Balancing Safety and Efficacy in Pediatric Asthma Management David P. Skoner, MD ABSTRACT. In the treatment of childhood asthma, bal- or most children, the onset of asthma occurs ancing safety and efficacy is key to achieving optimal before the age of 2 years, underscoring the need therapeutic benefit. Inhaled corticosteroids (ICS), be- for early treatment not only to control the de- cause of their efficacy, remain a cornerstone in managing F bilitating effects of asthma symptomatology but also persistent pediatric asthma, but also are associated with to prevent irreversible structural changes that can significant adverse effects, including growth suppres- lead to permanent airway obstruction.1 Because sion. Consequently, careful attention must be given to balancing their safety and efficacy, which should include asthma requires chronic—often lifelong—treatment, an understanding of airway patency and systemic ab- a critical issue in the management of pediatric sorption (dose, disease severity, propellant and lipophi- asthma is balancing the safety and efficacy of asthma licity of inhalant), bioavailability (inhalation technique, interventions to achieve optimal long-term results. propellant, delivery devices, and hepatic first-pass me- This review will examine some of the challenges to tabolism), techniques for using minimum effective doses balancing safety and efficacy associated with inhaled (dosing time, add-on therapy), and reduction of other corticosteroid (ICS) therapy and explore the potential exacerbating conditions (allergens, influenza, upper-res- benefits of other available alternative therapies for piratory diseases). The growth-suppressive effects of ICS managing persistent mild-to-moderate pediatric may be most evident in children with: 1) mild asthma asthma. because the relatively high airway patency may facilitate increased levels of deposition and steroid absorption in more distal airways, and 2) evening dosing that may ICS reduce nocturnal growth hormone activity. A step-down As the gold standard for the long-term manage- approach targeting a minimum effective dose and once- ment of asthma in adults and children, ICS reduce daily morning dosing is suggested for achieving the both asthma symptomatology and the markers of most acceptable safety/efficacy balance with ICS. The airway inflammation.2–4 Early intervention with ICS achievement of regular, safe, and correct ICS use requires may preserve pulmonary function and prevent irre- significant knowledge and time for both caregiver and ␤ versible airway obstruction, remodeling, and hyper- patient. Chromones, methylxanthines, long-acting -ago- 4–8 nists, and leukotriene receptor antagonists are currently responsiveness. Nevertheless, important chal- available alternatives to ICS for the control of persistent lenges present themselves with the use of ICS in childhood asthma. Chromones are safe but, like methyl- young children, particularly with the potential for xanthines, are difficult to use and frequently result in systemic adverse effects, including growth suppres- compromised effectiveness. Long-acting ␤-agonists are sion. not recommended as monotherapy for persistent asthma. Several factors that support leukotriene receptor antago- SOURCES AND DETERMINANTS OF SYSTEMIC nists as a therapeutic option for mild-to-moderate per- BIOAVAILABILITY OF ICS sistent pediatric asthma include established efficacy, Although ICS were developed to replace effica- good safety profiles, and simple, oral dosing. Physicians must evaluate and compare the balance of safety and cious, but more highly bioavailable oral glucocorti- efficacy for each agent to determine the appropriate costeroids, they can nonetheless manifest detectable asthma therapy for individual patients. Pediatrics 2002; systemic bioavailability. ICS can be absorbed from 109:381–392; pediatric asthma, inhaled corticosteroids, both the gastrointestinal (GI) system and the airway airway deposition, bioavailability, leukotriene receptor mucosa. Thus, factors that increase the degree of antagonists. airway delivery generally increase the systemic bio- availability of a drug. If sufficient drug enters the ABBREVIATIONS. ICS, inhaled corticosteroids; GI, gastrointesti- blood, effects can be detected using sensitive assays nal; CS, corticosteroids; BDP, beclomethasone diproprionate; of the hypothalamic-pituitary axis or methods to pMDI, pressurized metered-dose inhaler; CFC, chlorofluorocar- measure childhood growth. bon; DPI, dry powder inhalers; HFA, hydrofluoroalkane; FEV1, forced expiratory volume in 1 second; CAMP, Childhood Asthma Individual ICS and Delivery Devices Management Program; PEFR, peak expiratory flow rate. Systemic bioavailability of ICS occurs either through the inhaled fraction of corticosteroids (CS) From the Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania. that makes it into the airways (ϳ20%) or by swal- Received for publication May 4, 2001; accepted Oct 22, 2001. lowing ϳ80% of the delivered CS that makes it no Reprint requests to (D.P.S.) Section of Allergy and Immunology, Children’s further into the airway than the back of the throat. Hospital of Pittsburgh, 3705 Fifth Ave, Rm 4B320, Pittsburgh, PA 15213. E-mail: [email protected] The swallowed CS is subject to hepatic first-pass PEDIATRICS (ISSN 0031 4005). Copyright © 2002 by the American Acad- inactivation after it is absorbed from the gut. For emy of Pediatrics. fluticasone and mometasone, approximately 99% is Downloaded from www.aappublications.org/news byPEDIATRICS guest on September Vol. 30, 109 2021 No. 2 February 2002 381 inactivated in the liver, and for budesonide and tri- unique safety and efficacy profiles. For example, the amcinolone, 90% and 80% to 90%, respectively, are older pMDI formulation of budesonide delivered inactivated.9 Beclomethasone diproprionate (BDP), much less drug to the airways than the newer Tur- however, is not entirely inactivated in the hepatic buhaler DPI formulation (AstraZeneca, So¨dertalje, first pass (60% to 70%), and an active metabolite Sweden).14 Likewise, the change in formulation of (beclomethasone-17-monoproprionate) is formed the vehicle propellant from CFC to HFA may in- that has a potency similar to the parent BDP.9 It crease the bioavailability of ICS by improving the would therefore appear that the newer ICS (flutica- airway delivery, thereby increasing the potential for sone and mometasone) have a superior safety profile systemic adverse effects. The HFA formulation of based on hepatic inactivation of noninhaled drug BDP delivers smaller-sized particles (the average and that they should generate less concern about particle size of HFA-BDP is 1.1 ␮m compared with minimizing the swallowed portion of the drug. 3.5 ␮m for CFC-BDP). Furthermore, HFA-BDP’s av- Once present in the systemic circulation, the de- erage spray force is softer (3 times less), and has a gree of lipophilicity of each ICS may also have an longer duration and a warmer temperature, than that important influence. Fluticasone and mometasone of CFC (the temperature is approximately ϩ5°C for are highly lipophilic drugs and therefore are more HFA-BDP vs Ϫ20°C for CFC-BDP). Consequently, easily distributed into the systemic tissue compart- there is more lung deposition and less mouth depo- ments. Consequently, they have a large volume of sition for HFA-BDP than for CFC-BDP.15 In a clinical distribution at steady state. In contrast, triamcino- trial, the dose-response (forced expiratory volume in lone and budesonide have lower lipophilicity and, 1 second [FEV1], % predicted) curve for HFA-BDP consequently, a smaller volume of distribution. Be- was shifted to the left compared with the dose-re- cause the systemic tissue storage of an ICS acts as a sponse curve for CFC-BDP. To achieve the same slow release reservoir, the drugs with higher lipophi- improved FEV1 as HFA-BDP, 2.6 times the dose of licity would take a longer time to be cleared from the CFC-BDP would be required.16 With an increased larger distribution volume. Their lipophilicity could airway delivery, there may be increased absorption thus increase the potential for producing systemic and increased risk of systemic adverse effects. In adverse effects.9 The risk may be offset by the general contrast, HFA formulations of other drugs may de- approach to use relatively lower ␮g doses of the liver lower amounts to the airway compared with the more lipophilic and thus more potent ICS. older CFC formulation.17 The majority of drug in the blood, however, orig- In a separate pharmacokinetic comparison, the inates from that deposited in the lower airways, HFA formulation produced a significantly increased where it is directly absorbed into the vasculature maximum concentration of drug (Cmax) and area Ͻ Ͻ without undergoing metabolism or inactivation. under the curve (AUC(0–12 hrs))(P .001 and P Therefore, minimizing GI bioavailability via the se- .005, respectively) compared with the CFC formula- lection of newer ICS will not necessarily eliminate tion, resulting in up to twofold greater absorption of the possibility of systemic bioavailability, and the BDP. Therefore, clinically important systemic ad- risk of systemic adverse effects, such as growth sup- verse effects may be expected with the HFA if a pression, and a dose-related growth suppression nominal 1:1 dose switch were made between CFC could be expected of both newer and older ICS.10 and HFA formulations of BDP.18 Likewise, factors that increase airway dose and de- livery (ie, milder disease, increasing