H. Derendorf, PhD Department of Pharmaceutics University of Florida PO Box 100494 Gainesville FL 32610-0494 USA
Intranasal corticosteroids (INSs) are effective treatments for allergic rhinitis, rhinosinusitis, and nasal polyposis. In recent years, increased understanding of corticosteroid and glucocorticoid receptor pharmacology has enabled the development of molecules designed specifically to achieve potent, localized activity with minimal risk of systemic exposure. Pharmacologic potency studies using affinity and other assessments have produced similar rank orders of potency, with the most potent being mometasone furoate, fluticasone propionate, and its modification, fluticasone furoate. The furoate and propionate ester side chains render these agents highly lipophilic, which may facilitate their absorption through nasal mucosa and uptake across phospholipid cell membranes. These compounds demonstrate negligible systemic absorption. Systemic absorption rates are higher among the older corticosteroids (flunisolide, beclomethasone dipropionate, triamcinolone acetonide, and budesonide), which have bioavailabilities in the range of 34–49%. Studies, including 1-year studies with mometasone furoate, fluticasone propionate, and budesonide that evaluated potential systemic effects of INSs in children have generally found no adverse effects on hypothalamic–pituitary–adrenal axis function or growth. Clinical data suggest no significant differences in efficacy between the INSs. Theoretically, newer agents with lower systemic availability may be preferable, and may come closer to the pharmacokinetic/pharmacologic criteria for the ideal therapeutic choice.
Intranasal corticosteroids (INSs) are the most effective treatments available for allergic rhinitis (AR). They have been shown to be superior to oral H1 receptor antagonists for AR (1) and have been designated as the treatment of choice for this condition (2–4). The development of INSs is one of the best examples of molecular modification of drug structure and delivery to achieve an almost ideal therapeutic index.
Systemic corticosteroids, which were developed in the 1950s, are effective in treating AR, but the high risk of serious toxicity with long-term administration has hindered their usefulness (5). Initial attempts to deliver compounds such as hydrocortisone and dexamethasone directly into the airways were only partially successful (6). The first successful use of beclomethasone as a pressurized aerosol with no apparent evidence of systemic toxicity was published in 1972 (6). In the years since, corticosteroid molecules have been refined to create more potent agents with lower bioavailability and enhanced safety profiles. Currently, eight INS compounds are approved for the management of AR in the United States: triamcinolone acetonide, flunisolide, budesonide, beclomethasone dipropionate, ciclesonide, fluticasone propionate, mometasone furoate, and fluticasone furoate. The furoate moiety in the later compound is the same as that found in the mometasone furoate molecule, i.e. fluticasone furoate is fluticasone propionate with the furoate ester of mometasone furoate. Ciclesonide is essentially a prodrug, requiring conversion by esterases to an active metabolite, desisobutyryl-ciclesonide (des-ciclesonide) at the site of desired action (e.g. lung/nasal tissue). Subsequent intracellular esterification of des-ciclesonide with endogenous fatty acids produces reversible lipid conjugates of des-ciclesonide that become a reservoir of the drug in the lung or nasal mucosa (7, 8).
Each corticosteroid has characteristics that determine its pharmacokinetic profile and pharmacodynamic activity. This article will provide an overview of corticosteroid pharmacology in the allergic inflammatory process, review the characteristics of individual compounds, and evaluate these differences from a clinical perspective.
The allergic inflammatory process
Allergic rhinitis stems from localized type I hypersensitivity reactions in atopic individuals, who have IgE antibodies that bind to mast cell receptor sites. When crossbound by allergen, degranulation and release of inflammatory mediators occurs (Fig. 1). These mediators act quickly on nasal end-organs to elicit the well-known symptoms of sneezing, congestion, rhinorrhea, and pruritus. This acute phase of the allergic reaction develops within minutes of allergen exposure and is caused primarily by histamine and arachidonic acid metabolites (leukotrienes, prostaglandins, and thromboxanes) (9, 10).
The late-phase allergic reaction, which occurs within 6–12 h of allergen exposure, is characterized by an influx of monocytes, T lymphocytes, basophils, and eosinophils to the nasal mucosa. In fact, the presence of infiltrating eosinophils in the nasal mucosa is considered an important indicator of an allergic basis for the rhinitis. The release of toxic proteins (such as major basic protein and eosinophilic cationic protein) from eosinophils and soluble mediators from these recruited cells (primarily interleukins, tumor necrosis factor alpha, interferon-γ), along with continued release of leukotrienes from eosinophils and mast cells, facilitates the prolongation of symptoms (9, 10).
Intranasal corticosteroids downregulate the recruitment and influx of inflammatory cells, and inhibit the secretion of pro-inflammatory mediators during the late phase of the inflammatory response (9). This process is evidenced by reduced levels of histamine, leukotrienes, and mast cells recovered in the nasal fluid and mucosa of AR patients treated with INSs (9, 11–13).
The glucocorticoid receptor
Corticosteroid activity is mediated by intracellular activation of the glucocorticoid receptor (GR) (14, 15). In its inactive state, the GR exists as a cytosolic protein bound to two heat shock protein 90 chaperonin molecules. Binding to the corticosteroid ligand results in a conformational change that allows dissociation of the GR from the protein complex, and a quick translocation into the cell nucleus. The ligand-bound GR can modulate gene expression in the nucleus by binding to glucocorticoid response elements in promoter regions of responsive genes. The GR binds to the glucocorticoid response elements as a homodimer and acts as a transcription factor. It has recently become evident that the GR can also regulate gene expression unfacilitated by glucocorticoid response elements through direct interaction with transcription factors such as nuclear factor-κB and activating protein (14, 16, 17). The inhibition of these two factors leads to downregulation of the production of cytokines and other inflammatory molecules and is thought to be among the primary mechanisms for the anti-inflammatory effects of corticosteroids (14, 15).
Corticosteroid structure-activity relationships
Corticosteroid molecules are derived from the parent molecule, cortisol (10). The carbon framework of each corticosteroid is made up of three 6-carbon rings (rings A, B, and C) and one 5-carbon ring (ring D) (Fig. 2). All anti-inflammatory corticosteroids have features in common with cortisol and with each other: a ketone oxygen at position 3; an unsaturated bond between carbons 4 and 5; a hydroxyl group at position 11; and a ketone oxygen group on carbon 20. The variations occurring off ring D at positions 16, 17, and 21 are the greatest differentiating factors between the individual molecules. Structure–activity relationship studies of this region led to the identification of chemical groups that enhance topical activity and reduce systemic adverse events (5). For example, the furoate group of mometasone furoate was found to enhance molecular affinity for the GR binding site.
Other modifications have improved the activity of corticosteroid compounds. The 21-chloro-17(2′-furoate) group on the mometasone furoate structure improves anti-inflammatory activity, while the chloride at position 21 provides the additional benefit of inferring resistance to degradation by esterases (5). Halogen substitutions at positions 6 and 9 are thought to increase potency, as are side-chain substitutions at position 17 (18).
Pharmacodynamic properties of intranasal corticosteroids
Glucocorticoid potency can be measured in various ways, but is thought to be closely related to GR binding affinity. Fig. 3 illustrates the relative GR binding affinities for most intranasal compounds, as well as fluticasone furoate and des-ciclesonide, which is the active metabolite of the prodrug ciclesonide (19). The Valotis study was based on kinetic methods and was performed on cytosolic GR extracts from pooled human lung tissue. Receptor association and dissociation rate constants were determined, and relative receptor affinities calculated based on the equilibrium dissociation rate constants. The highest relative receptor affinities were associated with some of the newest compounds, fluticasone furoate, mometasone furoate, and fluticasone propionate, reflecting the improved understanding of the GR complex that has led to the design of more potent corticosteroid molecules in recent years.
Relative receptor affinity studies are highly dependent on assay methodology and prone to error (20). Although specific values vary between studies, most have shown a similar order of potency. An earlier study of INSs that used competition assay methodology reported a similar rank order of relative binding potency: mometasone furoate > fluticasone propionate > budesonide > triamcinolone acetonide > dexamethasone (15). Studies conducted before the development of mometasone furoate consistently described the same relative binding affinity order (15, 21–24); the binding affinity of des-ciclesonide (the active metabolite of the prodrug ciclesonide) is slightly less than that of fluticasone propionate (7, 19).
Corticosteroid potency also has been evaluated using the McKenzie assay, which compares the relative cutaneous vasoconstrictor and skin blanching responses of individual compounds (25). Using this methodology, the rank order of potency was: fluticasone propionate > mometasone furoate > budesonide > flunisolide > triamcinolone acetonide (26).
Results of studies using another marker of corticosteroid potency, transactivation potency, correlate with receptor binding affinity results. One study found mometasone furoate the most potent GR ligand, requiring the lowest concentration to affect 50% of the maximum level of transcription activation of a glucocorticoid response element reporter gene in cells (15). Overall rank of potency using this methodology was: mometasone furoate > fluticasone propionate > triamcinolone acetonide > budesonide > dexamethasone.
There is no evidence of a linear association between glucocorticoid potency and clinical response, nor is there a known ‘plateau’ beyond which greater potency does not add additional benefit. Likewise, it is not evident that the compound with the highest receptor affinity will have superior clinical efficacy. Although increased potency at intranasal sites would seem desirable, the possibility of greater potency at other sites could theoretically increase the risk of systemic adverse effects, as GRs are similar throughout the body.
The pharmacokinetic properties of an INS determine the concentration and disposition of drug at the receptor site, as well as the potential for the drug to reach the systemic circulation. Because the goals of INS therapy are to deposit drug at the site of action, have it remain there as long as possible, and limit the amount that leaves the site and enters the systemic circulation, the pharmacokinetic features of particular interest are lipophilicity and systemic availability.
The lipophilicity of a corticosteroid, as expressed in its log P (log of the octanol/water portion coefficient), provides an index of its lipid-partitioning potential (27). The more highly lipophilic compounds are absorbed more quickly and thoroughly by the nasal mucosa and retained longer in nasal tissue, increasing exposure to the GR (27). The addition of lipophilic side chain groups to a corticosteroid molecule facilitates its uptake across phospholipid cell membranes to the cytoplasmic interior, where it can interface with GRs (28). Lipophilicity also contributes to increased plasma protein binding. In this sense, lipophilicity is a desired characteristic. In the event of systemic absorption, lipophilicity may contribute to the accumulation of drug in other tissues, possibly contributing to unwanted side effects. Thus, the ideal combination of features would include a high degree of lipophilicity coupled with low systemic absorption and rapid clearance.
The order of lipid solubility for corticosteroids has been reported as: mometasone furoate > fluticasone propionate > beclomethasone dipropionate > budesonide > triamcinolone acetonide > flunisolide (27). Ciclesonide and des-ciclesonide have greater lipophilicity than fluticasone propionate (28). The furoate (mometasone) and propionate (fluticasone) ester side chains are pharmacologically similar moieties that contribute greatly to the lipophilicity of their associated compounds (29). The lipophilicity of fluticasone propionate has been reported as three times higher than beclomethasone dipropionate, 300 times more than budesonide, and at least 1000-fold greater than flunisolide or triamcinolone acetonide (26). Lipophilicity is an important determinant of drug solubility. Only dissolved corticosteroid can cross the membrane and be absorbed systemically. Any solid undissolved compound may be removed from the absorption site by mechanical physiological clearing mechanisms before the steroid can cross the membrane and become bioavailable.
In addition to degree of lipophilicity, systemic exposure of an INS is also dependent on oral and local bioavailability and hepatic first-pass effect. Following intranasal administration, a drug can enter the systemic circulation through direct local absorption in the nasal mucosa or oral absorption of swallowed material. As illustrated in Fig. 4, a large proportion of intranasally administered drug is quickly cleared from the nose into the throat and swallowed, becoming available for absorption from the gastrointestinal tract. A high rate of first-pass metabolism will inactivate the absorbed drug, but direct absorption into the systemic circulation through the nasal tissues bypasses the protective hepatic first-pass mechanism. Therefore, careful attention needs to be paid to the potential for direct systemic drug exposure of potent corticosteroid agents (30).
Systemic absorption rates are highest among the relatively older compounds, flunisolide, beclomethasone, and budesonide (Fig. 5). One-third to half of an intranasally administered dose of the older agents may reach the systemic circulation. For budesonide, systemic exposure is primarily due to absorption through the nasal mucosa (31, 32). The newer compounds—fluticasone propionate and mometasone furoate—are more lipophilic (5) and undergo rapid and extensive first-pass metabolism following oral administration, contributing to their negligible systemic absorption (29). While published data on fluticasone furoate are still sparse, in vitro data presented as a poster at the Congress of the European Academy of Allergology and Clinical Immunology in 2006 reported very high tissue binding affinity to human nasal tissue and, hence, low systemic absorption (19). A pharmacokinetic study of ciclesonide in both healthy subjects and patients with seasonal AR (SAR) found serum levels of ciclesonide and the active metabolite des-ciclesonide were below the lower limits of quantification (25 and 10 pg/ml, respectively) in the majority of subjects (33). The systemic bioavailability of des-ciclesonide following oral administration of ciclesonide was <1% (34).
While detecting the physical presence of corticosteroid molecules in blood samples is a relatively straightforward task, identifying potential physiologic consequences of their absorption is more difficult and necessitates the use of highly sensitive tests (35). One of the most sensitive measures of systemic corticosteroid bioactivity is suppression of endogenous cortisol secretion from the adrenal cortex. These determinations measure basal adrenocorticoid secretion (morning plasma cortisol, 24-h urinary-free cortisol, or overnight urinary cortisol) or dynamic function of the hypothalamic–pituitary–adrenal (HPA) axis to determine adrenal reserve (ACTH cosyntropin stimulation or corticotropin releasing factor test) (35, 36). Adrenocorticoid secretion is subject to a normal circadian rhythm, with highest plasma levels occurring between 5 and 9 am. ‘Spot’ sampling of early morning plasma cortisol, often used in clinical trials, can introduce an unacceptable degree of inter- and intrasubject variability (36). A more sensitive assessment of basal adrenocortical function involves overnight or 24-h evaluations of cortisol output via urine or plasma sampling (37). Urinary cortisol measurements are often corrected for creatinine excretion and expressed in terms of urinary : creatinine ratio (35).
Clinical trials evaluating the effects of INSs on HPA axis function and growth parameters in children have generally found that INSs do not affect growth. In one exception, mean urine cortisol : creatinine ratio was significantly lower during treatment with fluticasone propionate 200 μg/day than with triamcinolone acetonide 110 or 220 μg/day or placebo (38). Aside from this report, the use of INSs at recommended doses does not appear to have a significant effect on the HPA axis (36). The effects of these agents on bone growth and height have been evaluated in numerous studies, with knemometry considered the most reliable and sensitive indicator (38). One of the earliest studies (1993) reported slower lower leg growth velocity among 11 children receiving high-dose intranasal budesonide for 6 weeks compared with a pre-treatment run-in period (39). Other studies with budesonide, mometasone furoate, and fluticasone propionate utilizing knemometry have not demonstrated significant changes in lower leg growth velocity (38, 40, 41). Among studies based upon stadiometry measurements, only one reported a smaller mean increase in height among children treated with high-dose intranasal beclomethasone for 1 year compared with placebo (42). One-year studies involving mometasone furoate, fluticasone propionate, budesonide, and ciclesonide did not report any significant negative effects on height (43–46). A 12-month double-blind study of ciclesonide in children found no significant difference in standing height between treated children and those using placebo (46).
Onset of action
It was traditionally accepted that INSs should be used for days or weeks to achieve significant benefits, and because these agents were used primarily to control chronic symptoms, few studies focused on onset of action (27). Symptom improvement has been noted within 1–2 days following administration of most newer agents (27). A clinical study of ciclesonide nasal spray in patients with SAR reported a significantly greater effect of treatment on total nasal symptom scores compared with placebo as early as hour 12 (47). In subjects with SAR, mometasone furoate nasal spray significantly improved nasal symptom scores compared with placebo in as little as 7 h after a single 200 μg dose and total symptom scores as soon as 5 h (48). It is not uncommon for patients to use intranasal medications intermittently on an ‘as-needed’ basis (27), and such use may be justified given the potential for a more rapid onset of action than was previously ascribed to these medications.
Clinical efficacy and safety
The design of topically active INS formulations has provided a much better therapeutic ratio than oral corticosteroids (35). The pharmacodynamic and pharmacokinetic properties of these agents play an important role in facilitating local anti-inflammatory activity with a low rate of side effects. However, it remains to be seen whether the often subtle pharmacodynamic and pharmacokinetic differences between the compounds distinguish them in a clinical setting. Table 1 lists the INSs and their approved indications for AR in the United States.
*Available in two strengths: 32 and 64 μg per spray.
Beclomethasone dipropionate (Beconase AQ)
Adults and children > 12 years of age: 1 or 2 sprays (42–84 μg) per nostril b.i.d. (total dose 168–336 μg/day) Children 6–12 years: 1 spray (42 μg) per nostril b.i.d. for total of 168 μg/day up to 2 sprays per nostril b.i.d. for total of 336 μg/day
Budesonide (Rhinocort Aqua)*
Adults and children ≥ 6 years of age: 1 spray (32 μg/spray) per nostril q.i.d. up to a maximum of 256 μg/day (≥ 12 years of age) or 128 μg/day (6 to < 12 years of age)
Adults and children ≥ 12 years of age: 2 sprays (50 μg/spray) per nostril q.i.d.
Adults: 2 sprays (58 μg) per nostril b.i.d., not to exceed 8 sprays per nostril per day (464 μg) Children 6–14 years of age: 1 spray (29 μg) per nostril t.i.d. or 2 sprays (58 μg) per nostril b.i.d., not to exceed 4 sprays per nostril per day (232 μg)
Fluticasone furoate (Veramyst)
Adults and children≥12 years of age: 2 sprays (55 μg) per nostril q.i.d. Children 2–11 years of age: 1 spray (27.5 μg) per nostril q.i.d. up to 2 sprays (55 μg) per nostril q.i.d.
Fluticasone propionate (Flonase)
Adults: 2 sprays (100 μg) per nostril q.i.d. or 1 spray (50 μg) b.i.d. Adolescents and children≥4 years of age: 1 spray (50 μg) per nostril per day up to, but not in excess of, 2 sprays (100 μg) per nostril per day
Mometasone furoate (Nasonex)
Adults and children ≥ 12 years of age: 2 sprays (100 μg) per nostril q.i.d. Children 2–11 years of age: 1 spray (50 μg) per nostril q.i.d.
Triamcinolone acetonide (Nasacort AQ)
Adults and children ≥ 12 years of age: 2 sprays (110 μg) per nostril q.i.d. Children 6–12 years of age: 1 spray (55 μg) per nostril or 110 μg q.i.d., up to 2 sprays (110 μg each) per nostril or 220 μg q.i.d.
Based on currently available data, there is no clear evidence that any INS is superior to any other for AR symptom relief (27, 49), despite the pharmacologic differences between many of them. It is possible that the degree of anti-inflammatory activity required for AR symptom relief is low enough that relief is easily achieved by agents of varying potencies, or that GR saturation or near saturation occurs with all of the preparations (27, 50).
Differences in safety between INSs are more theoretical than evidence-based, with the greatest concern being systemic exposure and effects on adrenal function and growth in children. Pharmacokinetic studies confirm that the newer agents – mometasone furoate, fluticasone propionate, fluticasone furoate, and ciclesonide – exhibit negligible systemic absorption and would be expected to pose fewer risks. It could also be argued that their dramatically greater potency could pose safety risks, even if they were absorbed to only a small degree. To date, these concerns have not been realized. Special caution is warranted in treating individuals who may be using concomitant corticosteroid therapy for other medical conditions, such as asthma. The safety of overlapping corticosteroid therapy has not been well studied, but combined treatments may be a concern because of the worsening of total systemic corticosteroid load. A recent open-label study with intranasal mometasone furoate did not identify any increased incidence of adverse events when the agent was coadministered with treatments (the antihistamines desloratadine and levocetirizine and the corticosteroid betamethasone) for asthma, chronic rhinosinusitis, and nasal polyposis (51).
Common local side effects of INSs include dryness, stinging, burning, and epistaxis, the frequencies of which are similar in the various compounds. Nasal mucosal atrophy is a concern with chronic topical steroid use. A long-term study with mometasone furoate found no evidence of atrophy or metaplasia following 12 months of intranasal use (13). Similar studies with fluticasone propionate did not identify indications of atrophy and noted only a nonsignificant increase in metaplasia in one patient (52).
Lipid conjugation, or fatty acid esterification, is a process through which a corticosteroid molecule forms a reversible chemical bond with fatty acids in the nasal tissues. These drug-lipid complexes serve as a slow-release drug reservoir that holds the corticosteroid within the target area, increasing the local residence time. As the binding process is reversible, the retained corticosteroid remains available for binding to local GRs. This binding process may be partly responsible for the once-daily efficacy of many INSs. Lipid conjugation has been reported for budesonide (53) and des-ciclesonide (54).
Binding to proteins such as albumin and other biological material can occur at the local site of action, and also in general circulation if a corticosteroid is systemically absorbed. Most INSs have a high degree of protein binding, ranging from 71% (triamcinolone acetonide) to 99% (ciclesonide, des-ciclesonide). Only free drug is pharmacologically active, therefore a high degree of serum protein binding for these compounds is desirable to limit potential systemic adverse events (55). The measurement of binding at the local site of action is very difficult, and assessment of therapeutic efficacy is the best way to ensure that sufficient unbound drug is available at the site of action.
An increasing body of scientific knowledge continues to accumulate about corticosteroids and their effects on the GR and cellular transcription processes. Despite this information, clinical distinctions between the individual compounds are not readily apparent. As a class, the INSs demonstrate comparable efficacy in treating AR conditions. It could be argued that the newer agents, fluticasone propionate, mometasone furoate, ciclesonide, and fluticasone furoate, come remarkably close to the pharmacokinetic/pharmacodynamic criteria for the ideal INS because they have: 1) a high degree of GR affinity, potency, and specificity; 2) low systemic availability; 3) high rate of hepatic first-pass clearance and rapid systemic elimination; and 4) once-daily dosing. Even so, there continues to be a scientific pursuit of even more pharmacologically fine-tuned molecules. Whether such endeavors will produce new compounds with significantly distinguishing characteristics remains to be seen.
Research for this article was funded through a grant from Schering-Plough Corporation. Neither author received any payment for this article.
Dr Derendorf reports being a consultant (ad hoc) for Altana, GlaxoSmithKline, Sanofi-Aventis, and Schering-Plough.
Dr Meltzer reports receiving grant/research support from Alcon, Allux, Altana, AstraZeneca, Capnia, Clay-Park, Critical Therapeutics, Genentech, GlaxoSmithKline, Hoffmann-LaRoche, KOS, Medicinova, MedPointe, Merck, Novartis, Pharmaxis, Rigel, Sanofi-Aventis, Schering-Plough, Teva, and Wyeth; being a consultant for Abbott, Adelphi, Alcon, Allux, Altana, Amgen, AstraZeneca, Capnia, Critical Therapeutics, Dey, Evolutec, Genentech, GlaxoSmithKline, Greer, Inspire, KOS, MedPointe, Merck, Novartis, Pfizer, Rigel, Sanofi-Aventis, Schering-Plough, Shionogi, Verus, and Wyeth; and being a speaker for AstraZeneca, Alcon, Altana, Genentech, Genesis, GlaxoSmithKline, MedPointe, Merck, Pfizer, Sanofi-Aventis, Schering-Plough, and Verus.
Editorial assistance was provided by Adelphi Eden Health Communications.