Characterizing Longitudinal Pulmonary
Function (FEV1) Decline in Continuous
Smokers Using a Turnover Model
Pharmaceutical
s
!
March 11th, 2008
ACoP
Song Mu, PhD, Yu-Yuan Chiu, PhD, Brian Davies, PhD,
and Fred Bode, MD
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Motivation
• Roche is developing a compound to treat emphysema
through repair of damaged alveoli
• Traditional clinical endpoints, including FEV1 are slow in
response to treatment
• Smoking cessation was established by far as the only
means to slow the rate of decline in lung function of
smokers in the landmark Lung Health Study (LHS)
• Study of longitudinal pulmonary function decline in LHS
may help better understand the pulmonary system, and
specifically about alveoli turnover
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Background
The disease of emphysema
Source: http://www.mpg-inc.net/patientcaregivers.asp?issue=copd
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Death Rate of COPD
Jemal, A. et al. JAMA 2005;294:1255-1259.
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Pulmonary Function Measurement - Spirometer
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Spirometry: Normal and Patients with COPD
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http://www.goldcopd.com/OtherResourcesItem.asp?l1=2&l2=2&intId=969
OBJECTIVE
Characterizing longitudinal Forced Expiratory Volume in 1
second (FEV1) in healthy volunteers and continuous
smokers over 11 years to help detect treatment effect in
upcoming trials
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METHODS
Data: Lung healthy Study
Design of LHS:
• Open-label multi-center, sponsored by NIH
• Special intervention (SI) vs. usual care (UC)
• 5887 participants, 5 years
• Annual clinical visit
Results:
• smoking cessation reduced the rate of decline of lung
function
• Inhaled bronchodilator did not
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LHS3
•
•
•
•
•
•
Follow-up to LHS
4517 participates
Age at time of trial 61.3
Percent male 61.9%
Continuous smoker ~2360
6 years
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FEV1 from Healthy
FEV1 in demographically-matched healthy subjects was
calculated based on European Respiratory Society
(ERS) formula:
Male :
FEV 1 ( L) = 4.30 ⋅ Height − 0.029 ⋅ Age − 2.49
Female : FEV 1 ( L) = 3.95 ⋅ Height − 0.025 ⋅ Age − 2.60
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Model Description
Healthy :
Synthesis rate
dFA
= k s − k 1 ⋅ FA
dt
FA = α ⋅ FEV1
dFEV1 k s
=
dt
α
dFEV1 k s
=
dt
α
Ks
− k 1 ⋅ FEV1
 FEV1base 
 ⋅ γ − k 1 ⋅ FEV1
⋅ 
FEV
1


FEV1
Functional
Alveoli
Emphysema Patients :
K1
dFEV1 k s  FEV1base 
 ⋅ γ − (k 1 + k d ) ⋅ FEV1
=
⋅
dt
α  FEV1 
Kd
Destruction
Cell Death
Healthy
Emphysema
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Assumptions
• The amount of functional alveoli is directly proportional
to FEV1
• Emphysema patients share similar synthesis rate with
healthy but have an additional alveoli elimination
pathway
• Continuous smokers in LHS3 are treated as emphysema
patients for the modeling purpose
• Rate of alveoli synthesis is controlled by a feedback
mechanism
Imai K et al Eur. Respir J 2005 25:250-258
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RESULTS
Healthy: K1=0.0149 yr-1, γ=0.0109; Continuous Smoker: Kd=0.0468 yr-1
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Application
• Establish Kd once FEV1 from emphysema patients become
available
• Incorporate drug effect on Kd i.e. Kd⋅(1-Ed)
• Simulate future trials of various durations
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References
• J.E. Connett, J.W. Kusek et al. Design of the Lung
Health Study: A randomized clinical trial of early
intervention for chronic obstructive pulmonary disease.
Controlled Clinical Trials 1993,14:3s-19s.
• N.R. Anthonisen, J.E. Connett, R.P. Murray for the Lung
Health Study Research Group. Smoking and lung
function of lung health study participants after 11 years.
Am J Respir Crit Care Med 166:675-679, 2002.
• Standardized lung function testing. Bull Eur Physiopathol
Respir, Jul 1983, vol. 19 Suppl 5, p. 49.
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