The Proceedings of the American Thoracic Society 1:352-355 (2004)
© 2004 The American Thoracic Society
Designing Corticosteroid Drugs for Pulmonary Selectivity
Keith Biggadike,
Iain Uings and
Stuart N. Farrow
Respiratory and Inflammation Center of Excellence for Drug Discovery, GlaxoSmithKline, Stevenage, United Kingdom
Correspondence and requests for reprints should be addressed to Stuart N. Farrow, B.Sc., Ph.D., GSK, Gunnels Wood Road, Stevenage SG1 2NY, UK. E-mail stuart.n.farrow{at}gsk.com
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ABSTRACT
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Inhaled corticosteroids have become indispensable for the treatment of asthma and chronic obstructive pulmonary disease. Significant progress has been made toward minimizing side effects through the use of increasingly selective molecules, and through a variety of lung targeting strategies. Many of these developments have occurred in advance of a greatly improved understanding of corticosteroid biology at the molecular and pharmacologic level, and it has become clear that additional opportunities exist for the further enhancement of therapeutic index. This article discusses significant recent developments in the chemistry, biology, and pharmacology of corticosteroids, and considers the implications for the future use of inhaled corticosteroids.
Key Words: corticosteroid • asthma • antedrug • inhalation
Corticosteroids regulate a number of physiologic processes, including development, stress responses, and homeostasis, and also have a significant interaction with the immune system (1). These activities have important therapeutic consequences, and today corticosteroids are indispensable for the treatment of a wide variety of inflammatory diseases. A range of adverse effects, including osteoporosis and suppression of the hypothalamic-pituitary-adrenocortical axis, limits their systemic use; however, inhaled corticosteroids play a pivotal role in the treatment of asthma and chronic obstructive pulmonary disease (2, 3).
Although inhaled delivery has allowed the minimization of systemic exposure, there still remain a number of issues concerning potential adverse effects. These are reported to include reduction of growth velocity in children, bone mineral loss, ocular symptoms, and skin changes (3). Consequently there remains a significant opportunity to improve further the therapeutic index of inhaled corticosteroids. This article discusses current attempts to achieve this objective, focusing on approaches to develop corticosteroids with desirable lung retention and selectivity and also on the prospects for a fundamental improvement in therapeutic index based on recent progress in the understanding of corticosteroid pharmacology.
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INCREASED POTENCY
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The relative potency of corticosteroids is best assessed using in vitro assays of antiinflammatory activity. The active moieties of beclomethasone dipropionate (BDP), ciclesonide, and budesonide are roughly equipotent at repressing the activity of the proinflammatory transcription factor nuclear factor-
B in A549 lung epithelial cells, while fluticasone propionate (FP) and mometasone furoate (MF) are both considerably more potent, and are 1,000 times more active than cortisol (Figure 1). This high potency translates into the use of smaller doses to achieve equivalent clinical benefit. However, in vitro potency alone does not establish clinical dose. Drug delivery devices and pharmacokinetics have a strong influence not only on pulmonary efficacy but also on therapeutic index.
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REDUCED ORAL BIOAVAILABILITY
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Although inhaler devices are designed to deliver drugs locally into the lungs, a very large proportion of the dose (60–90%) is deposited in the mouth and pharynx, and enters the gastrointestinal tract (4). The level of systemic exposure to inhaled corticosteroid drugs thus depends not only on the efficiency of absorption through the lung, but also on the uptake of the swallowed dose. Two strategies have been adopted to reduce this oral component of systemic exposure. First, companies have developed improved delivery devices that deliver a greater proportion of the drug substance to the lung (see below). More importantly, the corticosteroids themselves have been manipulated to dramatically reduce the oral uptake. Steroids that are administered orally such as prednisolone, methylprednisolone, and dexamethasone all have oral bioavaibility greater than 80% (5). BDP still is well absorbed from the gut, having an oral bioavailability of 41% (6). The development of budesonide represented a significant advance, where the oral bioavailability was reduced to 11% (7). But the most recent generation of compounds, FP, ciclesonide, and mometasone furoate, have an oral bioavailability of less than 1% (8). Thus essentially all the systemic exposure from these compounds is a result of uptake through the target organ, i.e., the lung.
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METABOLIC INACTIVATION
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Inhaled corticosteroid drugs are rapidly cleared from the circulation by metabolism in the liver. However, the activity of the metabolites generated varies considerably. The first product of the metabolism of beclomethasone monopropionate (BMP) is beclomethasone itself, also a potent corticosteroid. The hepatic metabolism of FP generates a completely inactive 17ß-carboxylic acid metabolite. Although the oral bioavailability of mometasone furoate is reported to be as low as that for FP, the activity of the metabolites produced in this case have yet to be reported.
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PLASMA LABILE "ANTEDRUGS" OR "SOFT" DRUGS
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Although the current generation of molecules now have effectively optimized hepatic inactivation resulting in virtually no oral bioavailability, some active drug to reaches other tissues by absorption from the lung. A further reduction in systemic exposure therefore requires additional extrahepatic inactivation and effort has been directed toward compounds that are rapidly inactivated in plasma (9).
The terms "antedrug" (10) or "soft" drug (11) have been applied to compounds designed to exert their desired effect locally but which are inactivated in the circulation to reduce unwanted systemic effects. The ideal antedrug should combine stability in the target tissue with very rapid inactivation in the bloodstream. Considerable effort has been directed toward corticosteroid ester derivatives in the search for plasma labile antedrugs (12–18). However, the presence of esterase activity in the lung makes it unlikely that such ester-based antedrugs will deliver the ideal profile due to the potential for premature inactivation in the target tissue. Indeed, the ester-based antedrugs that have been evaluated in humans, such as Itrocinonide, have not shown sufficient efficacy in the lung (19). However, it has recently been discovered that glucocorticoid lactone (cyclic ester) antedrugs display the ideal combination of stability in lung tissue with extremely rapid inactivation in plasma (20). For example, the glucocorticoid lactone (Figure 2, Panel 1) is almost instantly inactivated in human plasma (t1/2 < 1 min) but is effectively stable in human lung S9 preparation. This profile is in marked contrast to the corresponding acyclic ester (Figure 2, Panel 2), which is more rapidly hydrolysed in lung S9 (t1/2 6 minutes) than in plasma (t1/2 24 minutes). The unique properties of such glucocorticoid lactone antedrugs have been shown to be the result of their hydrolysis in plasma being mediated by the enzyme human serum paraoxonase, an enzyme which, unlike other esterases, is confined to plasma and liver, making this an ideal antedrug inactivation mechanism.
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Figure 2. Inactivation of a glucocorticoid lactone in human plasma. The glucocorticoid lactone 1 is rapidly inactivated in human plasma, but stable in lung tissue. The corresponding acyclic ester 2 is more rapidly hydrolysed in lung tissue.
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LUNG RETENTION
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An alternative way of reducing the systemic liability is to find ways of retaining compounds in the lung. Although this may not reduce the overall exposure to the compound, it may reduce the maximal concentration to which the systemic compartment is exposed. FP is considerably more lipophilic than budesonide, and this results in an 80-fold slower rate of dissolution of the corticosteroid in the lung (21). The high lipophilicity of FP also generates a higher affinity for lung tissue (22), and together these factors increase the time for which fluticasone propionate is retained within the lung (23, 24).
Budesonide has been reported to form highly lipophilic fatty acid esters in the lung (25). These esters are postulated to serve as a depot from which the active molecule can be regenerated, and it has been suggested that this property may result in both prolonged tissue binding and slow release of budesonide, and therefore in improved topical selectivity and duration of action. While this has been most extensively studied for budesonide, other corticosteroids with free hydroxyl groups at position 21 could undergo the same modification (including BMP, flunisolide, and ciclesonide, but not FP).
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PRODRUG APPROACH
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In addition to the adverse effects of systemic exposure to steroids, local administration is associated with its own set of issues. Irritation of the larynx leading to dysphonea is widely reported. However, infections at the back of the throat as a result of local immune suppression are also fairly common. One way of attempting to avoid this issue is to use a prodrug approach, in which the active drug is generated in the lung. Both BDP and ciclesonide use this approach. However, there is little evidence to suggest that this leads to a significant reduction in local side effects. Highly lipophilic corticosteroid prodrugs have also been investigated in the search for compounds with prolonged intraluminal retention time (19).
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THE INFLUENCE OF PHARMACY ON PULMONARY TARGETING
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Delivery Devices and Formulation Approaches
In addition to the various chemical approaches discussed thus far, the recognition of the advantages of delivering a drug to the lung by inhalation has also led to numerous technological achievements and improvements in the field of inhaler delivery devices (26). This industry now supplies approximately a half billion inhalers for asthma treatment. These fall into three major groups: nebulizers, propellant-driven metered dose inhalers, and dry powder inhalers.
Another approach to achieving enhanced lung retention and prolonged duration has been use of various formulation strategies. For example, liposomal formulations of budesonide have been investigated, and BDP has also been encapsulated in polylactic acid microspheres (27, 28). In the future further improvements in formulation strategies are likely to result the increasing potency and selectivity of pulmonary drugs.
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STEROID RECEPTOR SPECIFICITY
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The molecular target of corticosteroid drugs is the glucocorticoid receptor, which is very closely related to the receptors for other steroid hormones. Consequently many steroidal drugs crossreact with the other receptors. Most inhaled corticosteroids in use show comparatively high affinity for the progesterone receptor and the mineralocorticoid receptor (Table 1), but are relatively specific for the glucocorticoid receptor compared with the androgen receptor or the estrogen receptor. Although the clinical significance of this crossreaction with other steroid receptors remains unclear, it seems reasonable to suppose that high specificity for the glucocorticoid receptor is a desirable property.
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NOVEL PHARMACOLOGIC APPROACHES
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It is clear that the current new generation corticosteroid drugs represent a class of highly optimized molecules. FP is extremely potent, acts specifically on the glucocorticoid receptor, and has very low systemic exposure as a result of optimized hepatic metabolism. The esterification of budesonide and ciclesonide in the lung may help to reduce their systemic exposure, while the prodrug approach used in ciclesonide may improve local side effects.
However, recent developments in the understanding of corticosteroid biology are beginning to indicate that there may be considerable further scope for improvement of therapeutic index. Here the focus has become the regulation of gene transactivation and transrepression in both a tissue- and pathway-specific manner, and the recognition that it might be possible to design corticosteroid receptor agonists with intrinsically different pharmacology (29).
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SELECTIVE PHARMACOLOGY
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As discussed previously, it has been comparatively straightforward to achieve increased receptor potency, with compounds such as FP and mometasone furoate having very high affinity for the glucocorticoid receptor. Therefore, until recently this strategy, coupled with improvements in pharmacokinetic properties, has led to the current generation of inhaled corticosteroids. Although corticosteroids have been in clinical use since the 1950s, and inhaled drugs from the 1970s, the molecular receptor for these molecules was not identified until 1985 (30). The receptor is a ligand-activated transcription factor, and it was therefore assumed that genes that were activated by this receptor mediated the antiinflammatory properties of corticosteroids. It was also established that the addition of corticosteroid induced a rapid translocation of the receptor to the cell nucleus, and that the receptor has a very widespread tissue distribution. Many genes were subsequently identified that contained corticosteroid response elements in their promoter regions, allowing the activated receptor to bind to the DNA and activate transcription. However, it also became increasingly clear that many proinflammatory genes whose activity was suppressed by corticosteroid did not contain these response elements, suggesting an alternative mechanism. These proinflammatory genes were in fact linked by their responsiveness to other transcription factors, principally nuclear factor-B and activator protein-1. It was then established that the activated corticosteroid receptor was able to bind directly to these other factors and suppress their activity (31). These observations have led to the mechanistic concept that corticosteroids can mediate gene expression either by direct transactivation of genes or by indirect transrepression.
The assumption that inhibition of proinflammatory gene activation through nuclear factor-B and activator protein-1 is the major source of the antiinflammatory activity of corticosteroids has become the focus of considerable experimental effort (29). Transgenic mice that are defective in their ability to induce gene transactivation through the corticosteroid receptor but retain wild-type transrepression activity have been used to support this hypothesis (32, 33). In this system corticosteroids retain their antiinflammatory efficacy, indicating that transactivation is not required. Additional studies have linked a significant number of corticosteroid-induced side effects to transrepression mechanisms, suggesting the possibility that a novel corticosteroid that selectively acted on the transrepression pathway might have an improved therapeutic index (34).
Several investigators have attempted to identify novel corticosteroids with such a transcriptional profile. A series of compounds, including RU24858, were reported to have high affinity for the corticosteroid receptor, but were only able to reach around 20 to 30% of the efficacy of dexamethasone in a transactivation assay (35). While this compound showed in vivo antiinflammatory activity comparable to prednisolone, there was no improvement in side effect parameters such as osteoporosis, weight reduction, or thymic involution (36, 37). It was subsequently shown that RU24858 had stronger in vivo transactivation activity, indicating that the in vitro assays used to characterize the compound were likely to have different coupling efficiency, although effects due to pharmacokinetic properties may also have affected the in vivo observations (38). Other studies have chosen to move away from classical steroidal templates in the search for corticosteroids with novel pharmacology. AL-438, for example, has been shown to have more transrepression than transactivation efficacy in a series of in vitro assays (29). It also displayed in vivo antiinflammatory activity and showed less increase in blood glucose levels as compared with prednisolone. This compound has also been profiled in an in vivo model of osteoporosis and was reported to display less adverse effects as compared with prednisolone (39). This compound, unlike RU24858, thus appears able to maintain the selective transrepression profile in vivo as well as in in vitro assays, although its in vivo efficacy is clearly less than prednisolone. More recently, another nonsteroidal compound has been reported to be equipotent to prednisolone by both topical and systemic administration (40). ZK216348 is claimed to have a markedly superior side effect profile as a result of its dissociation between transactivation and transrepression, based on measurement of blood glucose and spleen involution. Interestingly, the same compound's effects on the hypothalamic-pituitary-adrenocortical axis were also investigated. In this case, however, adrenocorticotropic hormone suppression was similar to prednisolone. This observation could be interpreted to suggest that a transpression selective corticosteroid might not have an improved therapeutic index as far as HPA axis effects are concerned. However, the results could potentially be explained by pharmacokinetic differences between the two compounds, as the pharmacokinetic of ZK216348 is not reported by the authors of the study.
Taken together, these studies indicate that there is indeed the potential to alter the molecular pharmacology of glucocorticoid receptor ligands. Further studies on these and other examples of transrepression selective corticosteroids, with the additional objective of excluding pharmacokinetic differences as the source of apparent selectivity, would appear to be clearly justified.
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FUTURE PROSPECTS
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Enormous progress has been made since the introduction of hydrocortisone as the first clinically used corticosteroid. Highly potent molecules are now available to treat asthma and chronic obstructive pulmonary disease, accompanied by a significant improvement in therapeutic index through the use of chemical design, inhaler devices, and other approaches to targeting lung delivery. Despite these developments, advances made in the understanding of corticosteroid biology and pharmacology indicate that there is still an opportunity for further optimization. In addition to the potential for transrepression by selective corticosteroids, which may even lead to novel agents for oral administration, the recent solution of the corticosteroid receptor crystal structure has shown for the first time how these molecules interact with their receptor at the molecular level (41). The resulting potential for rational drug design, coupled with precise pharmacologic assays, should lead to a new generation of inhaled corticosteroids.
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FOOTNOTES
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Conflict of Interest Statement: K.B., I.U., and S.N.F. are full-time employees of GlaxoSmithKline.
(Received in original form September 28, 2004; )
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ABSTRACT
INCREASED POTENCY
