Pharmacology Versus Convenience: A Benefit/Risk Analysis of Regular Maintenance Versus Infrequent or As-Needed Inhaled Corticosteroid Use in Mild Asthma

Abstract

Introduction: This study compared the bronchoprotective and benefit/risk profiles of various inhaled corticosteroid (ICS) dosing regimens in mild asthma.

Methods: A pharmacokinetic/pharmacodynamic model was developed and validated describing the relationship between ICS dose and time-course for airway bronchoprotection, [provocative concentration of adenosine monophosphate (AMP) causing ≥ 20% decline in forced expiratory volume in 1 s (FEV₁) (AMP PC₂₀)], for fluticasone furoate (FF), fluticasone propionate (FP) and budesonide (BUD). For regular ICS maintenance therapy (100% and 50% adherence) and infrequent or as-needed use (dosing 3-4 times per week), treatment effectiveness was expressed as percent time during 28 days when bronchoprotection exceeded either the threshold for a treatment-related bronchoprotective effect (AMP PC₂₀ ≥ 0.25 doubling dose) or the threshold for a clinically significant bronchoprotective effect (AMP PC₂₀ ≥ 1.0 doubling dose). This value was divided by the total ICS dose administered expressed in prednisolone equivalents to give a therapeutic index (TI).

Results: The model-predicted time course of ICS-induced bronchoprotection with regular daily maintenance dosing and 100% adherence showed that all ICS at the highest recommended doses for mild asthma exceeded the threshold for clinically significant bronchoprotective effect for all or most of the 28-day dosing period, mean (90% CI); 100% (96.1-100), 99.9% (8.0-100) and 100% (58.2-100) with TI values of 16.9, 6.6 and 5.4 for FF 100 µg OD, FP 200 µg BID and BUD 200 µg BID, respectively. For simulated poor adherence (50%) to regular daily maintenance therapy, corresponding mean (90% CI) values were; 75.7% (39.4-89.1), 52.3% (0.7-69.2) and 51.3% (28.6-58.3) with TI values of 25.7, 6.9 and 5.6. For simulated infrequent/as needed use the corresponding values were; 77.0% (37.6-87.0), 25.5% (0.0-38.0) and 26.2% (14.3-31.5) with TI values of 26.1, 6.7 and 5.7. For all regimen/scenarios, FF had the most sustained efficacy and favourable TI followed by FP and BUD.

Conclusions: At doses recommended for mild asthma, all ICS regimens provide sustained bronchoprotective efficacy when dosed regularly with high adherence. With poor adherence or use 3-4 times per week (infrequent/as needed), longer-acting ICS molecules will more likely provide sustained protection and a better TI versus shorter duration of action molecules (FF > FP ≥ BUD). These data highlight the benefits of using ICS as regular daily maintenance dosing in mild asthma and the potential risks of under-treatment with ICS (which may occur with ICS/formoterol as-needed approach in mild persistent asthma) associated with reduced levels of bronchoprotection.

Keywords: AMP challenge; Adherence; As-needed; Asthma; Budesonide; Fluticasone furoate; Fluticasone propionate; PK/PD model; Regular dosing.

Fig. 1

Relationship between estimated glucocorticoid receptor occupancy in the lung (GR_L) and bronchoprotection. Glucocorticoid receptor occupancy plotted as 100-GR_L after dosing with FF (25, 100, 200, 400, 800 µg/OD), FP (50 µg/OD, 100, 250, 500, 1000 µg/bid), BUD (100 µg/OD, 200, 400, 800, 1600 µg/bid) and bronchoprotection assessed as the reduction in airway hyper-responsiveness (AMP PC₂₀) assessed 12 h post-dose after 7 days dosing (data from [40]). The dotted line shows the non-linear correlation where AMP PC₂₀ = 101.72 (100-GR_L%)^−0.56 with a correlation coefficient of r² = 0.981. Inset the same data as a log-linear plot. AMP adenosine-5'-monophosphate, BUD budesonide, FF fluticasone furoate, FP fluticasone propionate

Fig. 2

Model validation. The model was validated by comparing the observed data values (AMP doubling dose versus placebo) with the corresponding model predicted values for four studies that were not part of the model building dataset (Table 1) shown as open circles. These data comprised a wide range of ICS doses, single and repeat doses regimens and AMP challenge assessment conducted at various times between 2 and 26 h post-dose. The data from the model building dataset [40] are shown as solid circles. The line of identity (slope = 1) ………… and linear regression (r² = 0.836) ……. are also shown

Fig. 3

Model predicted time course of ICS induced airway bronchoprotection during 28 days dosing. Dosing was with BUD 200 µg bid, FP 200 µg bid and FF 100 µg OD with: regular daily maintenance dosing regimen with adherence scenario of 100% adherence (column 1), regular daily maintenance dosing regimen with adherence scenario of 50% adherence (column 2), ICS dosing regimen when ICS used infrequently or PRN 3–4 times per week (column 3). For each ICS molecule, ICS doses represent the highest therapeutic dose for mild asthma. Horizontal dotted lines indicate thresholds for no treatment-related bronchoprotective effect defined as bronchoprotection less than an AMP PC₂₀ of 16 mg/mL (0.25 doubling doses) and a clinically significant bronchoprotective effect defined as bronchoprotection greater than an AMP PC₂₀ of 27 mg/mL (1.0 doubling doses). bid twice daily, BUD budesonide, FF fluticasone furoate, FP fluticasone propionate

Fig. 4

Percent time (hours) during 28 days above or below the thresholds for bronchoprotection. Thresholds for bronchoprotection were: no treatment-related bronchoprotective effect (left panel), or a clinically significant bronchoprotective effect (right panel) for BUD 200 µg bid, FP 200 µg bid and FF 100 µg OD with: regular daily maintenance dosing regimen with adherence scenario of 100% adherence, regular maintenance daily dosing regimen with adherence scenario of 50% adherence, infrequent ICS dosing regimen (3–4 times per week). bid twice daily, BUD budesonide, FF fluticasone furoate, FP fluticasone propionate, OD once daily

Fig. 5

Average daily prednisolone equivalent dose (µg/day) and cortisol suppression during 28 days dosing. Dosing was with BUD 200 µg bid, FP 200 µg bid and FF 100 µg OD with: regular daily maintenance dosing regimen with adherence scenario of 100% adherence, regular daily maintenance dosing regimen with adherence scenario of 50% adherence, infrequent ICS dosing regimen (3–4 times per week). bid twice daily, BUD budesonide, FF fluticasone furoate, FP fluticasone propionate, OD once daily

Fig. 6

Risk/benefit ratio (TI). Dosing was with BUD 200 µg bid, FP 200 µg bid and FF 100 µg OD with: regular daily maintenance dosing regimen with adherence scenario of 100% adherence, regular daily maintenance dosing regimen with adherence scenario of 50% adherence, infrequent ICS dosing regimen (3–4 times per week). Benefit/risk ratio = TI = % time (hours) during 28 days when bronchoprotection is above the threshold for no treatment-related bronchoprotective effect (left panel) or is above the threshold for a clinically significant bronchoprotective effect (right panel), each divided by the total 28-day systemic exposure in prednisolone equivalents, mg. bid twice daily, BUD budesonide, FF fluticasone furoate, FP fluticasone popionate, OD once daily