`
`
`
`HOCHHAUS ET ALNASAL TRIAMCINOLONE ACETONIDEPHARMACOKINETICS AND PHARMACODYNAMICS
`
`A New Solution-Based Intranasal
`Triamcinolone Acetonide Formulation in
`Patients with Perennial Allergic Rhinitis: How
`Does the Pharmacokinetic/Pharmacodynamic
`Profile for Cortisol Suppression Compare with
`an Aqueous Suspension-Based Formulation?
`
`Günther Hochhaus, Mario A. González, Robert J. Dockhorn,
`Jonathan Shilstone, and John Karafilidis
`
`The present study was undertaken to describe the
`pharmacokinetics of a new solution-based intranasal triam-
`cinolone acetonide formulation (Tri-Nasal®) in patients with
`perennial allergic rhinitis and to use a pharmacokinetic/
`pharmacodynamic (PK/PD) simulation approach to compare
`the potential effects on plasma cortisol with that of an aque-
`ous suspension-based nasal triamcinolone acetonide formu-
`lation (Nasacort® AQ). Data from an open-label, randomized,
`three-way crossover study in patients with perennial allergic
`rhinitis receiving three doses (100, 200, and 400 µg) of a nasal
`solution-based triamcinolone acetonide formulation (Tri-
`Nasal®) over 7 days were used to describe the pharma-
`cokinetics of this formulation. Available literature data for a
`suspension-based aqueous triamcinolone acetonide for-
`mulation (Nasacort® AQ) were used to describe its
`pharmacokinetic profile after similar single doses of 110, 220,
`and 440 µg. A PK/PD simulation approach was used to pre-
`
`dict the anticipated cumulative cortisol suppression (CCS) of
`these two formulations. These simulations suggested a
`cortisol suppression of 8% to 16% for the single and steady-
`state doses of the solution-based product. Similar CCS esti-
`mates were predicted for equivalent doses of the aqueous
`suspension-based triamcinolone acetonide formulation with
`no difference between both formulations. Post hoc power
`analysis suggested that the predicted cortisol suppression is
`not likely to be significant for either preparation, including
`the clinically recommended doses of 200 and 220 µg of the
`solution-based and suspension-based formulations, respec-
`tively. In summary, based on the results of this PK/PD simula-
`tion, the plasma levels observed after nasal administration of
`the solution or the aqueous suspension are unlikely to induce
`a clinically relevant cortisol suppression, especially for the
`recommended dosing regimens of 200 and 220 µg/day.
`Journal of Clinical Pharmacology, 2002;42:662-669
`©2002 the American College of Clinical Pharmacology
`
`From the Department of Pharmaceutics, College of Pharmacy, University
`of Florida, Gainesville (G. Hochhaus); Globomax Américas, Weston,
`Florida (M. A. González); International Medical Technical Consultants,
`Inc., Lenexa, Kansas (R. J. Dockhorn); and Muro Pharmaceutical, Inc.
`(Asta Medica), Tewksbury, Massachusetts (J. Shilstone and J. Karafilidis).
`Submitted for publication November 26, 2001; revised version accepted
`March 2, 2002. Address for reprints: Günther Hochhaus, Department of
`Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL
`32610.
`
`According to the American Academy of Allergy,
`
`Asthma, and Immunology, approximately 40 mil-
`lion persons in the United States suffer from allergic
`rhinitis. The typical symptoms of itching, sneezing, na-
`sal congestion, and runny nose are unpleasant and sig-
`nificantly affect the patient’s quality of life. Because of
`their effectiveness and high safety profile, intranasal
`glucocorticoids are the first-line treatment in the man-
`agement of seasonal and perennial allergic rhinitis.1,2
`
`662 • J Clin Pharmacol 2002;42:662-669
`
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`

`NASAL TRIAMCINOLONE ACETONIDE
`
`A new aqueous, solution-based triamcinolone
`acetonide formulation (Tri-Nasal®) has recently been
`approved by the Food and Drug Administration (FDA)
`for the treatment of the nasal symptoms of seasonal and
`perennial allergic rhinitis. The formulation delivers 50
`µg of triamcinolone acetonide (TAA) via a me-
`tered-dose manual spray pump and has a recom-
`mended daily dose of 200 µg (100 µg per nostril) given
`once a day. The efficacy of this solution-based formula-
`tion has been studied in patients with seasonal and pe-
`rennial allergic rhinitis.3 Comparable with studies for
`other nasal triamcinolone acetonide formulations, the
`solution-based formulation at daily doses of 100 to 400
`µg significantly reduced nasal symptoms, including
`sneezing, congestion, stuffiness, rhinorrhea, and itch-
`ing, when compared to placebo.3
`Despite the favorable safety profile of intranasal
`glucocorticoids, some systemic side effects, such as
`growth retardation and changes in bone density, may
`be possible. Suppression of serum cortisol is currently
`judged as a good surrogate marker for such systemic ef-
`fects. Pharmacokinetic/pharmacodynamic (PK/PD)
`models of serum cortisol suppression have been shown
`to be predictive in evaluating the degree of these ef-
`fects. The aim of this study was to evaluate the
`pharmacokinetics of Tri-Nasal® in patients with peren-
`nial rhinitis after single dosing and at steady state and
`to apply the generated PK profiles for a PK/PD-based
`simulative assessment of potential cortisol suppres-
`sion. For comparison, the same approach was used to
`evaluate a suspension-based triamcinolone acetonide
`formulation.
`
`MATERIALS AND METHODS
`
`Pharmacokinetics after
`Administration of Triamcinolone
`Acetonide (TAA) in Solution
`
`The pharmacokinetic profiles of the solution-based
`product were evaluated in 28 patients with a history of
`perennial allergic rhinitis (10 females). This three-way
`crossover study, which was approved by an institu-
`tional review board, included subjects with a mean age
`of 28.3 years (range: 19-40 years), mean height of 175
`cm (range: 163-191 cm), and a mean weight of 75.4 kg
`(range: 51.3-100.7 kg). Patients received each of the fol-
`lowing treatments in a randomized crossover fashion.
`Treatment 1 consisted of 100 µg Tri-Nasal® (triamcino-
`lone acetonide, 0.5 mg/ml nasal solution, 50 µg/actua-
`tion) dosed as 1 spray per nostril daily for 7 days. Treat-
`ment 2 consisted of 200 µg TAA dosed as two sprays
`
`per nostril daily for 7 days. Treatment 3 consisted of
`400 µg TAA dosed as four sprays per nostril daily for 7
`days. There was a 16-day washout period between
`treatments.
`On each treatment day, the patients received their
`assigned drug treatment in the morning following an
`8-hour fast. No food or beverages, with the exception of
`water, were consumed until the 2-hour blood sample
`was taken, after which a light breakfast was served;
`lunch was provided 5 to 6 hours after dosing, while
`dinner was supplied 10 to 12 hours after dosing. A light
`snack was also offered in the evenings. All meals were
`of low fat content, and the same menu was served on
`corresponding days of each study period. Skim milk
`was available, as well as beverages without caffeine
`and alcohol.
`On the designated pharmacokinetic evaluation day
`(day 1 and day 7 of a given study period), 7 ml venous
`blood samples were drawn into evacuated tubes con-
`taining EDTA at the following time points: 0 (predose);
`5, 10, and 30 minutes; and after 1, 2, 3, 4, 8, 12, 16, 20,
`and 24 hours. In addition, a trough blood sample was
`taken on the morning of day 6. Blood samples were
`centrifuged to obtain plasma and stored at –70°C until
`they were shipped on dry ice to the analytical facility. A
`validated high-performance liquid chromatography
`(HPLC)/radioimmunoassay (RIA) procedure was used
`to determine TAA in human plasma with a lower limit
`of quantification (LOQ) of 100 pg/ml. Aliquots of
`plasma sample were extracted with ethyl acetate, and
`the organic layer was evaporated to dryness under vac-
`uum. The reconstituted samples were injected onto a
`reverse-phase HPLC system using a C18 reversed phase
`column (Sperisorb ODSII, Aldrich) and mixture of wa-
`ter and acetonitrile (62.5:37.5, v:v) as mobile phase.
`The TAA-containing fraction was collected, concen-
`trated under vacuum, and assayed by RIA using an an-
`tiserum previously characterized by Haack and
`Vecsei.4 The LOQ was set as 0.1 ng/ml. Intraday vari-
`ability, assessed on three different occasions, was be-
`tween 4.7% and 24.9% (mean = 11%) for 0.1, 0.15,
`0.35, 0.75, and 1.5 ng/ml quality control samples. Ac-
`curacy was between 85.6% and 121.6%. Average
`interday variability was 18.8, 16.8, 18.7, 12.5, and 8.8
`(mean = 15.1%) for 0.1, 0.15, 0.35, 0.75, and 1.5 ng/ml
`quality controls, respectively. Accuracy for these sam-
`ples was between 100.9% and 109.6% (mean =
`106.7%).
`Data obtained for the solution-based formulation on
`day 1 and day 7 were analyzed by noncompartmental
`pharmacokinetic analysis. CL/f was calculated from
`dose and AUC0-∞. Analysis of variance (ANOVA) for the
`pharmacokinetic variables was performed using a stan-
`
`PHARMACOKINETICS AND PHARMACODYNAMICS
`
`663
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`

`HOCHHAUS ET AL
`
`Cort is the first-order elimina-
`by equation (1), where k e
`tion rate constant for cortisol.
`
`(1)
`
`C
`
`Cort
`tot
`
`.
`
`•
`
`eC
`
`ort
`
`k
`
`=
`
`R
`
`C
`
`−
`
`Cort
`dC
`tot
`dt
`
`Cortisol release after triamcinolone acetonide was de-
`scribed by
`
`(2)
`
`•
`
`C
`
`Cort,
`tot
`
`eC
`
`ort
`
`k
`
`−
`
` 
`
`fT
`
`AA
`
`fT
`
`AA
`+
`
`C
`
`C
`
`EC
`
`50
`
`−
`
`1
`
` 
`
`Cort
`dC
`tot
`dt
`
`=
`
`R
`
`C
`
`•
`
`TAA is the free triamcinolone acetonide concen-
`whereC f
`tration in plasma, EC50 is the free TAA concentration
`Cort is to-
`that reduces RC to 50% of the baseline value, C tot
`Cort is the elimination
`tal cortisol concentration, and k e
`rate of cortisol. As the maximum suppression of
`cortisol release (Imax) had been set to 1 (100%), this term
`is not shown in equation (2). Simulations were per-
`formed with Scientist 2.0 (Micromath, Salt Lake City,
`UT, 1995).
`The area under the simulated cortisol concentration-
`time curve (AUC) was calculated using the trapezoidal
`rule for a 24-hour period. The cumulative cortisol sup-
`pression (CCS) was calculated from simulated data for
`placebo (equation (1)) and treatment data (equation (2))
`according to
`
`CCS
`
`=
`
`•
`
`100
`
`AUC
`
`−
`
`AUC
`
`placebo
`
`placebo
`AUC
`
`treat
`
`,
`
`(3)
`
`where AUCplacebo is the AUC for placebo data and
`AUCtreat is the AUC after triamcinolone acetonide ad-
`ministration. Estimates for Rmax (2966 µg/ml), tmin (16.2
`
`h), tmax (20.7 h), k eCort (0.64 h–1), Vc (33.7 L), and EC50
`(0.21 ng/ml) were taken from the literature.7,8 A
`one-sided power analysis was performed by SAS (ver-
`sion 6.12, SAS Institute, Cary NC) to statistically assess
`the predicted cortisol suppression (power: 0.8, p =
`0.05, n = 28, 25% variability of placebo and active
`treatment AUC estimates for the 24-h cortisol
`concentration-time profile).
`
`RESULTS
`
`Figures 1A-C show the mean plasma TAA concentration-
`time profiles for day 1 and day 7 for the 100 µg, 200 µg,
`and 400 µg doses of Tri-Nasal®. The noncompartmental
`pharmacokinetic parameters are summarized in Table I.
`Although plasma samples were collected over a
`24-hour period, the limit of detection was approached
`for the majority of patients after 4 to 8 hours, and data
`are shown here only for this time period. Trough values
`on day 6, day 7, and day 8 (24-h value of day 7) were be-
`
`dard three-period crossover design with effects for se-
`quence, period, and dose. A Tukey multiple compari-
`sons procedure was used to compare pairs of doses.
`Two one-sided tests of equivalence (TOST) were also
`used to compare the different doses. Twenty percent
`was taken as equivalence criteria. This statistical analy-
`sis was conducted by Dr. Alan Bostrom (Crunch Soft-
`ware Corporation, San Francisco).
`The average kinetic data after administration of
`the three doses of Tri-Nasal® were also fitted to a one-
`compartment body model with first-order absorption.
`These fits were subsequently used within the PK/PD
`simulations.
`
`Pharmacokinetics of the
`Suspension-Based Formulation
`
`Pharmacokinetic profiles after administration of 110,
`220, and 440 µg Nasacort® AQ were constructed from
`literature data using published tmax, Cmax, and ke values
`in a one-compartment body model with first-order ab-
`sorption.3,5 This was necessary as these were the only
`data available for this preparation, and detailed con-
`centration-time profiles have not yet been published
`for Nasacort® AQ. The correctness of the fits (Figure 1)
`was verified by comparing the resulting AUC estimates
`with the published literature values. Differences be-
`tween simulated and published AUC estimates were
`less than 2%. The pharmacokinetic parameters were sub-
`sequently used within the PK/PD-based simulations.
`
`Evaluation of Pharmacodynamic
`Effects on Cortisol
`
`A previously published indirect response model was
`applied to predict the potential pharmacodynamic ef-
`fects on cortisol suppression induced by Tri-Nasal® and
`Nasacort® AQ.6
`For the PK/PD modeling of both preparations, the
`concentration-time profiles for total drug generated by
`the compartmental model (see above) were trans-
`TAA ) using a
`formed into the free TAA concentration (C f
`fraction unbound of 0.29.7
`In the absence of exogenous stimuli, a linear release
`model can adequately describe the circadian rhythm of
`endogenous cortisol release, with a maximum in the
`morning and a minimum around midnight.6 This ap-
`proach describes the increase and decrease of daily
`cortisol release RC with two straight lines, character-
`ized by the maximum cortisol release Rmax at time tmax
`and no cortisol release at time tmin. The resulting change
`Cort is described
`in total cortisol serum concentration C tot
`
`664 • J Clin Pharmacol 2002;42:662-669
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`

`Figure 1. Triamcinolone acetonide
`(TAA) plasma concentration-time
`profiles after administration of 100
`µg (A), 200 µg (B), and 400 µg (C) of
`TAA (Tri-Nasal®). Squares in A-C
`represent data for the first dosing
`(day 1, ---); circles represent pro-
`files of the last dosing day (day 7,
`—). Figure 1D illustrates fits ob-
`tained from literature estimates on
`Cmax, tmax, and kterm for the applica-
`tion of 110 µg TAA (䉱), 220 µg TAA
`(䊉), and 440
`g TAA (䊏) as
`Nasacort® AQ in patients with pe-
`rennial rhinitis.5 Fits (based on a
`one-compartment body model
`with first-order absorption) were
`used to predict 24-hour cortisol
`suppression.
`
`NASAL TRIAMCINOLONE ACETONIDE
`
`Tri-Nasal-200 ug
`
`2
`
`4
`Time (h)
`
`6
`
`8
`
`Nasacort AQ-110, 220, 440 ug
`
`1.5
`
`1.0
`
`0.5
`
`0.0
`
`0
`
`*
`
`Conc. (ng/ml)
`
`,
`
`1.5
`
`1.0
`
`0.5
`
`Conc. (ng/ml)
`
`Tri-Nasal-100 ug
`
`2
`
`4
`Time (h)
`
`6
`
`8
`
`Tri-Nasal- 400 ug
`
`)
`
`1.5
`
`1.0
`
`0.5
`
`Conc. (ng/ml)
`
`0.0
`
`0
`
`+
`
`1.5
`
`1.0
`
`0.5
`
`Conc. (ng/ml)
`
`0.0
`
`0
`
`2
`
`4
`Time (h)
`
`6
`
`8
`
`0.0
`
`0
`
`2
`
`4
`Time (h)
`
`6
`
`8
`
`low the limit of detection for all of the patients for all
`the doses tested, indicating the lack of any accumula-
`tion of the drug. There were no statistically significant
`differences in Cmax and AUC0-∞ between day 1 and day
`7. The lack of TAA accumulation suggests that steady
`state was achieved instantaneously. ANOVA analysis
`indicated dose-dependent statistical differences in
`AUC0-t, AUC0-∞, and Cmax. Furthermore, dose-adjusted
`estimates for Cmax, AUC0-t, and AUC0-∞ parameters as an-
`alyzed by TOST showed a lack of equivalence. This
`suggests a lack of dose linearity. The main PK parame-
`ters for the solution-based product were compared
`with literature data of the aqueous solution-based
`product.
`The average pharmacokinetic concentration-time
`profiles of the solution-based product were fitted to a
`one-compartment body model with first-order absorp-
`tion (for fits, see Figure 1). In addition, literature data
`for the aqueous suspension-based formulation (110 µg,
`220 µg, 440 µg; for PK fit, see Figure 1) were used to pre-
`dict the equivalent concentration-time profile for a sin-
`gle dose (see Materials and Methods section). These fits
`
`were used to predict the potential cortisol suppression
`of both TAA formulations using the PK/PD model de-
`scribed in the Materials and Methods section. Figure 2
`compares the resulting 24-hour cortisol plasma levels
`after active treatment with baseline levels (no treat-
`ment) for day 1 (100 µg: A1, 200 µg: A2, 400 µg: A3) and
`day 7 (shown for the 200 µg dose in Figure 2B) for the
`solution-based product. Simulations were also per-
`formed to convert previously published pharma-
`cokinetic profiles for equivalent doses of aqueous sus-
`pension-based TAA into corresponding cortisol sup-
`pression data (shown for the 220 µg dose in Figure 2C).
`These simulations were performed only for single-dose
`administrations, as the available PK data were too lim-
`ited to predict the multiple dosing situation. For the
`highest doses of both preparations, the resulting
`cortisol suppression estimates were less than 20% and
`between 10% and 13% for the clinically recommended
`doses of 200 and 220 µg TAA after administration of the
`solution and suspension-based formulations, respec-
`tively. Post hoc analysis of these data, assuming an
`interindividual variability of 25%, suggested that dif-
`
`PHARMACOKINETICS AND PHARMACODYNAMICS
`
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`

`HOCHHAUS ET AL
`
`Table I Mean Pharmacokinetic Parameters (n = 28) after Single Once-Daily
`Dosing of 100, 200, and 400 µg of Triamcinolone Acetonide Given as Tri-Nasal® on Days 1 and 7
`
`Parameter
`
`100 µg
`
`0.52 (0.34)
`Cmax (ng/ml)
`0.41 (0.30)
`tmax (h)
`1.20 (1.16)
`AUC0-t (ng•h/ml)
`1.54 (1.30)
`AUC0-∞ (ng•h/ml)
`3.2
`(1.6)
`MRT (h)
`kterm (h–1)
`0.40 (0.15)
`Values are given as mean (± SD).
`a. n = 26.
`
`Day 1
`200 µg
`
`0.77 (0.42)
`0.48 (0.62)
`1.86 (1.18)
`2.25 (1.29)
`3.9
`(4.4)
`0.42 (0.18)
`
`400 µga
`
`100 µg
`
`1.27 (0.85)
`0.40 (0.28)
`3.35 (2.18)
`3.83 (2.27)
`3.5
`(1.1)
`0.33 (0.10)
`
`0.57 (0.31)
`0.38 (0.24)
`1.29 (0.89)
`1.68 (0.95)
`4.5
`(3.9)
`0.37 (0.12)
`
`Day 7
`200 µg
`
`0.80 (0.37)
`0.39 (0.24)
`2.08 (1.15)
`2.58 (1.26)
`3.8
`(1.1)
`0.31 (0.12)
`
`400 µg
`
`1.26 (0.67)
`0.42 (0.29)
`3.56 (2.16)
`4.09 (2.21)
`3.6
`(0.9)
`0.32 (0.11)
`
`ferences between placebo and active treatment were
`not statistically significant for any of the dosing regi-
`mens tested. No statistical differences were predicted
`between the two formulations.
`
`DISCUSSION
`
`Potential systemic side effects of topical glucocorticoid
`therapy include growth retardation in children, reduc-
`
`Tri-Nasal-Day 1-400 µg
`
`4
`
`8
`
`12
`Time (h)
`
`16
`
`20
`
`24
`
`A3
`
`200
`
`160
`
`120
`
`80
`
`40
`
`Conc. (ng/ml)
`
`0
`
`0
`
`Tri-Nasal-Day 1-200 µg
`
`4
`
`8
`
`12
`Time (h)
`
`16
`
`20
`
`24
`
`Nasacort AQ-220 µg
`
`4
`
`8
`
`12
`Time (h)
`
`16
`
`20
`
`24
`
`A2
`
`200
`
`160
`
`120
`
`80
`
`40
`
`0
`
`0
`
`200
`
`160
`
`120
`
`80
`
`40
`
`0
`
`0
`
`Conc. (ng/ml)
`
`C
`
`Conc. (ng/ml)
`
`Tri-Nasal-Day 1-100 µg
`
`4
`
`8
`
`12
`Time (h)
`
`16
`
`20
`
`24
`
`Tri-Nasal-Day 7-200 µg
`
`4
`
`8
`
`12
`Time (h)
`
`16
`
`20
`
`24
`
`A1
`
`200
`
`160
`
`120
`
`80
`
`40
`
`0
`
`0
`
`200
`
`160
`
`120
`
`80
`
`40
`
`0
`
`0
`
`Conc. (ng/ml)
`
`B
`
`Conc. (ng/ml)
`
`Figure 2. Predicted hydrocortisone serum levels after nasal administration of triamcinolone acetonide (TAA) (solid lines): results are shown
`for the administration of a single dose of 100 µg (A1), 200 µg (A2), and 400 µg Tri-Nasal® on day 1 (A3), 400 µg Tri-Nasal® on day 7 (B), and after
`administration of a single dose of 440 µg TAA after administration of Nasacort® AQ (C). TAA plasma concentrations in Figure 1 were used to
`predict the change of cortisol plasma levels from baseline (---). Simulations were performed with the PK/PD model described in the Materials
`and Methods section and previously described pharmacodynamic parameters for cortisol suppression of TAA.7
`
`666 • J Clin Pharmacol 2002;42:662-669
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`

`NASAL TRIAMCINOLONE ACETONIDE
`
`tion in bone density, lymphopenia, and cortisol sup-
`pression. While the pharmacological consequences of
`cortisol suppression are disputed, suppression of
`24-hour plasma cortisol by exogenous glucocorticoids
`has been accepted as a sensitive surrogate marker of
`systemic exposure after systemic and local
`glucocorticoid therapy. The goal of this report was to
`use concentration-time profiles of two commercially
`available triamcinolone acetonide formulations as the
`basis for evaluating their systemic safety profile by as-
`sessing their potential for cortisol suppression.
`Previous work for other nasal glucocorticoids such
`as budesonide and fluticasone propionate have shown
`that the systemic availability depends on the properties
`of the formulation.9 The goal of this report was to assess
`potential differences between two nasal triamcinolone
`acetonide formulations. Formulation 1 represented a
`triamcinolone acetonide solution that was compared
`with literature data of an aqueous triamcinolone
`acetonide suspension.
`The plasma concentration time-profile of TAA after
`nasal administration of the solution-based product
`(Tri-Nasal ®) was in agreement with TAA’s
`physicochemical and PK properties. Peak plasma lev-
`els for the three doses of the solution-based product
`were between 0.5 and 1.3 ng/ml, similar to results for
`the aqueous suspensions of triamcinolone acetonide
`(Table II) but higher than for the chlorofluorocarbon
`(CFC) formulation.10
`
`The relatively short tmax value of about 0.4 hours was
`expected for the solution-based product, as TAA in so-
`lution should be absorbed relatively fast. Conse-
`quently, the mean residence time (3.2-3.9 h) over the
`investigated dose range was only slightly longer than
`that after IV administration (2.7 h11). The absorption of
`the solution-based product (tmax of 0.4-0.5 h), however,
`was somewhat faster than for the aqueous suspension
`(Table II), which showed tmax values of about 1.3 to 1.8
`hours. Even later tmax values were observed for
`CFC-based suspensions of TAA (tmax of 3-4 h10). The ex-
`tent of absorption, as indicated by AUC estimates, was
`similar for the aqueous suspension and solution. Inter-
`estingly, much lower Cmax and AUC values were ob-
`served for the CFC-based suspension.10 This indicates
`that the physicochemical factors of the formulation can
`significantly affect the absorption profile of an
`intranasal glucocorticoid. Because of the relatively fast
`absorption and short half-life of TAA, the lack of any
`drug accumulation during the 7-day once-a-day treat-
`ment was expected for the solution-based product.
`Similar results have been reported for the slower ab-
`sorbed CFC formulation. These findings ensure the
`safety of nasal TAA during once-a-day treatment.
`Interestingly, the pharmacokinetics of Tri-Nasal® did
`not show dose linearity, as the dose-normalized AUC
`and systemic availability decreased with dose (Table II).
`Because the pharmacokinetics of TAA after IV admin-
`istration are linear, and nasal absorption is likely to be a
`
`Table II Comparison of Pharmacokinetic Parameters for Tri-Nasal® and
`Nasacort® AQa and Predicted Cumulative 24-Hour Serum Cortisol Suppression (CCS)
`
`Cmax (ng/ml)
`
`AUC0-∞ (ng•h•ml–1)
`
`tmax (h)
`
`Predicted 24-Hour CCS (%)b
`
`Treatment
`Tri-Nasal® 100 µg
`Day 1
`Day 7
`Tri-Nasal® 200 µg
`Day 1
`Day 7
`Tri-Nasal® 400 µg
`Day 1
`Day 7
`Nasacort® AQ 110 µg
`Day 1a
`Nasacort® AQ 220 µg
`Day 1a
`Nasacort® AQ 440 µg
`Day 1a
`4.7
`0.82
`tmax, Cmax, and AUC0-∞ estimates for Tri-Nasal® were taken from Table I and are shown for comparison.
`a. Pharmacokinetic data for Nasacort® AQ were taken from the FDA NDA review.5
`b. Cortisol suppression was estimated by the PK/PD simulation procedure, as described in the Materials and Methods section.
`
`0.52
`0.57
`
`0.77
`0.80
`
`1.27
`1.26
`
`0.26
`
`0.50
`
`1.5
`1.7
`
`2.3
`2.6
`
`3.8
`4.1
`
`1.5
`
`2.8
`
`0.4
`0.4
`
`0.5
`0.4
`
`0.4
`0.4
`
`1.3
`
`1.4
`
`1.8
`
`8.1
`8.5
`
`10.5
`11.0
`
`14.9
`15.9
`
`8.6
`
`13.4
`
`19.5
`
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`HOCHHAUS ET AL
`
`the dosing regimens assessed in these simulations.
`This includes the daily-recommended doses of 200 µg
`Tri-Nasal® (10%) and 220 µg Nasacort® AQ (13%). In
`addition, as can be seen in Table II, the predicted CCS
`activity of Nasacort® AQ and Tri-Nasal® is not different.
`This is not surprising as the pharmacokinetic AUC0-∞
`estimates (a PK indicator of its cumulative systemic ex-
`posure) were similar for both preparations, and seem-
`ingly the differences in the absorption rate were too
`small to affect cortisol suppression in a significant way.
`The finding of statistically insignificant effects on
`24-hour serum cortisol is in agreement with the major-
`ity of clinical studies investigating the activity of
`Nasacort® AQ on the HPA axis,13-15 supporting the va-
`lidity of the simulation process. While clinical studies
`investigating the 24-hour serum cortisol suppression
`have not been published for the solution-based formu-
`lation, the similarity of the main pharmacokinetic pro-
`file of Tri-Nasal® and Nasacort® AQ and results within
`the PK/PD simulations argue for insignificant systemic
`exposure. These findings are also in agreement with
`the general view that intranasal glucocorticoids have a
`high safety profile.2 We conclude that the solution-
`based TAA formulation and aqueous TAA suspensions
`lack significant effects on the HPA axis at clinically rel-
`evant doses.
`
`3
`
`6
`
`4
`
`1
`
`2
`5
`
`25
`50
`Cortisol-Suppr. Measured (%)
`
`75
`
`75
`
`50
`
`25
`
`0
`
`0
`
`Cortisol-Suppr. Predicted (%)
`
`Figure 3. Predicted cumulative cortisol suppression (CCS) and CCS
`obtained from clinical trials after inhalation of triamcinolone
`acetonide (TAA) (data for nasal administration were not available).
`Correlations were taken from Derendorf et al.12 Triangles represent
`the following trials: (1) single dose of 1000 g (pMDI),16 (2) bid dosing
`of 1000 g TAA (CCS after last dose),16 (3) bid dosing of 1000 g TAA
`(CCS during last two doses),17 (4) single dose of 1000 g (pMDI),18 (5)
`bid dosing of 1000 g TAA (CCS after last dose),18 and (6) bid dosing
`of 675 g TAA (CCS during last two doses).19
`
`nonsaturable first-order process, it is likely that
`intranasal absorption is more efficient from a small de-
`livered volume than from a large volume. It is possible
`that after a large intranasal dose, some of the fluid may
`be swallowed or lost from the nostrils. Despite the lack
`of dose proportionality, the levels of plasma TAA in-
`crease with increasing dose. Similar findings of the
`lack of dose proportionality have been reported for
`Nasacort® AQ.3
`Current studies have shown that Tri-Nasal® at a dose
`of up to 400 µg/day for 42 days did not measurably af-
`fect adrenal response to a 6-hour cosyntropin stimula-
`tion test.3 Similar results have been described for
`Nasacort® AQ,3 but these tests are relatively insensitive
`when compared to the effects on the 24-hour serum
`cortisol. It was therefore of interest to predict the likely
`effects of both preparations on the 24-hour serum
`cortisol axis, the most sensitive marker of HPA axis
`modulation. Because of the lack of clinical data for the
`solution-based product, a PK/PD simulation model
`was employed to predict cortisol suppression for the
`solution-based product and compared the potential
`HPA axis suppression with that of the aqueous suspen-
`sion-based TAA formulation. The employed PK/PD
`model is able to predict endogenous plasma cortisol
`levels during treatment and to compare them with
`baseline data (Figure 2). Pure simulation approaches,
`as employed in this study, are only valid if the predic-
`tive power of such a model has been tested. Figure 3
`shows such correlations for TAA studies.12 The good
`correlation between PK/PD-based predictions of the
`cumulative plasma cortisol suppression and the
`cortisol suppression found in actual clinical studies
`demonstrated the validity of the approach to predict
`the potential cortisol suppression, even if the PK and
`PD estimates of these studies are not available. These
`correlations, although obtained from inhalation stud-
`ies, can be applied for nasal administration as the form
`of delivery will not affect systemic effects. We therefore
`used a similar approach for the prediction of the HPA
`axis suppression in this study, with the exception that
`the actual pharmacokinetic data were used to predict
`the effects on endogenous cortisol for Tri-Nasal® and
`Nasacort® dosing regimens (Table II). Cumulative
`cortisol suppression was predicted for Tri-Nasal® and
`Nasacort® AQ to increase with increasing dose from 8%
`to 19%. Considering an intersubject variability of 25%
`in the cortisol estimates, post hoc power analysis sug-
`gested that a suppression of 19% would not result in a
`statistically significant difference between active treat-
`ment and placebo. This indicates that the effects on
`cortisol are not significantly different from placebo for
`
`668 • J Clin Pharmacol 2002;42:662-669
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`NASAL TRIAMCINOLONE ACETONIDE
`
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