Pharmacological Basis of Differences in Dose Response, Dose Equivalence, and Duration of Action of Inhaled Corticosteroids.

INTRODUCTION: Asthma treatment guidelines classify inhaled corticosteroid (ICS) regimens as low, medium, or high dose. However, efficacy and safety are not independently assessed accordingly. Moreover, differences in ICS duration of action are not considered when a dose regimen is selected. We investigated the efficacy and safety implications of these limitations for available ICS molecules. METHODS: Published pharmacodynamic and pharmacokinetic parameters were used, alongside physiological and pharmacological principles, to estimate the efficacy and safety of available ICS molecules. Extent and duration of glucocorticoid receptor (GR) occupancy in the lung (efficacy) and cortisol suppression (systemic exposure and safety) were estimated. RESULTS: Some ICS regimens (e.g., fluticasone furoate, fluticasone propionate, and ciclesonide) rank high for efficacy but low for systemic exposure, contrary to how ICS dose equivalence is currently viewed. Differences in dose-response relationships for efficacy and systemic exposure were unique for each ICS regimen and reflected in their therapeutic indices. Notably, even low doses of most ICSs can generate high GR occupancy (≥ 90%) across the entire dose interval at steady state, which may explain previously reported difficulties in obtaining dose responses within the clinical dose range and observations that most clinical benefit typically occurs at low doses. The estimated post dose duration of lung GR occupancy for ICS molecules was categorized as 4-6 h (short), 14-16 h (medium), 25-40 h (long), or > 80 h (ultra-long), suggesting potentially large differences in anti-inflammatory duration of action. CONCLUSION: In a real-world clinical setting where there may be poor adherence to prescribed therapy, our findings suggest a significant therapeutic advantage for longer-acting ICS molecules in patients with asthma.

Patients with asthma often rely on inhaled corticosteroids to manage their symptoms by controlling lung inflammation. Inhaled corticosteroids can be used at low, medium, or high doses; however, the effectiveness, safety, and how long the effects last for a particular inhaled corticosteroid molecule are not considered when choosing them. This study investigated the safety and efficacy of different inhaled corticosteroid molecules. Leveraging published data on the mode of anti-inflammatory action and the rates these molecules are absorbed and eliminated from the body, we estimated their effectiveness and safety profiles, including duration of action in the lungs and systemic exposure levels. Some inhaled corticosteroid molecules such as fluticasone furoate, fluticasone propionate, and ciclesonide were found to exhibit high anti-inflammatory effectiveness in the lungs with minimal systemic exposure, contrasting the perceived similarities among currently used drug molecules. Anti-inflammatory duration of the unwanted systemic effect in the rest of the body was unique for each inhaled corticosteroid molecule. Notably, even the lowest doses of most inhaled corticosteroids were found to be effective in the lungs when taken as prescribed, supporting previous observations that clinical benefits are mostly realized at lower doses. Furthermore, estimated post dose durations of effectiveness for different inhaled corticosteroid molecules varied widely among different molecules, with some lasting a few hours and others lasting more than 80 h, suggesting significant differences in their duration of action. Overall, these findings demonstrate the potential advantage of using longer-acting inhaled corticosteroids, particularly for patients with asthma who may face challenges in adhering to prescribed regimens.

Comparative clinical pharmacology of mometasone furoate, fluticasone propionate and fluticasone furoate.

AIMS: To investigate the pharmacokinetics and effects on the hypothalamic-pituitary-adrenal (HPA) axis of mometasone furoate (MF), fluticasone propionate (FP) and fluticasone furoate (FF). METHODS: Study 1: Fourteen healthy participants received inhaled and intravenous MF (inhaled dose via Twisthaler) and FP (inhaled dose via Diskus), both given at 400 µg, using a randomised, single-dose, four-way crossover design. Study 2: Twenty-seven participants with mild to moderate asthma, who discontinued their corticosteroid medication for 5 days to obtain a baseline 24 h serum cortisol, received inhaled MF Twisthaler and FP Diskus, both given at 400 µg twice daily (BID), using a randomised, 14-day repeat dose, two-way crossover design. Study 3: Forty-four healthy participants were randomised to a double-blind, placebo-controlled, five-period crossover study where the following treatments were administered via the inhaled route for 7 days: FP Diskus (250, 500, 1000 µg BID), FF Diskus (100, 200, 400, 800, 1600 µg once daily [QD]) or placebo Diskus. In each study, 24-h serial blood samples were collected and assayed to assess concentrations of MF, 6ß-hydroxy mometasone, mometasone, FP, FF and cortisol. Pharmacokinetic and serum cortisol parameters were estimated as geometric means and 95% confidence intervals (CI). RESULTS: Study 1: For intravenous MF and FP, respectively: absolute bioavailability was 11.4% (95% CI: 7.5, 17.6) and 7.8% (6.3, 9.6); plasma clearance was 47 L/h (41, 52) and 60 L/h (52, 69); half-life was 7.4 h (6.9, 8.0) and 7.2 h (6.5, 8.0); and volume of distribution was 499 L (439, 567) and 623 L (557, 698). Inhalation of single dose MF or FP did not significantly affect serum cortisol (<10% reduction from baseline), whereas intravenous administration of MF or FP each changed serum cortisol by approximately -50% from baseline. Study 2: For MF and FP, respectively: area under the curve up to the last measurable concentration on Day 1 was 421 pg h/mL (270, 659) and 248 pg h/mL (154, 400), and on Day 14 was 1092 pg h/mL (939, 1269) and 591 pg h/mL (501, 696); absolute bioavailability was 12.8% (11.2, 14.2) and 8.9% (7.7, 10.2). On Day 14, 24-h serum cortisol change from baseline was -35% (-44%, -26%) and -18% (-28%, -5%) for MF and FP, respectively; the reduction was significantly greater for MF than FP (ratio for geometric adjusted mean serum cortisol concentration: 1.28 [1.04, 1.56]). Low plasma concentrations of 6ß-hydroxy mometasone were detected after intravenous dosing (Study 1) and after multiple inhaled dosing (Study 2); mometasone was not detected in any samples. Study 3: Inhaled FP and FF had similar systemic bioavailability estimates (12.0% [11.0, 13.2] and 15.0% [12.0, 17.3], respectively), but a differential effect on the HPA axis which was in agreement with the known 1.7-fold higher glucocorticoid receptor-binding affinity of FF versus FP. However, for FP 250 µg BID and FF 100, 200 and 400 µg QD, reduction in serum cortisol was not significantly different from placebo. For higher doses, FP 500 and 1000 µg BID, and FF 800 and 1600 µg QD, changes in serum cortisol concentration relative to placebo were -30%, -70%, -41% and -90%, respectively. Repeat inhaled dosing of FP 1000 µg/day (within the therapeutic dose range) resulted in comparable cortisol suppression to MF in the therapeutic range (30% reduction); whereas for FF this occurred at more than 3-fold above the therapeutic dose range (644 µg/day). CONCLUSIONS: Single inhaled and intravenous doses of MF and FP (400 µg) resulted in similar bioavailability and reductions in serum cortisol. Repeat dosing of inhaled MF and FP in the therapeutic range (800 µg/day) resulted in greater systemic exposure for MF, and a 35% reduction in serum cortisol that was 2-fold greater than for FP. The higher glucocorticoid receptor-binding affinity and bioavailability, lower clearance and the presence of active metabolites may contribute to the greater systemic exposure and effect on cortisol for MF. Repeat dosing of inhaled FP and FF resulted in similar systemic bioavailability but differed in terms of the dose required for comparable cortisol suppression to MF in the therapeutic range. Unlike FP and FF, MF has active metabolites that may contribute to its systemic effects, while device/formulation performance differences also exist between MF-containing products.

Intranasal Corticosteroids: Topical Potency, Systemic Activity and Therapeutic Index.

Intranasal corticosteroid (INCS) therapy is the preferred treatment option for allergic rhinitis (AR). Although all INCSs for the treatment of AR are considered safe and effective, differences in potency, molecular structure features and physicochemical and pharmacokinetic properties could result in differences in clinical efficacy and safety. Higher glucocorticoid receptor (GR) binding affinity of INCS is associated with higher lipophilicity, nasal tissue retention and topical potency. Higher topical potency is also accompanied by low oral bioavailability and high systemic clearance conferring low systemic exposure, reduced potential for systemic adverse effects and an improved therapeutic index. It has been shown that adverse events related to systemic exposure of INCSs in children are low. Although INCSs mostly produce low systemic effects, use of an INCS with low systemic exposure in patients on multiple corticosteroid (CS) therapies could help reduce the total systemic burden of CS therapy. Despite differences in topical potency, physicochemical and pharmacokinetic properties between INCSs, clinical studies of INCSs in the treatment of AR generally show no clinically important differences between these compounds, and poor correlation between INCS topical potency and clinical response. However, the lack of head-to-head comparisons of INCSs in clinical studies conducted in more severe AR patients should be noted. This narrative review provides an assessment of the therapeutic relevance of topical potency and the physicochemical and pharmacokinetic properties of INCSs and describes for the first time the relationship between topical potency and therapeutic index using pharmacological features of INCSs. It concludes that higher GR binding affinity and topical potency can potentially improve the therapeutic index of an INCS. Therefore, both efficacy and systemic exposure profiles should be considered when comparing INCS regimens in terms of therapeutic equivalence, to aid clinical decision-making and avoid the assumption that all INCS formulations are the same when considering treatment options.

Inhaled corticosteroids: potency, dose equivalence and therapeutic index.

Glucocorticosteroids are a group of structurally related molecules that includes natural hormones and synthetic drugs with a wide range of anti-inflammatory potencies. For synthetic corticosteroid analogues it is commonly assumed that the therapeutic index cannot be improved by increasing their glucocorticoid receptor binding affinity. The validity of this assumption, particularly for inhaled corticosteroids, has not been fully explored. Inhaled corticosteroids exert their anti-inflammatory activity locally in the airways, and hence this can be dissociated from their potential to cause systemic adverse effects. The molecular structural features that increase glucocorticoid receptor binding affinity and selectivity drive topical anti-inflammatory activity. However, in addition, these structural modifications also result in physicochemical and pharmacokinetic changes that can enhance targeting to the airways and reduce systemic exposure. As a consequence, potency and therapeutic index can be correlated. However, this consideration is not reflected in asthma treatment guidelines that classify inhaled corticosteroid formulations as low-, mid- and high dose, and imbed a simple dose equivalence approach where potency is not considered to affect the therapeutic index. This article describes the relationship between potency and therapeutic index, and concludes that higher potency can potentially improve the therapeutic index. Therefore, both efficacy and safety should be considered when classifying inhaled corticosteroid regimens in terms of dose equivalence. The historical approach to dose equivalence in asthma treatment guidelines is not appropriate for the wider range of molecules, potencies and device/formulations now available. A more robust method is needed that incorporates pharmacological principles.

Pharmacodynamic Studies to Demonstrate Bioequivalence of Oral Inhalation Products.

In the session on "Pharmacodynamic studies to demonstrate efficacy and safety", presentations were made on methods of evaluating airway deposition of inhaled corticosteroids and bronchodilators, and systemic exposure indirectly using pharmacodynamic study designs. For inhaled corticosteroids, limitations of measuring exhaled nitric oxide and airway responsiveness to adenosine for anti-inflammatory effects were identified, whilst measurement of 18-h area under the cortisol concentration-time curve was recommended for determining equivalent systemic exposure. For bronchodilators, methacholine challenge was recommended as the most sensitive method of determining the relative amount of ß-agonist or anti-muscarinic agent delivered to the airways. Whilst some agencies, such as the Food and Drug Administration (FDA), do not require measuring systemic effects when pharmacokinetic measurements are feasible, the European Medicines Agency requires measurement of heart rate and serum potassium, and some require serial electrocardiograms when bioequivalence is not established by pharmacokinetic (PK) studies. The Panel Discussion focused on whether PK would be the most sensitive marker of bioequivalence. Furthermore, there was much discussion about the FDA draft guidance for generic fluticasone propionate/salmeterol. The opinion was expressed that the study design is not capable of detecting a non-equivalent product and would require an unfeasibly large sample size.

Pharmacokinetics of fluticasone propionate and salmeterol delivered as a combination dry powder via a capsule-based inhaler and a multi-dose inhaler.

AIM: To compare salmeterol (SALM) and fluticasone propionate (FP) systemic exposure following inhaled salmeterol/fluticasone propionate combination (SFC) from a unit-dose capsule-based inhaler (Rotacaps(®)/Rotahaler(®)) and a multi-dose dry powder inhaler (Diskus(®)) in healthy volunteers. METHODS: An open-label, randomised, repeat-dose, cross-over, adaptive design study (n = 36 in each part) evaluated SFC 50/250 µg and SFC 50/100 µg in Rotacaps used with two types of Rotahaler inhalers (airflow resistance similar to (S) and lower than (L) Diskus) versus the Diskus. Primary endpoints were area under the concentration-time curve over the dosing interval [AUC0-τ] and maximum plasma concentration [Cmax]. RESULTS: SFC 50/250 µg Rotacaps/Rotahaler (S) showed 1.2-1.9-fold greater FP and SALM systemic exposure compared with Diskus. FP and SALM systemic exposure were comparable to DISKUS following SFC 50/250 µg Rotacaps/Rotahaler (L) (90% CI of ratio of Rotahaler to DISKUS within 0.8-1.25) for salmeterol (AUC0-τ and Cmax) and FP (AUC0-τ). Following SFC 50/100 µg Rotacaps/Rotahaler (L), FP and SALM systemic exposures were 1.2-1.4 fold higher in terms of FP (AUC0-τ and Cmax) and salmeterol (Cmax) compared with Diskus. SFC at both doses and via both inhalers was well tolerated. CONCLUSIONS: SFC 50/250 µg Rotacaps/Rotahaler (L) showed comparable systemic exposure to Diskus in terms of FP AUC and SALM AUC and Cmax. These results merit further progression of SFC 50/250 µg Rotacaps/Rotahaler (L) to phase 3 clinical evaluation in asthma and COPD patients. The lack of pharmacokinetic comparability between the inhalers for SFC 50/100 µg requires further evaluation.

Pharmacokinetics and pharmacodynamics of fluticasone propionate and salmeterol delivered as a combination dry powder from a capsule-based inhaler and a multidose inhaler in asthma and COPD patients.

BACKGROUND: The object of this study was to assess whether a capsule-based and multidose dry powder inhaler containing salmeterol (as xinafoate salt) 50 µg plus fluticasone propionate (FP) 250 µg [combination (SFC 50/250)] could be equivalent in terms of in vivo drug delivery and systemic exposure. METHODS: This was a randomized, double-blind, double-dummy, replicate treatment design comparative bioavailability study of SFC 50/250 delivered in a capsule-based inhaler (Rotahaler®) and a multidose dry powder inhaler (Diskus®). Subjects with asthma or chronic obstructive pulmonary (COPD) disease (n=60) were randomized to receive twice-daily SFC 50/250 via a Rotahaler and via Diskus each for two 10-day treatment periods (GlaxoSmithKline Protocol ASR114334). RESULTS: For FP and salmeterol, the in vitro aerodynamic particle size profiles were within±15% of Diskus for the fine particle mass (FPM) and emitted dose (ED) using the Andersen Cascade Impactor, and ED, mass median aerodynamic diameter, and geometric standard deviation using the New Generation Impactor (NGI). This was also the case for FP but not salmeterol for FPM and fine particle dose using the NGI. For the combined asthma and COPD subjects, the plasma AUC and Cmax for FP and salmeterol were higher for Rotahaler:Rotahaler/Diskus geometric mean ratios (90% confidence intervals) for FP AUC0-τ of 1.52 (1.37-1.67) and Cmax of 1.94 (1.75-2.10) and salmeterol AUC0-τ of 1.15 (1.09-1.21) and Cmax of 1.56 (1.42-1.67). Corresponding values for the primary pharmacodynamic endpoint, weighted mean (0-12 hr) serum cortisol, were 0.928 (0.886-0.971). Inhaled FP/salmeterol via both inhalers was well-tolerated. One serious adverse event, considered possibly related to study medication, resulted in subject withdrawal from the study. CONCLUSIONS: The in vitro tests and systemic pharmacodynamic endpoints revealed no major differences between the two inhalers, but lacked predictive power and sensitivity to guide in vivo drug delivery performance and systemic exposure. Based on pharmacokinetic endpoints, the inhalers were not considered bioequivalent in terms of systemic exposure. Further studies to refine the Rotahaler performance are ongoing.

Establishing bioequivalence for inhaled drugs; weighing the evidence.

INTRODUCTION: During drug development and product life-cycle management, it may be necessary to establish bioequivalence between two pharmaceutical products. Methodologies to determine bioequivalence are well established for oral, systemically acting formulations. However, for inhaled drugs, there is currently no universally adopted methodology, and regulatory guidance in this area has been subject to debate. AREAS COVERED: This paper covers the current status of regulatory guidance on establishing the bioequivalence of topically acting, orally inhaled drugs, the value and limitations of in vitro and in vivo bioequivalence testing, and the practical issues associated with various approaches. The reader will gain an understanding of the issues pertaining to bioequivalence testing of orally inhaled drugs, and the current status of regulatory approaches to establishing bioequivalence in different regions. EXPERT OPINION: Establishing bioequivalence of inhaled drug products involves a multistep process; however, methodologies for each step have yet to be fully validated. Our lack of understanding about the relationship between in vitro, in vivo and clinical data suggests that in most cases, unless there is a high degree of pharmaceutical equivalence between the test and reference products, consideration of a combination of preclinical and clinical data may be preferable to abridged approaches relying on in vitro data alone.

Pharmacokinetic, pharmacodynamic, efficacy, and safety data from two randomized, double-blind studies in patients with asthma and an in vitro study comparing two dry-powder inhalers delivering a combination of salmeterol 50 microg and fluticasone propionate 250 microg: implications for establishing bioequivalence of inhaled products.

BACKGROUND: The use of dry-powder inhalers (DPIs) to administer respiratory medicines is increasing, and new DPIs are likely to be developed because of expiring patents. However, there is considerable debate concerning the extent to which DPIs are interchangeable without altering disease control or the safety profile of the treatment. OBJECTIVE: This study was designed to compare the pharmacokinetic (PK), pharmacodynamic (PD), efficacy, and safety data for 2 DPIs delivering a combination of salmeterol 50 microg plus fluticasone propionate (FP) 250 microg (SFC 50/250) to investigate assumptions of bioequivalence. METHODS: Three studies compared SFC 50/250 delivery using a reservoir powder inhalation device (RPID) and a Diskus multiple-dose inhaler: an in vitro assessment of fine-particle-mass (FPM) profiles of the emitted doses; a PK/PD study of SFC 50/250 administered in two 14-day crossover treatment periods to 22 adults with moderate, persistent asthma to determine the equivalence of the RPID and Diskus inhaler in terms of drug delivery and systemic exposure; and a 12-week clinical efficacy and safety study of SFC 50/250 in 270 patients > or =12 years of age with moderate, persistent asthma to assess the equivalence of the RPID and Diskus inhaler based on peak expiratory flow (PEF) rates. FPM was summed from the quantity of active pharmaceutical ingredient deposited on stages 1 to 5 of a cascade impactor, representing an aerodynamic particle size range of 0.8 to 6.2 microm. Systemic exposure to SFC 50/250 was declared no greater with RPID than with the Diskus inhaler if the upper limit of the 90% CI for the ratio of FP AUC for the 2 devices was below the upper limit of the equivalence range (ie, <1.25). Adverse events, clinical laboratory test results, and vital signs were recorded throughout the 2 clinical studies. RESULTS: In vitro, mean FPM values for the RPID and Diskus inhaler, respectively, were 13.1 and 12.8 microg/dose for salmeterol (P = NS) and 66.8 and 66.2 microg/dose for FP (P = NS). The only notable differences were mean FP for particle sizes 2.3 to 3.2 microm (21.4 microg/dose for RPID, 25.6 microg/dose for Diskus) and for sizes 4.0 to 6.2 microm (17.3 microg/dose for RPID, 11.7 microg/dose for Diskus). In the PK/PD study, there were 22 patients (16 men and 6 women), most (86%) of whom were white. Mean (SD) age was 26.0 (5.0) years (range, 19-35 years), and mean (SD) weight was 67.3 (8.9) kg. The 2 inhalers did not meet the criteria for declaring bioequivalence: estimated ratios (RPID:Diskus) were 2.00 (90% CI, 1.56 to 2.55) for FP AUC up to the time point of next dosing and 1.92 (90% CI, 1.64 to 2.25) for salmeterol maximum observed plasma concentration at the end of the dosing interval (at steady state). Urine cortisol (0-24 hours) was significantly lower for the RPID than for the Diskus inhaler (ratio, 0.74 [95% CI, 0.57 to 0.96]; P = 0.026); no significant difference in plasma cortisol was noted between the 2 inhalers (ratio, 0.85 [95% CI, 0.7 to 1.04]). A small but statistically significant increase in maximum heart rate (5 beats/min) was noted in the RPID group (ratio, 1.05 [95% CI, 1.01 to 1.10]; P = 0.029). No notable differences in other PD end points were observed. Drug-related adverse events occurred in both groups (2 [dysphagia and tremor] in the RPID group and 3 [2 cases of dysphonia, 1 case of mucous-membrane irritation] in the Diskus group). There were 270 patients (136 females, 134 males) in the clinical efficacy and safety study, most (94%) of whom were white; mean (SD) age was 37.2 (17.0) years (range, 11-77 years) in the RPID group and 35.4 (17.2) years (range, 12-77 years) in the Diskus group. The RPID and the Diskus inhaler met the predefined equivalence criteria (+/-15 L/min) in terms of mean change in morning PEF from baseline: 3.9 L/min (95% CI, -3.1 to 11.0). The 2 SFC 50/250 inhalers were well tolerated; the most frequently reported adverse event was bronchitis, reported by 12% of the patients in the RPID group and 9% of those in the Diskus group. The only serious adverse event, which occurred in the RPID group and was related to bronchial infection, was considered unrelated to treatment. CONCLUSIONS: In vitro particle size distribution data were potentially superimposable for the RPID and the Diskus inhaler. The 2 devices were considered to be clinically equivalent in terms of mean morning PEF but were not considered equivalent in terms of PK systemic exposure. The 2 SFC 50/250 inhalers were well tolerated and had comparable safety profiles; no serious adverse events were attributed to the study product.

Relationship between systemic corticosteroid exposure and growth velocity: development and validation of a pharmacokinetic/pharmacodynamic model.

BACKGROUND: Use of high-dose oral corticosteroids (CSs) can reduce growth velocity (GV) in children, whereas use of low-dose topical CSs has either no effect or transient effects on short-term growth and no effect on final adult height Despite the large body of literature on this topic, some fundamental questions remain concerning the relationship between CS exposure and growth effects. OBJECTIVES: The aims of this study were to determine the relationship between CS exposure and GV in children receiving CS therapy for asthma or rhinitis, and to examine whether there is likely to be a link between GV and cortisol suppression. METHODS: Data from 32 published studies of the effect on growth of inhaled, intranasal, and oral CSs, including delivery by dry powder inhaler, metered-dose inhaler, and aqueous nasal spray, were consolidated by expressing CS exposure in cortisol equivalents using a physiologically based pharmacokinetic/pharmacodynamic approach. The relationship between change in GV and CS exposure in cortisol equivalents was described using a nonlinear sigmoid maximum-effect (E(max)) model with the following parameters: E(max) = -5.9 cm/y; steady-state unbound AUC for 50% reduction in GV, in cortisol equivalents = 20,000 ng.h/L; Hill constant = 1.2; and change in GV at zero systemic exposure = 0.06 cm/y. Validation was achieved by comparing the model's predictions with data from 5 studies that were not included in the model development The model was also used to predict the potential of various CS regimens to reduce GV. RESULTS: Exploratory data analysis established that change in GV was highly correlated with exposure in cortisol equivalents (P < 0.001). CSs with high systemic bioavailability by the intranasal route were predicted to have short-term growth effects exceeding the clinical equivalence limit for change in GV (+/-0.8 cm/y), whereas those with lower bioavailability were predicted to produce systemic exposures below the threshold for significant effects on GV The findings were similar for inhaled CSs and for regimens combining delivery by the intranasal and inhaled routes. In descending order, the model predicted the following ranking of the potential of the various intranasal, inhaled, and oral regimens to reduce GV, expressed as fractions or multiples of the pediatric dose (in microg/d): oral prednisolone 5000 microg/d, 0.14; inhaled beclomethasone dipropionate metered-dose inhaler 400 microg/d, 0.54; inhaled budesonide dry powder inhaler 400 microg/d, 0.66; intranasal triamcinolone acetonide aqueous nasal spray 220 microg/d, 0.74; inhaled triamcinolone acetonide metered-dose inhaler 400 microg/d, 0.75; intranasal beclomethasone dipropionate aqueous nasal spray 336 pg/d, 0.89; inhaled mometasone furoate dry powder inhaler 200 microg/d, 2.4; intranasal budesonide aqueous nasal spray 128 microg/d, 2.5; inhaled fluticasone propionate dry powder inhaler 200 microg/d, 2.6; intranasal mometasone furoate aqueous nasal spray 100 microg/d, 120; and intranasal fluticasone propionate aqueous nasal spray 100 pg/d, 150. Values >1 are predictive of no significant effect on GV. The model predicted that a 10% to 15% reduction in plasma cortisol concentration should be detectable at the lower equivalence limit for growth reduction (-0.8 cm/y). The validation procedure showed that the model was capable of predicting the results of the 5 comparative growth studies not included in model development with a correlation coefficient of 0.98. CONCLUSIONS: Growth effects appear to be nonlinearly related to CS exposure; therefore, no-effect exposure should be possible for CSs with low systemic exposure. Growth inhibition appears unlikely to occur in the absence of detectable reductions in cortisol concentrations.

Hypothalamic-pituitary-adrenal axis function after inhaled corticosteroids: unreliability of urinary free cortisol estimation.

Free cortisol in the urine (UFC) is frequently measured in clinical research to assess whether inhaled corticosteroids (ICS) cause suppression of the hypothalamic-pituitary-adrenal axis. Thirteen healthy male subjects received single inhaled doses (of molar equivalence) of fluticasone propionate (FP), triamcinolone acetonide (TAA), budesonide (BUD), and placebo in this single blind, randomized, cross-over study. UFC output was measured using four commercial immunoassays in samples collected in 12-h aliquots over 24 h. The cortisol production rate was assessed from the outputs of cortisol metabolites. UFC showed a 100% increase over placebo levels in the Abbott TDX assay after the administration of BUD. The other assays detected variable suppression (ranging from 29-61% suppression for FP, 30-62% suppression for TAA, and 25% suppression to 100% stimulation for BUD). Suppression was more pronounced in the first 12 h after TAA and in the second 12 h after FP. Similar suppression was found in each 12-h period after BUD. UFC estimation based on immunoassays after ICS may be an unreliable surrogate marker of adrenal suppression. Many of the published studies describing or comparing the safety of different ICS should be reevaluated, and some should be interpreted with caution.

Bioavailability and metabolism of mometasone furoate: pharmacology versus methodology.

The degree of systemic exposure ofter inhalation of corticosteroids is of great clinical concern. For optimum outcome, the pulmonary deposition should be sufficiently high to produce the desired anti-inflammatory effect in the lungs, whereas the plasma concentrations due to the absorption of the corticosteroid from the lung and the gut should be minimal. Recently, it has been reported that inhaled mometasone furoate has a systemic bioavailability of less than 1%, which is much lower than other corticosteroids currently available. However, critical evaluation of the study methodology and results does not support this finding. A major shortfall of the study was an insufficient analytical sensitivity, resulting in a calculated average plasma concentration profile that was entirely below the limit of quantification. These numbers were generated by replacing all concentrations below the limit of quantification byzero and then calculating an average value. This procedure can lead to erroneous results and misinterpretation. Furthermore, the potential contribution of active metabolites needs to be adequately addressed in comparisons of inhaled corticosteroids. Reliable estimates of systemic drug exposure are critical in evaluating the real safety profiles and therapeutic index for inhaled corticosteroids that are effective in treating chronic asthma.