A dose-response study comparing suppression of plasma cortisol induced by fluticasone propionate from Diskhaler and budesonide from Turbuhaler

Grahnén, A; Jansson, B.; Brundin, R. M.; Ling-Andersson, A.; Lönnebo, Anna; Johansson, Maria; Eckernäs, S.‐Å.

doi:10.1007/s002280050287

Cited by 53 publications

(18 citation statements)

References 10 publications

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“…It is apparent that the recovery from cortisol suppression after the last dose differs between the three formulations, with budesonide Turbuhaler having the fastest recovery and¯u ticasone pMDI the slowest (Figure 3). This is consistent with a previous study in which plasma cortisol was statistically signi®cantly suppressed compared with baseline up to 24 h following the last dose of¯uticasone via Diskhaler (1000 mg twice daily) but not for budesonide via Turbuhaler (800 mg twice daily) [11].…”

Section: Regimensupporting

confidence: 93%

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Pharmacokinetics and systemic activity of fluticasone via Diskus^® and pMDI, and of budesonide via Turbuhaler^®

Thorsson

Edsbäcker

Källén

et al. 2001

Brit J Clinical Pharma

156

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Aims To determine the basal pharmacokinetics, lung uptake and plasma cortisol suppression for two commonly prescribed inhaled corticosteroids. Methods Twenty-one subjects (13 healthy and 8 mild asthmatic patients) received uticasone propionate via a chloro¯uorocarbon-propelled pressurized metered-dose inhaler (pMDI) (healthy subjects only) and Diskus 1 and budesonide via Turbuhaler 1 , 1000 mg twice daily for 7 days. Intravenous doses (200 mg) of both compounds were used as references. Plasma concentrations of¯uticasone and budesonide were determined during 48 h by liquid chromatography plus tandem mass spectrometry (LC-MS-MS). Plasma concentrations of cortisol were determined by LC-MS every second hour for 24 h at baseline, and following each treatment. Results The volume of distribution was found to be larger and the elimination half-life and mean absorption time longer for¯uticasone than for budesonide. The systemic availability of budesonide via Turbuhaler (39%) was signi®cantly higher than that of uticasone via Diskus (13%) (ratio 3.0 [2.5, 3.6] with 95% con®dence interval [CI]), and via pMDI (21%) (ratio 1.8 [1.3, 2.3]). In addition, at steady state the systemic availability of¯uticasone via pMDI was signi®cantly higher than via Diskus (ratio 1.6 [1.1, 2.2]). The lung deposition of budesonide via Turbuhaler was 2.2-fold [1.7, 2.9] higher than that of¯uticasone pMDI and 3.4-fold [2.8, 4.0] higher than that of uticasone Diskus. In addition, the lung deposition of¯uticasone via pMDI was 1.5-fold [1.1, 2.9] higher than that via the Diskus inhaler. Plasma cortisol (24 h) was signi®cantly reduced vs baseline for all three treatments. The cortisol concentration vs baseline was 12% for¯uticasone pMDI, which was signi®cantly lower (ratio 0.32 [0.24, 0.42]) than that for¯uticasone Diskus (39%), and for budesonide Turbuhaler (46%) (ratio 0.27 [0.21, 0.37]). The plasma cortisol concentration did not differ signi®cantly between treatments with¯uticasone Diskus and budesonide Turbuhaler (ratio 0.87 [0.65; 1.15]). Conclusions Budesonide and¯uticasone differ in their pharmacokinetic properties in that although clearance is the same, the rate of uptake and elimination is slower for uticasone. Despite a signi®cantly higher pulmonary availability of budesonide via Turbuhaler, the plasma cortisol suppression is less than that of¯uticasone via pMDI and similar to that of¯uticasone via Diskus. There is no indication of any difference between healthy subjects and mild asthmatic patients in the pharmacokinetics and plasma cortisol suppression of¯uticasone and budesonide.

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Section: Regimensupporting

confidence: 93%

“…Available documentation on pharmacokinetics and systemic effects of¯uticasone and budesonide is mainly based on studies in healthy subjects [1,5,6,10,11]. One reason for this is to minimize the between-subject variability [12].…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics and systemic activity of fluticasone via Diskus^® and pMDI, and of budesonide via Turbuhaler^®

Thorsson

Edsbäcker

Källén

et al. 2001

Brit J Clinical Pharma

156

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“…This lung retention results in slow systemic absorption via the pulmonary route and a systemic availability of 13% for FP-DPI and 21% for FP-MDI [28]. However, FP has a long half-life in plasma (about 12–15 h) and the affinity with which this molecule binds to the glucocorticoid receptor is higher than those of BUD-DPI and BDP-MDI [36], giving equal (FP-DPI via Diskus®) or higher (FP-MDI) systemic activities [28,37,38,39]. …”

Section: Discussionmentioning

confidence: 99%

Use of the Low-Dose Corticotropin Stimulation Test for the Monitoring of Children with Asthma Treated with Inhaled Corticosteroids

Demay

Magny²,

Idres³

et al. 2006

Horm Res Paediatr

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Objective: Subnormal hypothalamic-pituitary-adrenal (HPA) function and rare cases of adrenal crisis have been reported in asthmatic children treated with inhaled corticosteroids. We investigated subnormal HPA activity and followed up affected patients until recovery of normal HPA functions. Study Design: 100 children with persistent asthma underwent low-dose corticotropin testing, with the administration of 1 µg of 1–24 ACTH intravenously. Treatments were beclomethasone dipropionate as a metered-dose inhaler, n = 14, budesonide as a dry-powder inhaler, n = 16, fluticasone propionate as a metered-dose inhaler n = 31 or a dry-powder inhaler n = 39. The mean commercially labelled dose was 520 ± 29 µg/day (mean ± SEM, range: 160–1,000) and the equipotent dose (which compares the efficiency of these drugs for treating asthma and their responsibility for systemic effects) was 890 ± 55 µg/day (range: 200–2,000). Results: The mean stimulated cortisol level ± SEM (and range) of the patient was 482 ± 12 (148–801), and that of 40 age-matched controls was 580 ± 12.5 (439–726), (SD = 79). The result was subnormal (more than 2 SD below the mean of the controls) in28 of the 100 patients. One–four stepwise decreases of 10–100% in the daily equipotent doses received by the patients with abnormal low-dose corticotropin testing results led to normal results in subsequent low-dose corticotropin testing in 27 retested patients. The mean time interval between two tests was 5 months (range: 2–6 months) and the mean period required for normalization of the test was 13 months (range: 2–21). Only one case of asthma exacerbation and no adrenal crisis were observed over these periods. Conclusions: Decreasing daily equipotent doses led to recovery of normal HPA function without asthma exacerbation. Thus, a revision of the doses of inhaled corticosteroids used in asthmatic children with a progressive decrease to the consensus-recommended doses should decrease the systemic effects of inhaled corticosteroids, while minimizing the risk of asthma exacerbation.

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“…The budesonide Turbuhaler and fluticasone Diskhaler are therapeutically equivalent on a milligram-for-milligram basis, whereas the fluticasone Diskhaler exhibits 1.7-fold greater adrenal suppression than the budesonide Turbuhaler. 30,45 This shows that differences in glucocorticoid receptor potency alone cannot account for the 1.7-fold greater adrenal suppression seen with fluticasone. The greater degree of systemic bioactivity with fluticasone probably represents a complex interplay of factors, including accumulation in blood, retention in systemic tissue, and prolonged receptor occupancy.…”

mentioning

confidence: 95%

“…31 In a different study in healthy volunteers, a dose comparison was performed with budesonide and fluticasone given via their respective dry-powder inhaler devices, which showed a relative potency ratio of 1.7 for 24-hour cortisol levels and 2.3 for 8 AM cortisol levels. 30 The lower potency ratios for fluticasone vs budesonide when given via drypowder inhalers reflect the greater drug delivery to the lung from the budesonide Turbuhaler (a reservoir drypowder inhaler) compared with the fluticasone Diskhaler device (a blister dry-powder device), whereas the fluticasone metered-dose inhaler delivers more drug than the budesonide metered-dose inhaler. 64 The reason for the higher ratio with 8 AM than with 24-hour cortisol levels probably reflects the longer elimination half-life of fluticasone, such that there will be higher levels of fluticasone at 8 AM when used with a 12-hour dosing interval.…”

mentioning

confidence: 99%

Systemic Adverse Effects of Inhaled Corticosteroid Therapy

1999

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Objective: To appraise the data on systemic adverse effects of inhaled corticosteroids.Methods: A computerized database search from January 1, 1966, through July 31, 1998, using MEDLINE, EMBASE, and BIDS and using appropriate indexed terms. Reports dealing with the systemic effects of inhaled corticosteroids on adrenal gland, growth, bone, skin, and eye, and reports on pharmacology and pharmacokinetics were reviewed where appropriate. Studies were included that contained evaluable data on systemic effects in healthy volunteers as well as in asthmatic children and adults. A statistical meta-analysis using regression was performed for parameters of adrenal suppression in 27 studies.Results: Marked adrenal suppression occurs with high doses of inhaled corticosteroid above 1.5 mg/d (0.75 mg/d for fluticasone propionate), although there is a considerable degree of interindividual susceptibility. Metaanalysis showed significantly greater potency for doserelated adrenal suppression with fluticasone compared with beclomethasone dipropionate, budesonide, or triamcinolone acetonide, whereas prednisolone and fluticasone propionate were approximately equivalent on a 10:1-mg basis. Inhaled corticosteroids in doses above 1.5 mg/d (0.75 mg/d for fluticasone propionate) may be associated with a significant reduction in bone density, although the risk for osteoporosis may be obviated by postmenopausal estrogen replacement therapy. Although medium-term growth studies showed suppressive effects with 400-µg/d beclomethasone dipropionate, there was no evidence to support any significant effects on final adult height. Long-term, high-dose inhaled corticosteroid exposure increases the risk for posterior subcapsular cataracts, and, to a much lesser degree, the risk for ocular hypertension and glaucoma. Skin bruising is most likely to occur with high-dose exposure, which correlates with the degree of adrenal suppression.Conclusions: All inhaled corticosteroids exhibit doserelated systemic adverse effects, although these are less than with a comparable dose of oral corticosteroids. Metaanalysis shows that fluticasone propionate exhibits greater dose-related systemic bioactivity compared with other available inhaled corticosteroids, particularly at doses above 0.8 mg/d. The long-term systemic burden will be minimized by always trying to achieve the lowest possible maintenance dose that is associated with optimal asthmatic control and quality of life. Med. 1999;159:941-955 Arch Intern

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A dose-response study comparing suppression of plasma cortisol induced by fluticasone propionate from Diskhaler and budesonide from Turbuhaler

Abstract: The results of the present study show that FP-DH suppresses plasma cortisol more than BUD-TBH on a equivalent basis with regard to both magnitude and duration.

Cited by 53 publications

References 10 publications

Pharmacokinetics and systemic activity of fluticasone via Diskus^® and pMDI, and of budesonide via Turbuhaler^®

Pharmacokinetics and systemic activity of fluticasone via Diskus^® and pMDI, and of budesonide via Turbuhaler^®

Use of the Low-Dose Corticotropin Stimulation Test for the Monitoring of Children with Asthma Treated with Inhaled Corticosteroids

Systemic Adverse Effects of Inhaled Corticosteroid Therapy

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A dose-response study comparing suppression of plasma cortisol induced by fluticasone propionate from Diskhaler and budesonide from Turbuhaler

Abstract: The results of the present study show that FP-DH suppresses plasma cortisol more than BUD-TBH on a equivalent basis with regard to both magnitude and duration.

Cited by 53 publications

References 10 publications

Pharmacokinetics and systemic activity of fluticasone via Diskus® and pMDI, and of budesonide via Turbuhaler®

Pharmacokinetics and systemic activity of fluticasone via Diskus® and pMDI, and of budesonide via Turbuhaler®

Use of the Low-Dose Corticotropin Stimulation Test for the Monitoring of Children with Asthma Treated with Inhaled Corticosteroids

Systemic Adverse Effects of Inhaled Corticosteroid Therapy

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Product

Resources

About

Pharmacokinetics and systemic activity of fluticasone via Diskus^® and pMDI, and of budesonide via Turbuhaler^®

Pharmacokinetics and systemic activity of fluticasone via Diskus^® and pMDI, and of budesonide via Turbuhaler^®