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Circadian Rhythm of Serum Cortisol after Repeated Inhalation of the New Topical Steroid Ciclesonide

Department of Clinical Pharmacology (A.W., D.H., M.Z., G.E.), Ernst Moritz Arndt University, Greifswald 17487, Germany; Byk Gulden Pharmaceuticals (W.T., V.W.S., T.B., W.W., A.D.), Konstanz 78467, Germany; and Oranienburger Pharmawerk (H.J.K.), Oranienburg 16515, Germany

Address all correspondence and requests for reprints to: Prof. Werner Siegmund, M.D., Institute of Pharmacology, University of Greifswald, Friedrich-Loeffler-Streat 23d, Greifswald D-17487, Germany. E-mail: . siegmuw{at}mail.uni-greifswald.de

Abstract

The new inhalative glucocorticoid ciclesonide which is activated in lung to a more potent metabolite was hypothesized to have low risk for systemic and local side-effects in man. Therefore, a placebo-controlled, randomized, double-blind, four-period, change-over equivalence study in 12 healthy male volunteers (age 21–28 yr, body weight 62–90 kg) was conducted to assess the influence of three dosage regimens (800 µg in the morning, 800 µg in the evening, 400 µg twice daily for 7 d, metered inhalers) on the circadian time serum cortisol rhythm.

Results: Serum cortisol showed the typical circadian rhythm. The geometric mean of the 24-h mesor (AUC_{(0–24 h)}/24 h) was 7.22 µg/dl for placebo, 6.75 µg/dl for the 800 µg ciclesonide morning dose, 7.08 µg/dl for the 800 µg evening dose, and 6.75 µg/dl for 400 µg ciclesonide inhaled twice daily. Because there was also no influence on cortisol amplitude and acrophase (time of maximum), the profiles after ciclesonide were equivalent to the placebo control. The small differences were considered not to be of clinical significance.

In conclusion, inhaled ciclesonide in daily doses of 800 µg for 7 d is without clinically relevant effects on the hypothalamic-pituitary-adrenal axis independent of the time of administration.

BRONCHIAL ASTHMA AND chronic bronchitis are among the most common chronic diseases world-wide. In industrialized countries, the prevalence of asthma and the mortality associated with asthma have increased over the last 20 yr. Asthma results from complex interactions between allergens, inflammatory cells, and their mediators. It involves processes of airway wall remodeling and genetic factors and it is characterized by airway obstruction, inflammation, and progressive bronchial hyperreactivity (1, 2, 3).

Inhalative glucocorticoids are the most effective agents currently used in patients of all ages. However, dose increase in long-term therapy of severe asthma is limited by systemic side-effects such as suppression of the hypothalamic pituitary adrenal (HPA) function, growth impairment, disturbed glucose tolerance, or increased risks for osteoporosis and cataract formation (4). The systemic bioactivity of inhalative glucocorticoids is mainly determined by pulmonary deposition because the swallowed part of the dose undergoes extensive first-pass metabolism (5). The major challenge in developing novel inhalative glucocorticoids is to design substances with high local potency in the airways but without side effects.

Ciclesonide (Fig. 1) is a potent new nonhalogenated glucocorticoid with essentially no oral bioavailability. It is activated in the lung to a potent metabolite whose affinity to the glucocorticoid receptor is about 100 times higher compared with parent ciclesonide. Ciclesonide was found clinically effective in patients with bronchial asthma and caused lower airway responsiveness to adenosine-5'-monophosphate (6). The active compound is assumed to have a minor potential for systemic side effects because a relevant fraction of the inhaled dose persists in the lung and the absorbed part is highly bound to plasma proteins. To show that ciclesonide in the expected upper therapeutic doses does not significantly disturb HPA function, the influence of repeated inhalation of 800 µg on the 24-h serum cortisol profile was assessed in a placebo-controlled, randomized, double-blind, change-over equivalence study in healthy volunteers. Because endogenous cortisol secretion follows a strict diurnal rhythm and the effects of inhaled glucocorticoid are expected to be circadian time dependent, we compared repeated inhalation of the total dose in the morning with inhalation in the evening and administration of the half dose twice daily.

View larger version (10K): [in this window] [in a new window]   Figure 1. Structural formula of ciclesonide, a nonhalogenated inhalative glucocorticoid.

Subjects

Twelve healthy male Caucasian volunteers (age 21–28 yr, median 24 yr; body weight 62–90 kg, median 77 kg) were included into the study. They were of good health as shown by medical history, physical examination (including inspection of the oropharynx), routine clinical-chemical and hematological screening, and 12-lead electrocardiogram. All subjects were nonsmokers and negative for HBV and HIV, drugs. They did not drink alcohol on a regular basis. Further important exclusion criteria were history of endocrine disorders, topical or systemic steroids within 3 months, time shift of more than 3 h (e.g. intercontinental flight) within 2 wk and extreme somatic or psychological stress within 4 wk before the study. None of the volunteers took medications, and all abstained strictly from alcohol during the whole study. All subjects had given their informed written consent before participation. The study protocol had been approved by the independent local ethics committee.

Study protocol

This placebo-controlled, randomized, double-blind, four-period, change-over, equivalence study with at least 7 d washout between the treatment periods was performed according to the current criteria of Good Clinical Practice (7). The subjects were randomly allocated (Latin square with three subjects per sequence) to the following treatments: 1) placebo; 2) 800 µg ciclesonide in the morning; 3) 800 µg ciclesonide in the evening; 4) 400 µg ciclesonide twice daily. According to the double-blind technique, the study medication was administered using pressurized metered dose inhalers of identical appearance for 7 d as follows: 1) four puffs placebo at 0700 h and four puffs placebo at 0700 h; 2) 4 puffs of 200 µg ciclesonide at 0700 h and four puffs placebo at 1900 h; 3) four puffs placebo at 0700 h and four puffs of 200 µg ciclesonide at 1900 h; 4) four puffs of 100 µg ciclesonide at 0700 h and four puffs 100 µg ciclesonide at 1900 h. In the presence of an investigator, the subjects had to draw a deep breath while a puff was released. There was no difference between the taste of ciclesonide and placebo.

In the evening of the sixth treatment day, the volunteers were hospitalized for 36 h to measure 24-h profiles of cortisol in serum on the seventh treatment day. Venous blood samples were collected before the morning inhalation at 0700 h and after 1, 2, 3, 5, 7, 9, 11, 12, 13, 14, 15, 17, 19, 21, 23, and 24 h. The last ciclesonide administration was at 1900 h of the seventh treatment day. Serum was separated by centrifugation and stored at -20 C until the quantitative cortisol analysis. Safety and local tolerability of ciclesonide were assessed by repeated inspection of nose, mouth, and throat before and 1 h after the morning administrations on d 1 and 7, and before the morning inhalations on d 2–6 of each treatment period. The state of the airway mucosa was rated according to predefined criteria, and a symptom score was recorded. Adverse events were monitored continuously. A reduced medical examination was performed before starting treatment periods 2, 3, and 4. Between and during the treatment periods, the subjects were supposed to keep their usual daily schedule; strenuous physical exercise was not permitted. During the hospitalization, they had to eat standard food at 0700 h, 1200 h, and 1800 h and to follow identical rest periods.

Assay of cortisol

The quantitative assay of cortisol in human serum was done by a fluorescence polarization immunoassay (TDxFLx, Abbott, Wiesbaden, Germany). The limit of quantification was 2.5 µg/dl. The interassay errors were as follows: accuracy -5.9% to +1.0% of the nominal concentrations (relative error); precision 6.6–11.1% of means (coefficients of variation) as calculated with 52 quality control sets (4, 15, 40 µg/dl). The quality of calibration fulfilled the criteria defined by the manufacturer of the cortisol assay. The recovery of cortisol was between 94 and 101%.

Biostatistical methods

Quantification of the circadian rhythm of serum cortisol was done as defined in Lemmer 1989 (8). The primary variable for the confirmatory biostatistical analysis was the 24-h time average of cortisol in serum determined from 0700 h on d 7 up to 0700 h on d 8 (defined as mesor: AUC_{(0–24 h)}/24 h). The amplitude of the circadian rhythm was approximated by half of the difference between the maximum and minimum cortisol serum level during 24 h. Treatments were compared by means of a standard ANOVA for the four-period change-over design using a multiplicative model and a logarithmic transformation (9). Geometric mean and 90%-confidence limits were given for the respective ratios ciclesonide/placebo. As equivalence acceptance limits, 0.80 and 1.25 had been stipulated. The acrophase was defined as the time point of the maximum cortisol serum concentration. The nontransformed acrophases were also analyzed by ANOVA. The score sums of the repeated otorhinolaryngological examinations and the results of the other safety measurements were considered as secondary variables; their analysis was merely descriptive.

Results

All 24-h profiles of serum cortisol showed typical circadian rhythms with peaks at about 0800 h and troughs between 2100 h and 0200 h of the next day (Fig. 2). The mean cortisol concentrations with standard deviations are given in Table 1. Cortisol profiles obtained after ciclesonide medication were very similar to the placebo control. The results of the summary statistics of the 24-h mesor and the amplitude of serum cortisol are listed in Table 2. There were only minor differences between the three ciclesonide treatments and placebo. Both 24-h mesor and amplitude of serum cortisol after all treatment regimens were equivalent to those under placebo as the 90% confidence limits for the respective ratios were entirely within the a priori defined equivalence acceptance limits of 0.80 and 1.25. Concerning the acrophase (time of maximum cortisol concentration), the mean difference vs. placebo did not exceed 0.25 h and, therefore, was not considered as clinically relevant.

View larger version (25K): [in this window] [in a new window]   Figure 2. Mean 24-h profiles of serum cortisol of 12 healthy volunteers treated for 7 d with (A) placebo twice daily, (B) 800 µg ciclesonide in the morning and placebo in the evening, (C) 800 µg ciclesonide in evening and placebo in the morning, and (D) 400 µg ciclesonide in the morning and 400 µg ciclesonide in the evening in a randomized, double-blind, change-over, equivalence study with at least 7 d wash-out.

Repeated otorhinolaryngological examinations during the study did not disclose any pathological findings; the median score sum was not influenced by ciclesonide. The safety measurements made during the study and at final check revealed no clinically significant findings. Some minor deviations of the clinical-chemical and hematological findings from the reference ranges were without clinical relevance. The following adverse events occurred during the study: 1x herpes labialis (after ciclesonide), 1x headache (after placebo), 2x rhinitis (during wash-out), 1x burning of tongue and mouth mucosa (during ciclesonide-treatment but without relation to dose administration).

Discussion

Due to the wide use of inhaled glucocorticoids, greater attention has been directed to their systemic side-effects one of which is the suppression of the HPA function; it is the most sensitive marker currently assessable. Determination of the 24-h profiles of cortisol in serum or plasma has been found to be best suited to assess functional disturbances of this system in patients treated with inhaled corticosteroids (10, 11). Compared with this method, determination of the morning serum levels alone is of minor sensitivity because of the large inter and intrasubject variability (12). The urinary cortisol excretion may be as sensitive as the integrated plasma cortisol measurement in detecting adrenal suppression (13, 14). However, its reliability depends on the compliance of volunteers to collect urine adequately (15). Even stimulation or stress tests with the adrenocorticotropic hormone, CRH, vasopressin or insulin are inferior to the 24-h cortisol profile because their responses may be positive despite reduced cortisol secretion (16, 17, 18). There is ample evidence that budesonide, fluticasone propionate, triamcinolone and other inhalative glucocorticoids suppress adrenocortical function in a dose-dependent manner (11, 13, 14, 19, 20, 21, 22, 23). The systemic bioactivity seems to be related to the potency of the drugs as shown for fluticasone propionate, budesonide or triamcinolone acetonide (14, 20, 22, 24). Further determinants of pronounced systemic side effects are the glucocorticoid receptor residency half-time, the degree of their first-pass degradation and the duration of treatment (21, 25, 26).

In a placebo-controlled, double-blind study conducted in healthy volunteers, we have shown that the 24-h profile of cortisol obtained after repeated inhalation of 800 µg of the new inhalative glucocorticoid ciclesonide was still equivalent to that observed under placebo. Our findings must be seen in the light of the very low oral bioavailability of ciclesonide and the formation of an active metabolite in vivo, which enables drug targeting of the lung while high protein binding may prevent pharmacodynamically effective free drug concentrations. The study medication was safe and well tolerated. There were neither significant systemic adverse drug reactions nor damage of the mucous membranes of the upper airways as assessed by repeated otorhinolaryngological examinations. However, the results of our study were limited by the fact, that only young, male Caucasian volunteers were included.

It is well known that the endogenous release of cortisol and the 24-h cortisol serum profile follow a circadian rhythm with a maximum in the morning and minimum during the night. Therefore, suppression of the cortisol release after administration of glucocorticoids is expected to be dependent on the time of dosing. It is recommended to administer glucocorticoids in the morning to minimize the undesired systemic effects on the hypothalamic pituitary adrenal axis (27, 28). Evening administration of ciclesonide did not lead to any additional effects on cortisol release compared with morning or twice daily administration. Therefore, time of ciclesonide administration can be individually adapted to the therapeutic need of the patients without additional risk for disturbances of the HPA function.

In conclusion, the novel inhalative glucocorticoid ciclesonide was found to be safe in healthy volunteers, without clinically relevant systemic effects on the hypothalamic pituitary adrenal axis. The promising safety profile of ciclesonide might be related to high lung tissue affinity and deposition and low systemic availability of the free active form of the drug.

Acknowledgments

We are grateful to Hannelore Kreher, Gitta Schumacher, and Sabine Bade for their skilful technical assistance.

Footnotes

Abbreviation: HPA, Hypothalamic pituitary adrenal.

Received October 31, 2001.

Accepted January 25, 2002.

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