Inhaled corticosteroids: potency, dose equivalence and therapeutic indexGlucocorticosteroids 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 inhaled corticosteroids potency comparison fully explored. Inhaled corticosteroids exert their anti-inflammatory activity locally in the airways, and hence this inhaled corticosteroids potency comparison be dissociated from their potential to cause systemic adverse effects. The molecular structural features that safest bulking steroid glucocorticoid receptor binding affinity and selectivity drive topical anti-inflammatory activity.
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. A more robust method is needed that incorporates pharmacological principles.
Glucocorticosteroids are natural and synthetic analogues of the hormones secreted by the hypothalamic—anterior pituitary—adrenocortical HPA axis which have anti-inflammatory activity. It is a widely held assumption that the therapeutic index of synthetic glucocorticoids, generally termed corticosteroids, cannot be improved by increasing their potency via enhanced glucocorticoid receptor binding affinity.
This is probably valid for systemically administered corticosteroids, unless selectivity for glucocorticoid receptors vs. However, a similar rationale is commonly adopted for inhaled corticosteroids, where potency is not considered to affect the topical efficacy to systemic activity ratio [ 2 ], with efficacy and potency differences being overcome by giving larger doses of the less potent drug [ 3 ].
There are several reasons why this rationale may not be valid for inhaled corticosteroids. First, they exert their anti-inflammatory activity at the site of action in the airways, which is not in equilibrium with the downstream systemic drug concentrations responsible for the unwanted systemic effects [ 4 ].
Secondly, it assumes that increasing inhaled corticosteroid potency is not associated with changes in other features of the molecule [ 5 ]. However, in reality, the molecular structural features that increase glucocorticoid receptor binding affinity and selectivity also result in physicochemical and pharmacokinetic changes that together may potentially enhance targeting to the airways and reduce systemic exposure.
Currently, there are eight inhaled corticosteroid molecules approved for clinical use that span a wide range of potency and other attributes.
This article explores the relationship between inhaled corticosteroid potency and therapeutic index. Beclomethasone dipropionate BDP was introduced in as the first synthetic corticosteroid asthma controller medication administered via the inhaled route [ 6 ]. At the time, it was heralded as a major breakthrough that freed asthma sufferers from the fear of the adverse effects associated with chronic systemic corticosteroid use. Drug discovery and development in this area has identified molecules with greater selectivity, potency and improved targeting to the lung via low oral bioavailability and high systemic clearance.
However, in the minds of many prescribers and patients, it is unclear whether having a wider choice of inhaled corticosteroid molecules and inhaler options available offers any advantages. These structural modifications also result in greater specificity for the glucocorticoid receptor, a longer duration of receptor occupancy and less association with nontarget steroid receptors.
They also lead to increased lipophilicity and reduced aqueous solubility [ 7 ]. Lipophilicity, aqueous solubility, plasma protein binding and tissue distribution all follow the same trend.
Metabolic stability is important for efficacy but is only an advantage if the rate of systemic clearance is also high. For BDP and CIC, clearance includes extra-hepatic metabolism as they are also pro-drugs and converted to their active metabolites by esterases found in lung and others tissues. By contrast, FP and FF are not pro-drug esters of fluticasone, and their efficacy is dependent on the intact molecules.
The two molecules are distinct, with different properties — the furoate ester in FF being responsible for the greater lipophilicity, lower solubility and enhanced glucocorticoid receptor binding affinity compared with FP and other inhaled corticosteroid molecules [ 8 ].
Furthermore, fluticasone is not a metabolite and is devoid of activity. The duration of action of glucocorticoids in the lung has also been related to their residence time there [ 8 — 10 ]. A prolonged pulmonary residence time is apparent when the elimination half-life following inhaled administration is significantly longer than found following intravenous administration. This tendency has been noted for the more lipophilic inhaled corticosteroids, with the following order of lung retention times: In addition, FF has greater glucocorticoid receptor affinity in vitro and a longer duration of action in experimental models of lung inflammation than FP [ 11 , 12 ].
This is a feature of glucocorticoids with hydroxyl groups and has been proposed as an alternative mechanism of prolonged tissue retention in the lung, although it is unclear whether this has any benefit in prolonging the duration of action [ 7 , 13 ].
The potential advantage of higher inhaled corticosteroid potency is that a lower inhaled dose is required to occupy the same numbers of glucocorticoid receptors in the airways, resulting in a lower daily dose for equivalent efficacy. Theoretically, the major factors expected to drive the relative efficacy of an inhaled corticosteroid are potency, device efficiency delivered lung dose and pulmonary residency time.
Although the other factors are likely to contribute to differences in efficacy, it is clear that topical potency in the airways is the most important. Despite this observation, the pulmonary residence time described above does appear to influence some aspects of efficacy. The main consequence of this appears to be a longer duration of action rather than greater efficacy per se , with the corticosteroid with the longest lung retention time FF being suitable for once-daily dosing, and those with shorter lung retention times requiring twice- FP , three- or four-times TAA daily dosing regimens [ 7 ].
The exception to this is FF, which has the longest lung retention and highest potency, where administering the same total daily dose as either a once-daily or twice-daily regimen has equivalent efficacy [ 15 ]. The inhaler device efficiency is expected to influence inhaled corticosteroid therapeutic dose equivalence. Also included are low-, mid- and high-dose regimens of all currently available inhaled corticosteroids, illustrating for each dose level a distinct exponential decline in therapeutic daily dose with increasing potency.
Therefore, one might expect that all dose regimens in the low-, mid- or high-dose categories, as defined by each regression line, should have equivalent efficacy. This may be the case, but is difficult to verify as the extent to which each product's recommended doses are based on comprehensive dose ranging in all severities of asthma is variable.
This analysis includes ICS dose regimens that are not approved for clinical use. Clinical experience with inhaled corticosteroids in asthma indicates that most of the benefit in terms of improving lung function is achieved with low—mid doses, with fewer patients benefiting from higher doses [ 17 , 18 ]. Consequently, for inhaled corticosteroids it is difficult to demonstrate a clear dose response for clinical endpoints within the efficacious dose range.
Although this calculation is a worst-case scenario for drug availability at the site of action, it nevertheless suggests the potential for a high degree of glucocorticoid receptor occupancy, even for low doses of the least potent inhaled corticosteroid molecules. Considering these factors, all commonly prescribed inhaled corticosteroid doses would be at the top of the dose response curve, unless only a small fraction of the lung dose reaches the site of action and is pharmacologically active.
If this premise is correct, it underlines the importance of potency in driving receptor occupancy and clinical efficacy. The factors that contribute to a low potential for systemic effects are those which minimize circulating drug concentrations. These are a low dose, which leads to low absorption from the lung; low bioavailability of the swallowed faction of the dose; and high clearance of the absorbed dose.
These lead to lower total and unbound systemic drug concentrations. Plasma protein binding is probably a less important factor for the more potent inhaled corticosteroid molecules as evidence suggests that this is a relatively low-affinity interaction and therefore may have less impact on systemic bioactivity [ 21 ]. The volume of distribution is a major determinant, together with the clearance, of the elimination half-life and time taken to reach steady state for systemic concentrations, but the all-important steady-state drug concentration that the patient is continually exposed to with chronic long-term use is a consequence of the clearance rate and input rate dose rate and bioavailability.
The systemic activity and associated adverse effects are related to this concentration, together with the glucocorticoid receptor binding potency. A higher potency alone would lead to greater systemic effects but the structural changes that lead to higher potency and a lower dose also result in a lower rate and extent of bioavailability and high clearance. The measurement of inhaled corticosteroid-mediated adrenal suppression, such as inhibition of cortisol secretion, is the most sensitive and easily monitored biomarker of adverse systemic inhaled corticosteroid effects.
This is a risk factor in inhaled corticosteroid therapy as the body does not distinguish between endogenous and synthetic exogenous glucocorticoids. Low-dose therapy with inhaled glucocorticoids may make only a small contribution to the glucocorticoid pool.
Therefore, homeostasis is maintained and the daily glucocorticoid requirements remain within physiological limits. However, when high doses of glucocorticoids are administered, it is possible that the extra glucocorticoid added to the endogenous pool may become the majority of the daily requirements. Under these circumstances, the normal daily requirements can be exceeded, even if endogenous glucocorticoid production is suppressed to very low levels, and if this is maintained for a prolonged period, there is a risk of adrenal insufficiency [ 22 ].
This approach relates the normal endogenous glucocorticoid production rate to the exogenous contributions from inhaled corticosteroids by converting them into cortisol-equivalent exposures. The calculation takes account of the bioavailability, relative potency, plasma protein binding and systemic clearance of the exogenous glucocorticoids to express the systemic exposure for each exogenous corticosteroid as a cortisol-equivalent area under the plasma concentration—time curve [ 23 ].
However, where data of this type were available, the estimated values were in close agreement [ 24 — 34 ]. The cortisol suppression estimates were a worst-case scenario as they assumed that lung delivery and systemic exposure was as seen in healthy subjects or mild asthmatics. However, it has been shown that inhaled corticosteroid lung deposition and systemic exposure to inhaled corticosteroid are lower in more severe asthma, when lung function is lower [ 35 ].
The glucocorticoid receptor binding potency of an inhaled corticosteroid can influence both its efficacy and systemic effects, but for potency to influence the therapeutic index there needs to be a differential effect on efficacy or systemic exposure. This relationship is approximately exponential or linear on a log-dose scale. The higher the therapeutic index, the greater the separation between systemic adverse effects and the desired local effects in the airways.
Furthermore, it is the inhaled corticosteroid molecules with highest potency, longest lung retention, lowest oral bioavailability and highest systemic clearance FF, MF, FP, CIC that have the highest therapeutic index.
To put these values into context, 5 mg day —1 and 20 mg day —1 dose regimens of oral prednisolone had corresponding therapeutic index values of 0. Current asthma treatment guidelines [ 36 , 37 ] make assumptions about dose equivalence that position low doses as effective doses without significant risk of adverse effects, and high doses as those achievable with an acceptable systemic adverse-effect profile. It is also recognized that most of the therapeutic benefit is achieved at low—mid doses and that not all patients benefit from high doses [ 17 , 18 ].
Asthma treatment guidelines [ 36 , 37 ] also classify the various inhaled corticosteroid formulations into low-, mid- and high doses. Although it is not claimed that within these classification doses are therapeutically equivalent, this is unavoidably implied and leads to the perception that efficacy and safety cannot be separated and that they are interchangeable products. Indeed, most inhaled corticosteroid molecules have been evaluated in isolation using different dose ranges in each severity of asthma.
Few studies have compared more than two inhaled corticosteroids and none has explored multiple products across a range of doses comparing both efficacy and safety endpoints [ 2 ]. It is acknowledged that the major determinants of inhaled corticosteroid therapeutic equivalence are potency and the efficiency of the device used for lung delivery, but there is incomplete consideration of the systemic exposure and relative risk of adverse effects so as to arrive at a relative therapeutic index for each dose of each inhaled corticosteroid.
Historically, when this approach was applied to a narrow range of similar inhaled corticosteroid molecules, the consequences probably had less of an impact. Another area of difficult interpretation is that of inhaler performance and its impact on dose equivalence. Two questions often arise: The answer is not simple to arrive at as improving the device efficiency is often accompanied by a reduction in the average particle size emitted, which may also lead to a shift in the pattern of lung deposition.
Although it has been proposed that small particles may be better able to treat small airways disease, this hypothesis has not been proven [ 38 ]. Smaller particles may also have a higher rate of dissolution and reduced mucociliary clearance, resulting in increased absorption and systemic exposure. This may confound the interpretation of changes in device efficiency as consequences occur for both efficacy and systemic exposure.
For an inhaled corticosteroid that has minimal oral absorption of the swallowed dose FF, MF, FP, CIC , it is not likely that increasing lung deposition would have much impact on the therapeutic index as most of the inhaled dose that reaches the lungs and site of action is also available for systemic absorption.
A more efficient device would allow a lower dose to be administered to achieve an effective dose at the site of action but the swallowed dose would also be lower, and hence the systemic absorption. On the positive side, small particles may deposit less in the oropharynx and more easily reach the peripheral airways. However, on the negative side, smaller particles are more likely to be exhaled and if they do deposit in the airways they are more likely to dissolve and be absorbed rapidly.
There are examples where device efficacy has been improved for inhaled corticosteroid molecules, e. The exponential relationship between in vitro glucocorticoid receptor binding affinity and therapeutic dose for inhaled corticosteroids is evidence that more potent molecules can be administered at much lower doses to achieve similar clinical efficacy.
Furthermore, the structural features of inhaled corticosteroids that give rise to more potent molecules also drive lower systemic exposure, and together these factors can improve the therapeutic index. In this way, enhanced inhaled corticosteroid potency leads to greater lipophilicity, slower dissolution and pulmonary absorption of inhaled drug particles with longer retention times in the airways.