: Use of a pharmacokinetic
`model incorporating discontinuous gastrointestinal absorption to ex-
`amine the occurrence of double peaks in oral concentration-time pro-
`files. Pharm Res 1992;9:350-356.
`28. Wang Y, Roy A, Sun L, Lau CE: A double-peak phenomenon in the
`pharmacokinetics of alprazolam after oral absorption. Drug Metab
`Dispos 1999;27:855-859.
`29. Nishiyama T, Matsukawa T, Hanaoka K: The effects of age and
`gender on the optimal premedication dose of intramuscular
`midazolam. Anesth Analg 1998;86:1103-1108.
`30. Greenblatt DJ, Wright CE: Clinical pharmacokinetics of
`alprazolam: therapeutic implications. Clin Pharmacokinet
`1993;24:453-471.
`31. Holazo AA, Winkler MB, Patel IH: Effects of age, gender and oral
`contraceptives on intramuscular midazolam pharmacokinetics. J
`Clin Pharmacol 1988;25:1040-1045.
`32. Yonkers KA, Kando JC, Cole JO, Blumenthal S: Gender differ-
`ences in pharmacokinetics and pharmacodynamics of psychotropic
`medication. Am J Psychiatry 1992;149:587-595.
`33. Kristjánsson F, Thorsteinsson SB: Disposition of alprazolam in
`human volunteers: differences between genders. Acta Pharm Nord
`1991;3:249-250.
`
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