Improving Airway Delivery of Inhaled Corticosteroids in Asthma

Asthma and Small Airway Inflammation Asthma is a chronic inflammatory disease of the lungs Inflammation may be triggered by a wide variety of allergens Large airway inflammation has long been recognized as a major factor in asthma Recent evidence suggests that small airways may also play a significant role in the disease

Small Airway Inflammation in Asthma: Histopathologic Evidence Reprinted with permission from Kraft M, et al. Am J Resp Crit Care Med. 1996;154:1505-1510.

Inhaled Corticosteroids in Asthma Corticosteroids are the most potent anti-inflammatory agents used for asthma treatment Oral corticosteroids are generally associated with systemic adverse effects Inhaled corticosteroids are considered the preferred first-line, long-term controllers for older children and adults

Currently Available Inhaled Corticosteroids Beclomethasone dipropionate Budesonide Flunisolide Fluticasone propionate Triamcinolone acetonide

Conventional Metered-Dose Inhalers Most commonly used inhalation devices Deliver measured dose of drug via aerosol Contain drug suspension in propellant Most common propellant is CFC

Limitations of Standard CFC-MDIs Depleting effects of CFCs on ozone High oropharyngeal deposition Limited airway deposition Actuation/inhalation discoordination

CFCs and Ozone Depletion Revised Montreal Protocol calls for phase-out of CFC products by year 2000 MDIs provide essential treatment for a large population of asthma patients Development of non-CFC inhalers is imperative

CFC-MDIs and Oropharyngeal Deposition Majority of dose is deposited in oropharynx Local adverse effects include oropharyngeal candidiasis, throat discomfort, inhaler-induced cough, dysphonia Swallowed drug may contribute to systemic adverse effects

CFC-MDIs and Lung Deposition Reported rates for lung deposition of inhaled corticosteroids generally range from 5% to 30% (in vitro and in vivo studies) Human data are limited; this will change as the technology advances

MDI Spacers: Effects on Discoordination and Deposition Oropharyngeal deposition and discoordination problems (involving actuation of the MDI, inhalation of the dose, and rate of inhalation) limit drug delivery to the lungs Spacers are intended to reduce oropharyngeal deposition as well as discoordination, thereby increasing lung deposition Data regarding lung deposition are equivocal

Transition to CFC-Free Devices: Strategies for Improving Drug Delivery Increase respirable proportion of dose/improve deposition in lung Improve deposition in large and small airways

CFC-Free Devices: Dry Powder Inhalers No propellant, breath actuated High inspiratory flow may increase deposition in oropharynx Few comparative data for MDIs vs. dry powder inhalers

CFC-Free Devices: Dry Powder Inhalers (cont’d) In vivo studies indicate that dry powder inhalers deliver 15-32% of a corticosteroid dose to the lung Budesonide study (Thorsson et al, 1994): 32% lung deposition for dry powder inhaler vs. 15-18% for MDI Fluticasone study (Thorsson et al, 1996): 15% lung deposition for dry powder inhaler vs. ~30% systemic bioavailability previously reported for MDI delivery

HFA-MDIs HFAs are effective propellants with no ozone-depleting potential HFA-134a is effective as a propellant in inhalers and safe in humans HFA-134a/salbutamol MDIs, the first HFA-containing inhalers, are available in the US (Proventil HFA™) and Europe (Proventil HFA, Airomir®) HFA-134a/BDP MDI (QVAR™) has recently been developed

Characteristics of HFA-MDIs Contain solution or suspension of drug in HFA propellant (compared with CFC-MDIs, which always contain a solution) Evaporation of propellant leaves particles of smaller aerodynamic diameter than those produced by CFC-MDIs, potentially reducing oropharyngeal deposition and increasing lung deposition of drug

HFA-134a/salbutamol MDI (Airomir): Clinical Studies Airomir is an HFA-134a/salbutamol MDI currently available in the U.K. Airomir delivered more salbutamol as small particles (<5 m) compared with a salbutamol CFC-MDI (Ventolin®)

HFA-134a/salbutamol MDI (Proventil): Clinical Studies Variable Proventil HFA Ventolin Proportion of responders 140/193 (73)* 138/186 (74)* Time to onset of effect 6.4  4.8 5.9  4.7 for responders, min Peak percent change 32.0  25.7* 32.9  24.4* Time to peak effect, min 50.6  36.1* 45.1  35.1* Duration of effect, h 2.6  2.4* 2.7  2.4* AUC, %  h 92.7  121.2* 90.9  104.5* Predose FEV1, L 2.25  0.74* 2.25  0.73* *P <0.01 vs. HFA placebo. Bleeker ER, et al. Chest.1998;113:283-289.

HFA-134a/salbutamol MDI (Proventil): Clinical Studies (cont’d) Postexercise Change From Predose FEV1† Proventil HFA Ventolin Proventil Placebo Smallest percent change in FEV1 postexercise Number of patients with >20% fall in FEV1 postexercise 2.0 ± 9.9* 2.0 ± 11.4* 3.6 ± 10.2* -23.7 ± 14.5 1 (5%)* 1 (5%)* 0 (0%)* 12 (60%) 20 * * * * 10 * * Placebo Proventil Ventolin Proventil HFA * * Mean Percent Change From Predose FEV1 -10 -20 5 10 15 30 45 60 75 90 Time Postexercise (min) *P <0.001 for each treatment vs. placebo; †Mean±SD. Dockhorn, et al. Ann Allergy Asthma Immunol. 1997;79:85-88.

Particle Size and Deposition for CFC-BDP and HFA-BDP (QVAR™ ) 25 20 • HFA-BDP CFC-BDP BDP (g) 15 • • 10 • • 5 • • • • • • • • • Stem >10 Acuator Throat 9.0 - 10 <0.43 5.8 - 9.0 4.7 - 5.8 3.3 - 4.7 2.1 - 3.3 1.1 - 2.1 0.65 - 1.1 0.43 - 0.65 Andersen Cascade Impactor Components Leach CL. Resp Med. 1998;92(suppl A):3-8.

CFC-BDP vs. HFA-BDP: Proportion of Total Dose by Particle Size 70 60 • HFA-BDP CFC-BDP 50 % Total Delivered 40 30 • 20 • • 10 • • • • • • • >10 1.1 - 2.1 Throat 9.0 - 10 5.8 - 9.0 4.7 - 5.8 3.5 - 4.7 2.1 - 3.5 0.65 - 1.1 0.43 - 0.65 Particle Size (microns) Adapted from Tansey I. Br J Clin Pract. 1997;89(suppl):22-27.

BDP Deposition in Healthy Subjects CFC-BDP HFA-BDP Reprinted with permission from Leach CL. Resp Med. 1998;92(suppl A):3-8.

BDP Deposition in Healthy Subjects (cont’d) Lungs Mouth Exhaled HFA-BDP (50 g) 55% 29% 14% HFA-BDP (100 g) 60% 29% 11% CFC-BDP (50 g) 4% 94% 0% CFC-BDP (250 g) 7% 90% 2% Leach CL. Eur Resp J. 1998;12:1346-1353.

BDP Deposition in Asthmatic Subjects HFA-BDP Reprinted with permission from Leach CL. Resp Med. 1998;92(suppl A):3-8.

BDP Deposition in Asthmatic Subjects (cont’d) Lungs Mouth Exhaled HFA-BDP (50 g) 56% 33% 9% CFC-BDP (50 g) 5% 93% 2% Leach CL. Eur Resp J. 1998;12:1346-1353.

HFA-BDP Deposition Under Various Conditions Lungs Mouth Exhaled Spacer Autohaler (automatic actuation) 57% 28% 14% — P&B coordinated actuation 58% 26% 13% — P&B 0.5 sec early actuation 34% 57% 8% — P&B + Aerochamber 60% 4% 12% 24% Adapted from Leach, et al. Abstract presented at the European Respiratory Society Meeting, September 1998, Geneva, Switzerland.

Adjusted Mean AM PEF and Mean FEV1 by Week in Patients Receiving HFA-BDP 400 g/d or CFC-BDP 800 g/d HFA-BDP 400 g/day CFC-BDP 800 g/day HFA-placebo 475 3.00 450 2.75 425 Mean AM PEF (L/min) Mean FEV1 (L) 400 2.50 375 350 0.25 Run-in Oral Steroid Tx Weeks 1-3 Weeks 4-6 Weeks 7-9 Weeks 10-12 Run-in Oral Steroid Tx Weeks 1-3 Weeks 4-6 Weeks 7-9 Weeks 10-12 Time on Treatment Time on Treatment Gross, et al. Chest. 1999;115(2):343-351.

Mean Change in FEV1 % Predicted at Week 6 in Patients Receiving HFA-BDP or CFC-BDP 100, 400, or 800 g/d HFA-BDP* CFC-BDP* 100 g 400 g 800 g 100 g 400 g 800 g Baseline 52.3  1.26 53.1  1.24 52.1  1.19 53.6  1.16 51.6  1.22 53.0  1.23 Mean  at 18.1  1.61 19.4  1.57 23.8  1.51 14.9  1.52 17.7  1.56 21.5  1.57 week 6 CFC-BDP doses 2.6 times higher than those of HFA-BDP were required for similar improvements in FEV1 (Finney bioassay method; 95% CI, 1.1 to 11.6) *Mean  standard error. Adapted from Busse W, et al. Abstract presented at the World Asthma Meeting, December 1998, Barcelona, Spain.

Effectiveness of Half-Dose HFA-BDP: Additional Data Percentage of Patients With No Asthma-Related AE HFA-BDP (200-800 g/day) CFC-BDP (400-1600 g/day) 20 40 60 80 100 Day 1 Week 4 8 Month 6 10 12 Prenner B, et al. Abstract presented at the 55th Annual American Academy of Allergy, Asthma, and Immunology Meeting, February 1999, Orlando, Florida.

Recommendations for Switching Patients from CFC-BDP to HFA-BDP Suggested Conversion of Doses: Treatment Total Daily Dose (g; ex-valve) CFC-BDP 300 400-500 600-700 800-1000 HFA-BDP 100 200 300 400 Note: The conversion to the HFA-BDP dose should be based on the dose of CFC-BDP that would be given to the individual patient at the time of the switch. Adapted from Davies, et al. Abstract presented at the European Respiratory Society Meeting, September 1998, Geneva, Switzerland.

Effects of HFA-BDP on Adrenal Function No difference vs. CFC-BDP effect on 24-h urinary free cortisol at equal doses (800 g/d) Decreased AM plasma cortisol (below normal range) in <4.4% of patients for HFA-BDP up to 800 g/d, compared with 14.6% of patients receiving CFC-BDP 1500 g/d (P <0.05) No difference vs. CFC-BDP effect on AM plasma cortisol over long-term (12 mos.) treatment

Adverse Events in HFA-BDP Phase III Trials HFA-BDP CFC-BDP HFA-Placebo (800 g/d) (1500 g/d) Patient with at least one 82 (11%)* 65 (16%) 28 (10%) adverse event All inhalation-route disorders 59 (8%)* 47 (12%) 13 (4%) Cough 5 (<1%) 6 (2%) 3 (1%) Dysphonia 22 (3%) 11 (3%) 4 (1%) Increased asthma symptoms 1 (<1%)* 5 (1%) 1 (<1%) Site sensation 27 (4%) 23 (6%) 5 (2%) Taste sensation 13 (2%) 8 (2%) 2 (<1%) All respiratory system disorders 17 (2%) 7 (2%) 13 (4%) *P <0.05 (HFA vs. CFC). Adapted from Thompson PJ, et al. Resp Med. 1998;92(suppl A):33-39.

Conclusions Mandated phase-out of CFC products has permitted improvements in inhaled corticosteroid treatment Dry powder formulations may produce higher levels of drug deposition in the lung than conventional MDIs; however, comparative data are limited HFAs have been shown to be safe and effective substitutes for MDI propellants

Conclusions (cont’d) HFA-BDP MDI (drug-propellant solution) delivers extrafine aerosol Decreased oropharyngeal deposition Increased proportion of particles in respirable range and smaller mean particle diameter Increased lung deposition, including intermediate and peripheral airways (as assessed by imaging studies) HFA-BDP is as effective as CFC-BDP at approximately half the dose (reflected in current recommendations re: switching agents) HFA-BDP is at least as safe and well tolerated as CFC-BDP