Effect of Fluticasone Propionate Nasal Spray
`on Bioavailability of Intranasal Hydromorphone
`Hydrochloride in Patients with Allergic Rhinitis
`
`George A. Davis, Pharm.D., Anita C. Rudy, Ph.D., Sanford M. Archer, M.D.,
`Daniel P. Wermeling, Pharm.D., and Patrick J. McNamara, Ph.D.
`
`Study Objective. To investigate the effect of the nasal corticosteroid
`fluticasone propionate on the bioavailability and pharmacokinetics of
`single-dose intranasal hydromorphone hydrochloride in patients with
`allergic rhinitis.
`Design. Randomized, three-way, crossover pharmacokinetic study.
`Setting. University clinical research unit.
`Patients. Twelve patients with allergic rhinitis.
`Intervention. Hydromorphone hydrochloride 2.0 mg was administered by
`intravenous infusion (treatment A), intranasal spray without allergic
`rhinitis treatment (treatment B), and intranasal spray after 6 days of
`fluticasone propionate (treatment C). Blood samples were collected serially
`from 0–16 hours.
`Measurements and Main Results. Pharmacokinetic parameters were
`determined by noncompartmental methods. An analysis of variance
`(ANOVA) model was used for statistical analysis. Mean (% coefficient of
`variation) absolute bioavailability of intranasal hydromorphone was 51.9%
`(28.2) and 46.9% (30.3) in patients with allergic rhinitis with and without
`treatment with fluticasone propionate, respectively. Mean maximum
`concentration (Cmax) values were 3.02 and 3.56 ng/ml, respectively. No
`statistical differences in Cmax and area under the concentration versus time
`curve were detected between intranasal treatments. Bioavailability values
`for both intranasal treatments were lower than those in healthy volunteers
`(57%). Median time to Cmax (Tmax) values were significantly different
`(p=0.02) for treatments B and C (15 and 30 min, respectively) using rank-
`transformed Tmax for ANOVA. Adverse effects were consistent with known
`effects of hydromorphone administered by other routes, with the exception
`of bad taste after intranasal administration.
`Conclusion. Hydromorphone was rapidly absorbed after nasal administration,
`with maximum concentrations occurring for most subjects within 30 minutes.
`Allergic rhinitis may affect pain management strategies for intranasal
`hydromorphone, with a delay in onset of action for patients treated with
`fluticasone propionate.
`Key Words:
`intranasal hydromorphone, allergic rhinitis, fluticasone
`propionate, bioavailability.
`(Pharmacotherapy 2004;24(1):26–32)
`
`Methods to improve routes of delivery of
`opioid analgesics, including the intranasal route,
`
`are receiving growing interest.1 Most patients
`with moderate-to-severe pain from cancer can be
`
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`EFFECT OF FLUTICASONE ON INTRANASAL HYDROMORPHONE KINETICS Davis et al
`
`27
`
`managed with oral opioids, but 33–70% require
`alternative routes of administration.2–4 For
`ambulatory postoperative patients, oral opioids
`are the mainstay of pain control, but other routes
`are recommended for treatment of acute pain.5
`Nasal administration may have advantages over
`more invasive routes, including ease of
`administration, rapid onset, and patient control.
`Several opioids have been studied for intranasal
`administration, including alfentanil,6 fentanyl,7
`sufentanil, 8 oxycodone, 9 buprenorphine, 10
`butorphanol,11 methadone,12 and, most recently,
`hydromorphone.13, 14
`Hydromorphone, a µ-selective opioid agonist
`5–8 times more potent than morphine, is effective
`in managing postoperative and moderate-to-
`severe chronic pain.15–17 Similar to morphine,
`orally administered hydromorphone undergoes
`extensive first-pass effect resulting in a low and
`variable systemic bioavailability ranging from
`Intranasal administration has been
`10–65%.18–21
`investigated because it bypasses gut metabolism
`and first-pass effect. A study of hydromorphone
`pharmacokinetics in healthy volunteers reported
`mean bioavailabilities of 52% and 57% after
`single intranasal doses of 1.0 and 2.0 mg,
`In patients with nonallergic
`respectively.14
`rhinitis, bioavailabilities were 54.4% and 59.8%,
`respectively, with and without rhinitis treatment
`(oral pseudoephedrine hydrochloride or
`intranasal oxymetazoline hydrochloride) (Davis
`et al, unpublished data, 2001). In both studies,
`intranasal hydromorphone was well tolerated,
`with bad taste being the most common adverse
`event.
`Rhinitis (inflammation of the nasal mucosa) is
`classified by etiology as allergic or nonallergic.
`Allergic rhinitis is the most prevalent, affecting
`20–40 million people in the United States
`annually.22, 23 Rhinitis is a hypersensitivity
`reaction manifested by increased cholinergic and
`From the Colleges of Pharmacy (Drs. Davis, Wermeling,
`and McNamara) and Medicine (Dr. Archer), University of
`Kentucky; and Intranasal Technology, Inc. (Drs. Rudy and
`Wermeling), Lexington, Kentucky.
`Supported by Intranasal Technology, Inc., Lexington,
`Kentucky.
`Presented at the annual meeting of the American College
`of Clinical Pharmacy, Tampa, Florida, October 21–24, 2001.
`Manuscript received June 30, 2003. Accepted pending
`revisions July 23, 2003. Accepted for publication in final
`form September 19, 2003.
`Address reprint requests to George A. Davis, Pharm.D.,
`Division of Pharmacy Practice and Science, College of
`Pharmacy, University of Kentucky, 800 Rose Street, Room
`C117, Lexington, KY 40536-0293; e-mail: gadavi00@email.
`uky.edu.
`
`sensory nerve activity in the nasal mucosa,
`resulting in one or more of the following
`symptoms: nasal itching, rhinorrhea, nasal
`congestion, and sneezing.23 Parasympathetic
`nerve stimulation dilates arterioles, which causes
`increased permeability and congestion of the
`nasal mucosa and promotes nasal airway glands
`to increase secretion. Sensory nerve stimulation
`leads to perception of nasal itch and congestion
`that causes sneezing. The early inflammatory
`response of allergic rhinitis is mediated primarily
`by immunoglobulin E causing release of
`inflammatory mediators (e.g., histamine,
`leukotrienes, prostaglandins).24–26 Late-phase
`response is characterized by T lymphocyte
`activation, production of TH2-type cytokines, and
`Intranasal corticosteroids
`tissue eosinophilia.25
`are the most effective agents for managing
`allergic rhinitis.26–29 Corticosteroids potently
`inhibit T lymphocyte responses, and in clinical
`studies in subjects with allergic rhinitis, they
`were extremely effective in blocking both early-
`and late-phase allergic reactions.27
`Because of the highly vascular nature of nasal
`tissues, inflammation from rhinitis results in
`increased nasal blood flow and permeability of
`the nasal mucosa.30, 31 It follows that inflammation
`and treatment with a nasally inhaled corticosteroid
`could alter the extent and rate of nasal absorption
`of other drugs. The objectives of our study were
`to assess the bioavailability and tolerance of a
`single dose of intranasal hydromorphone, and the
`effect of nasal corticosteroid fluticasone propionate
`on the rate and extent of absorption of intranasal
`hydromorphone in patients with allergic rhinitis.
`
`Methods
`Twelve nonsmoking subjects with perennial or
`seasonal allergic rhinitis (5 men, 7 women; 10
`Caucasian, 2 African-American; age range 21–45
`yrs, mean 29.4 yrs) participated in this open-
`label, randomized, three-way crossover inpatient
`study after giving informed consent. The study
`was conducted according to principles of the
`Helsinki Declaration and was approved by the
`medical institutional review board of the
`University of Kentucky.
`Participants were selected based on medical
`history, physical and nasal examinations, vital
`signs, and clinical laboratory tests. They were
`required to have a history of seasonal or perennial
`allergies, and were screened by an allergy
`questionnaire to distinguish between allergic and
`nonallergic rhinitis. Participants had no acute or
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`

`28
`
`PHARMACOTHERAPY Volume 24, Number 1, 2004
`
`chronic nasal symptoms other than allergic
`rhinitis; no clinically significant nasal surgery,
`polyps, or other physical abnormalities of the
`nose; and no cardiovascular, gastrointestinal,
`renal, hepatic, pulmonary, or hematologic
`disease. They abstained from alcohol and
`beverages containing caffeine for 48 hours before
`the dosing period and during the study.
`
`Hydromorphone Hydrochloride and Fluticasone
`Propionate Administration
`Subjects were randomized to receive single
`doses of hydromorphone hydrochloride 2.0 mg
`administered intravenously (treatment A),
`intranasally with no pretreatment (treatment B),
`or intranasally after 6 days of pretreatment with
`fluticasone propionate 200 µg (treatment C).
`The three treatment periods were separated by a
`6-day washout period. For intravenous
`administration, hydromorphone hydrochloride
`2.0 mg (Dilaudid Injection, 1 mg/1 ml; Knoll
`Pharmaceutical, Whippany, NJ) was diluted to 10
`ml and infused over 10 minutes. Intranasal doses
`of hydromorphone hydrochloride (1.0 mg/100
`µl) were administered by a single-dose spray
`pump (Pfeiffer of America, Princeton, NJ) to the
`lateral wall of each nostril. Subjects were asked
`to blow their noses gently immediately before
`and not again until 60 minutes after intranasal
`administration.
`Subjects were instructed not to take any new
`systemic or additional nasal drugs, prescription
`or nonprescription, during the study that might
`interact with hydromorphone metabolism or
`nasal physiology, with the exception of
`fluticasone propionate provided for the study.
`Allergy shots were not allowed for 1 week before
`any treatment. Subjects receiving treatment A
`were allowed to take their usual rhinitis drugs as
`approved by the medical supervisor. Six days
`before treatment B, subjects were asked to stop
`taking nasal and systemic treatment for rhinitis.
`Six days before treatment C, subjects were
`allowed to take only fluticasone propionate 4
`sprays (50 µg/spray) every evening until the day
`they received treatment C.
`
`Blood Samples
`Blood samples (10 ml) were collected in glass
`tubes containing heparin and centrifuged, and
`plasma was separated and stored at -20°C at the
`study site until analyzed for hydromorphone
`concentration. Serial blood samples were
`obtained by venipuncture according to the
`
`following schedule: 0 (predose), 5, 10, 15, 20,
`30, and 45 minutes, and 1, 2, 3, 4, 6, 8, 12, and
`16 hours after drug administration.
`
`Hydromorphone Assay
`The sample analysis was conducted using a
`validated
`liquid
`chromatography–mass
`spectrometry–mass spectroscopy assay method
`(AAI Development Services, Inc.–Kansas City,
`Shawnee, KS). Concentrations less than 20
`pg/ml were reported as below quantification
`limit. Samples with concentrations greater than
`2000 pg/ml were reanalyzed using a dilution so
`that the assayed concentration was within the
`range of 20–2000 pg/ml. Between-day and
`within-day accuracy and precision were below
`12% relative standard deviation.
`
`Pharmacokinetic Analyses
`Pharmacokinetic parameters were determined
`by standard noncompartmental methods with
`log-linear least square regression analysis to
`determine elimination rate constants using
`WinNonlin Standard, version 3.2 (Pharsight
`Corp., Palo Alto, CA). Areas under the concen-
`tration versus time curves from time zero to
`infinity (AUC0–∞) were calculated using a combi-
`nation of linear and logarithmic trapezoidal rules,
`with extrapolation to infinity by dividing the last
`measurable serum concentration by the elimination
`rate constant (␭z). 32 Values for maximum
`concentration (Cmax) and time to Cmax (Tmax)
`were determined by WinNonlin. The elimination
`half-life was determined from 0.693/␭z.
`Clearance/bioavailability was calculated by
`dividing the dose by AUC0–∞. Volume of
`distribution at steady state was calculated as
`clearance x mean residence time for intravenous
`data with correction for the infusion time.32
`
`Statistical Analyses
`Statistical analyses were performed with PC-
`SAS, version 6.12 (SAS Institute, Cary, NC).
`Statistical tests were two-sided with a critical
`level of 0.05. Analysis of variance (ANOVA) with
`factors for sequence, subject (sequence),
`treatment, and period was performed for log-
`transformed AUC and Cmax. Least squares
`geometric means from ANOVA were used to
`calculate ratios and their 90% confidence
`intervals (CIs) among treatment groups for AUC
`and Cmax. The carryover effect for the two
`intranasal treatments was analyzed using an
`
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`EFFECT OF FLUTICASONE ON INTRANASAL HYDROMORPHONE KINETICS Davis et al
`
`29
`
`Table 1. Pharmacokinetic Parameters After Single-Dose Hydromorphone Hydrochloride 2.0 mg
`Administration in Each Treatment Group
`Treatment C
`Treatment B
`Parameter
`Treatment A
`Tmax (hrs)
`0.500 (0.167–1.967)
`0.250 (0.167–0.5)
`0.167 (0.083–0.167)
`3.02 (57.3)
`3.56 (36.3)
`Cmax (ng/ml)
`34.76 (47.0)
`4.85 (31.7)
`6.44 (48.8)
`Half-life (hrs)
`5.61 (56.3)
`AUC0–t (ng•hr/ml)
`7.76 (29.6)
`6.70 (28.9)
`15.54 (20.7)
`AUC0–∞ (ng•hr/ml)
`8.31(26.7)
`7.44 (26.0)
`16.29 (21.3)
`5.27 (25.8)
`6.05 (33.4)
`MRT (hrs)
`3.28 (26.4)
`—
`—
`Clearance (L/hr)
`113 (19.7)
`Vss (L)
`—
`—
`370 (31.3)
`51.9 (28.2)
`46.9 (30.3)
`Bioavailability
`Assume 100
`Treatment A = intravenous hydromorphone HCl 2.0 mg; treatment B = intranasal hydromorphone HCl 2.0 mg
`without pretreatment with fluticasone propionate; treatment C = intranasal hydromorphone HCl 2.0 mg with
`pretreatment with fluticasone propionate; AUC0–t = area under the concentration-time curve from time zero to
`time t; AUC0–∞ = area under the concentration-time curve from time zero to infinity; MRT = mean residence time;
`Vss = volume of distribution at steady state.
`Data are mean (% coefficient of variation), except for Tmax values which are median (range).
`
`values greater than 30 minutes and one reached
`95% of peak by 30 minutes. No significant sex
`differences were found for AUC0–t and AUC0–∞
`(p>0.1). A significant difference was found for
`Cmax values between men and women (p<0.02,
`men < women). Table 2 summarizes ratios and
`90% CIs of Cmax and AUC values after the three
`treatments. The AUC 0–t and AUC0–∞ were
`comparable between intranasal treatments.
`
`Discussion
`To our knowledge, this is the first study to
`evaluate effects of allergic rhinitis and pretreat-
`ment with an intranasal corticosteroid on the
`
`(cid:0)(cid:0)
`(cid:0)(cid:0)
`(cid:0)(cid:0)(cid:0)(cid:0)(cid:0)(cid:0)(cid:0)(cid:0)(cid:0)(cid:0)(cid:0)(cid:0)(cid:0)(cid:0)(cid:0)
`
`(cid:0)
`
`(cid:0)
`
`(cid:0)
`
`0(cid:0)(cid:0)(cid:0)(cid:0)(cid:0)
`
`0
`
`(cid:0)00
`
`(cid:0)0
`
`(cid:0)
`
`0(cid:0)(cid:0)
`
`Plasma concentration (ng/ml)
`
`ANOVA of log-transformed AUC and Cmax. The
`difference in Tmax between intranasal treatments
`was compared by ANOVA of rank-transformed
`Tmax.
`
`Results
`Safety Assessment
`Twelve subjects completed the study without
`clinically significant or serious adverse events.
`The most common adverse effects were those
`generally associated with hydromorphone,
`sedation and nausea. Their intensity tended to
`be greater for the intravenous treatment than for
`the two intranasal treatments. One frequently
`reported adverse event for the intranasal
`formulation was a bad taste in the back of the
`throat. No clinically relevant changes were seen
`in physical examinations, nasal evaluations, or
`laboratory tests.
`
`Pharmacokinetic and Statistical Analyses
`Table 1 summarizes pharmacokinetic data for
`the three treatments. The mean plasma concen-
`tration versus time profiles over the first 3 hours
`for intranasal doses and 12 hours for all doses are
`shown in Figure 1. Hydromorphone appears to
`have a biphasic concentration versus time profile
`after intravenous administration. The graphs
`show that hydromorphone’s absorption after
`intranasal administration was rapid. Median
`Tmax values were 15 and 30 minutes for the
`intranasal doses after treatments B and C,
`respectively. The range of Tmax values after
`treatment C from 10–120 minutes suggested
`delayed absorption, but only three subjects had
`
`(cid:0)
`
`(cid:0)0
`
`(cid:0)(cid:0)
`
`0(cid:0)0(cid:0)
`
`0
`
`(cid:0)
`
`(cid:0)
`
`(cid:0)
`Time (hours)
`Figure 1. Mean ± SD plasma hydromorphone concentration
`versus time profiles after single doses of hydromorphone
`HCl 2.0 mg by intravenous (IV) infusion (treatment A), and
`intranasal (IN) administration without (treatment B) and
`with (treatment C) pretreatment with fluticasone
`propionate. The inset is comparison of treatments B and C
`during the first 3 hours.
`
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`30
`
`PHARMACOTHERAPY Volume 24, Number 1, 2004
`
`Table 2. Summary of Ratios of Least Squares Geometric Means and 90% Confidence Intervals
`Geometric Meansa
`Ratios (90% confidence intervals)
`C:B
`B:A
`C
`B
`C:A
`A
`Parameter
`AUC0–∞ (ng•hr/ml)
`1.11 (0.96–1.28)
`0.45 (0.39–0.52)
`7.99
`7.20
`0.50 (0.43–0.58)
`15.98
`AUC0–t (ng•hr/ml)
`1.15 (0.99–1.34)
`0.42 (0.36–0.49)
`7.39
`6.43
`0.48 (0.42–0.57)
`15.25
`Cmax (ng/ml)
`0.77 (0.58–1.03)
`0.11 (0.08–0.14)
`2.60
`3.38
`0.08 (0.06–0.11)
`31.57
`A = treatment with intravenous hydromorphone HCl 2.0 mg; B = intranasal hydromorphone HCl 2.0 mg without pretreatment with fluticasone
`propionate; C = intranasal hydromorphone HCl 2.0 mg with pretreatment with fluticasone propionate; AUC0–∞ = area under the concentration-
`time curve from time zero to infinity; AUC0–t = area under the concentration-time curve from time zero to time t; Cmax = maximum
`concentration.
`aLeast squares geometric means are from an analysis of variance with factors sequence, subject (sequence), treatment, and period for log-
`transformed AUCs and Cmax.
`
`pharmacokinetics of intranasal hydromorphone.
`It was conducted because physiologic changes
`associated with rhinitis and treatment theo-
`retically could affect drug absorption through the
`nasal mucosa. Clinicians should understand the
`potential effects of this common ailment on
`bioavailability and plasma concentrations of this
`potent opiate.
`Intranasal hydromorphone in our untreated
`patients with allergic rhinitis had rapid absorp-
`tion, similar to studies in healthy volunteers,14
`lactating women,13 and those with nonallergic
`rhinitis (Davis et al, unpublished data, 2001).
`However, absorption in patients with rhinitis
`pretreated with fluticasone propionate was
`delayed, with a median Tmax of 30 minutes. The
`range of bioavailabilities (32–73%) in our
`subjects was similar to that in other studies. In
`healthy volunteers, mean absolute bioavailability
`after intranasal hydromorphone hydrochloride
`After
`use was 57% (range 36–78%).14
`pretreatment with either an oral decongestant
`(pseudoephedrine hydrochloride) or nasal
`vasoconstrictor (oxymetazoline hydrochloride)
`in patients with nonallergic rhinitis, mean
`absolute bioavailability of intranasal hydro-
`morphone was 54% (range 33–96%), but it was
`not significantly different from 60% in untreated
`patients (range 50–89%) (Davis et al, unpublished
`data, 2001). In our study, absorption of
`intranasal hydromorphone in patients with
`(46.9%) and without (51.9%) fluticasone
`propionate pretreatment was somewhat lower
`than previously reported. However, fluticasone
`propionate did not affect systemic bioavailability
`of intranasal hydromorphone significantly
`compared with the untreated group.
`Our results suggest that the fraction of the
`intranasal dose of hydromorphone absorbed by
`inflamed nasal mucosa is similar in subjects
`treated and not treated with a nasal corticosteroid.
`
`The lack of effect of nasal mucosa inflammation
`on drug absorption is consistent with studies
`with butorphanol,33 buserelin,34 and triamcinolone
`acetonide,35 but not desmopressin.36 The absolute
`bioavailability of intranasal butorphanol was
`around 70% when administered with and without
`the topical nasal decongestant oxymetazoline in
`patients with acute or allergic rhinitis.33 This was
`similar to the bioavailability of intranasal butor-
`phanol in healthy volunteers.11, 37, 38 However,
`pretreatment with the topical decongestant
`significantly slowed the rate of absorption and
`lowered the Cmax of intranasal butorphanol.33
`Vasoconstriction and reduced blood flow were
`suggested to affect the rate but not extent of
`intranasal absorption of butorphanol. Absorption
`of intranasal buserelin, measured as the serum
`luteinizing hormone response, was not affected
`in volunteer men after experimental induction of
`rhinitis with histamine.34 Short- and long-term
`intranasal administration of triamcinolone
`acetonide to patients with inflamed nasal mucosa
`did not result in enhanced systemic drug
`absorption or accumulation.35 However, the
`antidiuretic activity and, presumably, absorption
`of intranasal desmopressin were enhanced in
`healthy men after experimental induction of
`Increased
`rhinitis with intranasal histamine.36
`intranasal absorption of desmopressin was
`attributed to the apparent increase in nasal blood
`flow.
`Our study was not designed to measure
`analgesic effects of intranasal hydromorphone
`when administered concomitantly with fluti-
`casone propionate. However, plasma concentrations
`were consistent with the therapeutic range
`reported in pharmacokinetic studies.39, 40 When
`hydromorphone concentrations were measured in
`patients treated for chronic severe pain, the
`minimum effective plasma concentration was
`approximately 4 ng/ml.39 For patients with
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`AQUESTIVE EXHIBIT 1119 Page 0005
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`EFFECT OF FLUTICASONE ON INTRANASAL HYDROMORPHONE KINETICS Davis et al
`
`31
`
`chronic cancer pain, a half-maximum concentration
`of 20 ng/ml was required to maintain a therapeutic
`effect.40 However, both of these studies reported
`wide interindividual variability with the
`concentrations.
`Pharmacodynamic studies evaluating intranasal
`formulations of opioids for analgesia are limited.1
`Onset and effect of intranasal compared with
`intravenous administration of fentanyl, 41, 42
`meperidine,43 and butorphanol44 were evaluated
`for moderate-to-severe post-operative pain.
`Collectively, mean onset times varied from 12–21
`minutes and times to maximum effect from
`26–106 minutes.
`Intranasal, intravenous, and
`oral methadone were compared in healthy
`volunteers using pupil size as an indicator for
`central opioid effects.12
`Intranasal methadone
`had rapid absorption and onset of action
`resulting in a maximum effect at 30 minutes,
`which was only slightly slower than that for
`intravenous administration (15 min) but much
`faster than that of oral administration (2 hrs).
`Future studies evaluating the pharmaco-dynamic
`response of intranasal hydromorphone and
`analgesia are warranted.
`
`Conclusion
`Hydromorphone was rapidly absorbed after
`nasal administration, with maximum concentrations
`for most subjects occurring within 30 minutes.
`In general, the treatment-related adverse events
`were those commonly associated with hydro-
`morphone. The frequent unpleasant taste also
`has been reported for other nasal opioids. 1
`Pretreatment with fluticasone propionate
`significantly delayed absorption of intranasal
`hydromorphone compared with no pretreatment.
`No significant difference in bioavailability was
`seen between treated and untreated rhinitis.
`
`Acknowledgment
`We acknowledge Jodi Miller, Pharm.D., M.S., for
`her assistance with data analysis and reviewing the
`manuscript.
`
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