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CLINICAL STUDIES |
From ALTANA Pharma AG, Konstanz, Germany (Dr Nave), ALTANA Pharma, Florham Park, New Jersey (Dr Wingertzahn), Teijin America Inc, Princeton, New Jersey (Dr Brookman), and Teijin Pharma Limited, Tokyo, Japan (Mr Kaida, Dr Matsunaga).
Address for reprints: Ruediger Nave, PhD, Altana Pharma AG, Byk-Gulden-Str. 2, 78467 Konstanz, Germany.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Key Words: Intranasal corticosteroid • nasal allergies • systemic bioavailability • cortisol • adrenal function
Although modern INCS are generally well tolerated with minimal effect on endogenous cortisol levels,3 data have demonstrated that suppression occurs in some patients,4-6 and the long-term consequences in these patients are unknown. Intranasal corticosteroids with high systemic bioavailability and low levels of plasma protein binding have increased risk for side effects. Patients with comorbid conditions that require corticosteroid treatment are also at increased risk for side effects because of the potential increase in overall steroid burden when coadministered with INCS. Coadministration of INCS and inhaled corticosteroids is an anticipated occurrence in patients with asthma, as AR is often a comorbid condition7 and inhaled corticosteroids are the mainstay of asthma management. Therefore, there is a need to improve topical nasal corticosteroid treatment through the creation of an INCS that is both effective and has a minimal risk for side effects.
Ciclesonide (CIC) is a novel corticosteroid under development for the treatment of asthma and AR. Ciclesonide is administered as an inactive parent compound that is converted to the pharmacologically active metabolite, desisobutyryl-ciclesonide (des-CIC), in the upper and lower airways. The relative glucocorticoid receptor binding affinity of des-CIC is 100-fold greater than that of the parent compound (relative glucocorticoid receptor binding affinities are 1200 and 12, respectively; dexamethasone reference is 100).8 Conversion of CIC to des-CIC is catalyzed by endogenous esterases in human nasal and bronchial epithelial cells (Figure 1).9,10 The combination of low systemic bioavailability (<1%),11 rapid clearance (elimination half-life, 3.5 hours),11 and high percentage of plasma protein binding (99%)12 of the active metabolite decreases systemic corticosteroid exposure and thereby reduces the risk for side effects, making CIC an ideal candidate for a safe and effective INCS.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Study Design and Treatment
In this phase I, single-center, randomized, double-blind,
placebo-controlled, multiple-dose, modified sequential design study, healthy
volunteers or asymptomatic subjects with a history of SAR were randomized to
receive CIC or placebo via intranasal pump spray for 14 days. Healthy
volunteers were administered CIC 50, 100, 200, or 400 µg once daily, CIC
400 µg twice daily, or placebo. Asymptomatic subjects with SAR were
administered CIC 400 µg twice daily or placebo. Participants treated with
CIC 400 µg twice daily were housed in the clinical research facility
(Pharma Bio-Research Group BV, Zuidlaren, the Netherlands) for the entire
treatment period. All other participants were housed in the clinical research
facility for all or part of days 1, 2, 13, 14, and 15. This study was approved
by an Independent Ethics Committee (Stichting Beoordeling Etheik Bio-Medisck
Onderzoek, Assen, the Netherlands) and conducted in accordance with the
principles of the revised version of the Declaration of
Helsinki.13
Pharmacokinetics
Blood samples for the determination of the pharmacokinetics of CIC and
des-CIC were collected predose and 10, 20, and 30 minutes and 1, 1.5, 2, 3, 4,
7, 12, and 24 hours after dosing on days 1 and 14. In addition, blood samples
were collected before dosing on days 11, 12, and 13. Blood samples were
coagulated for 30 minutes at 4°C and then centrifuged for 10 minutes at
1500 x g. Serum was transferred to polyethylene tubes (2 aliquots of
1 mL), immediately frozen, and stored at –20°C until analysis.
Measurements of CIC and des-CIC in serum were performed by MDS Pharma Services
(Fehraltorf, Switzerland) using a fully validated LC-MS/MS method after
solid-phase extraction. Deuterated CIC and des-CIC served as internal
standards. Serum samples (0.5 mL) were diluted with 2 mL of 100 mM phosphate
buffer (pH 2.8) and applied to solid-phase extraction cartridges (Isolute C8,
Phenomenex, Cheshire, United Kingdom). Cartridges were washed twice with 50%
methanol in water, and the analytes were eluted with 1 mL acetonitrile, which
was subsequently evaporated. Ciclesonide and des-CIC concentrations were
determined using reversed-phase high-performance liquid chromatography with
MS/MS detection (Sciex API3000). A Symmetry C18 (3.5 µm, 2.1 x 50 mm,
Waters Corporation, Milford, Mass) column and a mobile phase consisting of
ammonium acetate in acetonitrile were used for separation. The mass
transitions in negative multiple reaction monitoring mode were 599.4 to 338.8
m/z and 529.3 to 356.5 m/z for CIC and des-CIC, respectively. The lower limits
of quantification (LLOQ) were 25 and 10 pg/mL for CIC and des-CIC,
respectively.
Safety Assessments
Subject-assessed nasal tolerability symptoms were measured by visual analog
scale at the screening visit and on days 1, 3, 7, 14, 21, and 28. The visual
analog scale measures symptoms of nasal obstruction, itching, rhinorrhea, and
sneezing with a range of 0 mm (no complaints) to 100 mm (very serious
complaints). Adrenal function was monitored by diurnal serum free cortisol
measured on days 1 and 14 and 24-hour urine cortisol concentrations measured
on days 1, 7, and 14. Serum cortisol concentrations were measured using an
Immulite® technique in the single mode, and urine cortisol concentration
was measured using an enzyme-linked immunosorbent assay (Milenia ELISA kit) in
the duplicate mode. Both assay kits were provided by Diagnostic Products
Corporation (Los Angeles, Calif). The LLOQ was 10 ng/mL for serum and urine
cortisol concentrations. Physical examinations, vital sign measurements, and
hematology, laboratory, nasal, and electrocardiogram assessments were
performed at the screening visit and periodically throughout the study.
Adverse events were also monitored throughout the study.
Statistical Methods
Pharmacokinetic parameters and cortisol measurements are presented using
descriptive statistics. Data are presented as the mean and standard deviation,
unless otherwise stated.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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5.9% for
CIC and 7.2% for des-CIC. The concentrations of CIC were below the LLOQ in
almost all of serum samples assayed. Only 1 healthy volunteer from the CIC
400-µg once-daily treatment group and 1 healthy volunteer from the CIC
400-µg twice-daily treatment group had serum levels of CIC above the LLOQ
during the study, both on day 14 (48.9 and 46.2 pg/mL, respectively). The
concentrations of des-CIC were below the LLOQ in the majority of all serum
samples assayed. For example, in 324 samples from healthy volunteers in the
highest dose group (CIC 400 µg twice daily), only 7 samples (1 in each
of the 6 subjects) achieved des-CIC levels greater than 20 pg/mL (equivalent
to 2 times the LLOQ). The highest value of des-CIC recorded was 28.8
pg/mL. As the majority of samples assayed were below the LLOQ, pharmacokinetic parameters, including area under the curve and elimination half-lives, could not be calculated for CIC or des-CIC in any of the CIC dose levels tested. Furthermore, no mean values for the maximum concentration (Cmax) of des-CIC could be calculated. However, in healthy volunteers median values for Cmax of des-CIC at steady state were below the LLOQ of 10 pg/mL, 11.5 pg/mL, and 17.0 pg/mL for doses of CIC 200 µg once daily, 400 µg once daily, and 400 µg twice daily, respectively. The corresponding median Cmax value for asymptomatic subjects with SAR was less than 12.9 pg/mL. Individual time to Cmax values were generally obtained at 3 or 4 hours after CIC administration.
Adrenal Function
Serum free cortisol pharmacodynamic parameters were similar among all
treatment groups at the start and conclusion of the study
(Table I and
Figure 3). The area under the
effect curve during a dosing interval of 24 hours (AUEC0-24) for
serum free cortisol demonstrated comparable ranges on days 1 and 14 (1952-2678
µg·h/L and 1942-2637 µg·h/L, respectively). There were no
apparent differences in serum free cortisol levels between subjects treated
with CIC versus placebo. Diurnal variation in serum free cortisol was
maintained in participants administered CIC nasal spray. No differences in
daily fluctuation were observed among dose groups, between participants
administered CIC versus placebo, or between healthy volunteers and
asymptomatic subjects with SAR. Urinary free cortisol levels were comparable
between treatment groups on days 1 and 14 for healthy volunteers and
asymptomatic subjects with SAR (Table
II). Although there was a trend for a decrease in 24-hour urinary
free cortisol excretion from day 1 to day 14, these decreases occurred in the
placebo treatment groups and in participants treated with CIC and did not
differ appreciably between the groups. Furthermore, the greatest decrease
between days 1 and 14 occurred in placebo-treated asymptomatic subjects with
SAR (54 µg, 44%), suggesting negligible effects on cortisol after
administration of CIC.
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Safety
A total of 134 treatment-emergent adverse events was reported by 41
participants during the course of the study. The most common adverse events
were headache (11%), fatigue (7%), and rhinitis (7%). The majority of adverse
events (97%) were mild in intensity. The frequency of adverse events was
consistent between CIC nasal spray treatment groups and did not demonstrate a
trend toward increased frequency of adverse events with increasing CIC dose.
The frequency of adverse events was comparable among healthy volunteers and
asymptomatic subjects with SAR. The most common adverse events considered by
the investigator to be possibly or probably related to study medication were
nose congestion, headache, and rhinorrhea. No adverse events were considered
by the investigator to be definitely related to study medication. No serious
adverse events were reported.
Mean visual analog scale scores per treatment group did not exceed 10 mm, except on 1 occasion when the score reached 16 mm. This high value was the result of 1 participant scoring 95 mm because of an incident of rhinitis. No clinically relevant changes in vital signs, electrocardiogram, or laboratory parameters were observed during the study.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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In comparison, other INCS currently administered for the treatment of AR—budesonide, flunisolide, fluticasone propionate, and mometasone furoate—have reported variable bioavailability (calculated as the percentage of drug absorbed into systemic circulation for intranasal administration versus intravenous administration), with a high of 102% (budesonide).14,15 Notably, the sensitivity of the assays used in some of these studies to determine bioavailability was insufficient to detect low plasma drug concentrations, with an LLOQ of 50 pg/mL.15 Therefore, it is difficult to assess whether these drugs lacked appreciable systemic concentrations or whether the low levels in the plasma were the result of using an insensitive assay.
Low or negligible serum levels of CIC and des-CIC are in concordance with values reported for fluticasone propionate and mometasone furoate, which also exhibit low absolute bioavailability. In a pharmacokinetic study of intranasal fluticasone propionate and mometasone furoate administration in healthy volunteers, despite the low mean maximum plasma concentrations (27.7 and 25.5 pg/mL, respectively), even when administered at high doses (2400 µg/d), there was still sufficient circulating drug to calculate pharmacokinetic parameters.16 It should be noted that the dose of fluticasone propionate or mometasone furoate was 3 times higher than the maximum dose of CIC administered in our study. Ciclesonide serum concentrations were considerably lower than those attained with comparable doses of triamcinolone acetonide administered intranasally in subjects with PAR; reported mean maximum plasma concentrations of triamcinolone acetonide ranged from 260 to 1270 pg/mL.17 In addition, after doses of budesonide 400 or 800 µg administered to healthy volunteers intranasally as a pressurized aerosol, aqueous pump spray, or powder, mean Cmax values ranged from 0.51 to 1.06 nmol/L (220-456 pg/mL).18 Furthermore, quantifiable amounts of the active beclomethasone dipropionate metabolite, beclomethasone 17-monopropionate, were detected in the plasma of healthy volunteers after intranasal administration of beclomethasone dipropionate 1344 µg, with a mean maximum plasma concentration of 310 pg/mL.19
Low levels of CIC were observed in healthy volunteers and in asymptomatic subjects with SAR. Although not sufficient for the calculation of pharmacokinetic parameters, CIC and des-CIC serum concentrations did reach the quantifiable range at some time points in a few participants. Although in the CIC 400-µg twice-daily treatment groups there were fewer values above the LLOQ in asymptomatic subjects with SAR compared with healthy volunteers, it should be noted that these data were drawn from a small number of subjects. One explanation for this apparent difference in systemic exposure between populations is that changes in the nasal mucosa in subjects with SAR affect the absorption of the drug. It has been shown that chronic exposure to allergens can lead to structural changes of the nasal mucosa, including thickening of the basement membrane zone20 and proliferation of the nasal epithelia.21 Consequently, it is possible that in subjects with a history of AR, changes in the nasal mucosa may have reduced drug absorption and thereby systemic exposure to drugs administered intranasally. Therefore, in selecting a population in which to study high doses of intranasal CIC, it was important to include healthy volunteers to ensure that no underlying disorder could decrease drug absorption.
As expected, intranasal CIC (50-800 µg/d) administration was generally safe and well tolerated in both healthy volunteers and asymptomatic subjects with SAR. Increasing the dose of CIC did not correlate with an increase in adverse event frequency, and the incidence of treatment-emergent adverse events was comparable between healthy volunteers and subjects with SAR. These data are consistent with earlier findings in a 7-day trial of CIC nasal spray delivered via a pressurized metered-dose inhaler versus placebo in subjects with AR, wherein the frequency of treatment-emergent adverse events was low and no local or systemic side effects were reported.22
Ciclesonide administration did not appear to affect adrenal function in this study population. The diurnal variation in serum free cortisol levels was comparable between participants treated with CIC or placebo. Although INCS are generally thought to have little effect in adults or children, decreases in urinary cortisol have been reported in studies of fluticasone propionate 200 to 400 µg/d, budesonide 400 to 800 µg/d, and beclomethasone dipropionate 800 µg/d in healthy volunteers.23 Furthermore, growth rate was reduced in a 1-year study of aqueous beclomethasone dipropionate 168 µg twice daily administered intranasally in children with PAR, even in the absence of measurable evidence of hypothalamic-pituitary-adrenal axis suppression.24
In conclusion, the favorable safety and tolerability profile of CIC nasal
spray suggests that it may provide a safe treatment option for AR. Systemic
exposure to CIC is low and is below the LLOQ in the majority of samples
tested, despite the use of a sensitive assay. At daily doses of CIC 200
µg, none of the subjects had detectable serum levels of CIC or des-CIC at
any time point. Treatment with CIC nasal spray at daily doses 800 µg/d
was not associated with measurable systemic effects as assessed by 24-hour
serum and urine free cortisol levels.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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