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 C 20% decline in forced expiratory volume in 1 s (FEV 1 ) (AMP PC 20 )], 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 PC 20 C 0.25 doubling dose) or the threshold for a clinically significant bronchoprotective effect (AMP PC 20 C 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 lg OD, FP 200 lg BID and BUD 200 lg 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;

New Versus Old: The Impact of Changing Patterns of Inhaled Corticosteroid Prescribing and Dosing Regimens in Asthma Management

“…Eligible publications identified in our literature review, from which the actual dose of ICS could be estimated from the available data, were used to simulate the extent and duration of airway efficacy and systemic activity for each ICS dose regimen of interest using previously validated and published PK/PD modeling and simulation methodology [7]. In addition to simulating the outcome for ICS use patterns documented in published studies, we also simulated the airway efficacy and systemic activity for regular daily and as-needed ICS dosing in mild asthma, and investigated the impact of 50%, 70%, and 100% adherence for BUD and FP regular daily doses (these values are in line with reports of ICS adherence in patients with asthma of 22-63% in the literature [8,15,16]).…”

“…For these clinical trials, where we simulated the outcomes in terms of bronchoprotection and systemic activity, it was possible to estimate the total ICS dose administered but not necessarily how this dose was taken by the participants, in terms of the split between maintenance and reliever doses. Since it is unlikely that adherence to the maintenance regimen was 100% (based on information available in published studies [7][8][9][10][11]), we also investigated an 85% adherence scenario assuming that this was a more feasible usage pattern among patients with asthma. For moderate and moderate-to-severe asthma simulations, a higher threshold for clinically significant bronchoprotection (C 1.5 and C 2.0 doubling dose difference, respectively) was used on the assumption that higher ICS doses/ bronchoprotective effects are required than in mild asthma.…”

“…The anti-inflammatory efficacy of ICS molecules is determined not only by their glucocorticoid receptor binding affinity but also by their pharmacokinetic (PK), pharmacodynamic (PD), and physicochemical properties, and on the administered dose [5,6]. Together, these factors can influence the extent and duration of treatment efficacy and the extent of unwanted systemic activity, and can also lead to differences in the risk-benefit profile of ICS dose regimens, particularly where regular daily maintenance therapy is deviated from-i.e., when adherence is poor or when as-needed dosing is adopted as an alternative to regular daily dosing [7]. Although some studies have compared regular daily dosing with as-needed regimens in the management of asthma [8][9][10][11], further investigation is needed to determine the relative risk-benefit of these ICS dose regimens options for various treatment outcomes.…”

“…We also used selected ICS/long-acting b 2 -agonist (LABA) combination therapies, including regular twice-daily ICS/LABA, and BUD/formoterol (FOR) maintenance and reliever therapy (MART) dosing data in clinical studies of patients with moderate-to-severe asthma. Finally, using the actual patterns of ICS use data collected from the structured literature review, and other ICS use scenarios of interest, we used previously validated and published PK/ PD modeling/simulation methodology [7] to simulate airway efficacy and systemic activity for these ICS dosing regimens in mild and moderate-to-severe asthma.…”

Patients' and physicians’ perspectives on the burden and management of asthma: Results from the APPaRENT 2 study

“…Moreover, early intervention with ICS prevents the development of irreversible airway obstruction that occurs over time [13]. This preventive treatment of the underlying pathophysiology of asthma results in reduced inflammation, reduced airway remodeling, and sustained bronchoprotective efficacy, which have been identified as hallmarks of PRD with ICS [10,12,14,15]. With consistent regular dosing, reliance on self-driven symptom tracking is reduced, and therefore the risk of over-or under-treatment by the patient is minimized [16].…”