0. Improving Airway Delivery of Inhaled Corticosteroids in Asthma

1. 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

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

3. 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

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

5. 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

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

7. 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

8. 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

9. 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

10. 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

11. 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

12. 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

13. 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 % for MDI
Fluticasone study (Thorsson et al, 1996): 15% lung deposition for dry powder inhaler vs. ~30% systemic bioavailability previously reported for MDI delivery

14. 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

15. 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

16. 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®)

17. 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   for responders, min
Peak percent change  25.7*  24.4*
Time to peak effect, min  36.1*  35.1*
Duration of effect, h 2.6  2.4* 2.7  2.4*
AUC, %  h  121.2*  104.5*
Predose FEV1, L  0.74*  0.73*
*P <0.01 vs. HFA placebo. Bleeker ER, et al. Chest.1998;113:

18. 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%)* (5%)* (0%)* (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.

19. 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
<0.43
Andersen Cascade Impactor Components
Leach CL. Resp Med. 1998;92(suppl A):3-8.

20. CFC-BDP vs. HFA-BDP: Proportion of Total Dose by Particle Size70 60 •
HFA-BDP
CFC-BDP 50
% Total Delivered 40 30 • 20 • • 10 • • • • • • •
>10
Throat
Particle Size (microns)
Adapted from Tansey I. Br J Clin Pract. 1997;89(suppl):22-27.

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

22. 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:

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

24. 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:

25. 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.

26. 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):

27. 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       1.23
Mean  at       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.

28. Effectiveness of Half-Dose HFA-BDP: Additional Data
Percentage of Patients With No Asthma-Related AE
HFA-BDP ( g/day)
CFC-BDP ( 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.

29. Recommendations for Switching Patients from CFC-BDP to HFA-BDP
Suggested Conversion of Doses:
Treatment Total Daily Dose (g; ex-valve)
CFC-BDP
HFA-BDP
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.

30. 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

31. 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 (8%)* (12%) 13 (4%)
Cough (<1%) 6 (2%) 3 (1%)
Dysphonia (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%) (2%) (<1%)
All respiratory system disorders (2%) (2%) (4%)
*P <0.05 (HFA vs. CFC). Adapted from Thompson PJ, et al. Resp Med. 1998;92(suppl A):33-39.

32. 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

33. 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