Biology Reference
In-Depth Information
to reach primary end points in asthma and COPD trials (200-800
m
g OD, p.o.), and,
consequently, further development was terminated.
2.6 Roflumilast
Roflumilast (6, Nycomed) was developed as a novel, once-daily oral treatment
for severe COPD that targets the underlying inflammatory disease processes
(Hatzelmann and Schudt
2001
; Bundschuh et al.
2001
; Hatzelmann et al.
2010
).
Roflumilast inhibits the PDE4 activity in human neutrophils (IC
50
at 0.7 nM)
without affecting any other isoenzyme of the 11 PDE families, even at 10,000-fold
higher concentrations, and has a considerably higher potency for PDE4 inhibition
than cilomilast (Hatzelmann and Schudt
2001
; Hatzelmann et al.
2010
).
Roflumilast N-oxide is the active metabolite of roflumilast sharing highly potent
(IC
50
at PDE4 of human neutrophils of 2 nM) and selective PDE4 inhibition with
the parent compound (Hatzelmann and Schudt
2001
).
Roflumilast and roflumilast N-oxide are “balanced” PDE4 inhibitors. In in vitro
investigations, roflumilast and roflumilast N-oxide demonstrated a broad potential
to reverse malfunctions of human inflammatory and structural cells related to
COPD (such as neutrophils, macrophages, T-cells, airway epithelial cells, lung
fibroblasts, bronchial and pulmonary artery smooth muscle cells, and endothelial
cells). In mice studies, roflumilast alleviated the inflammatory response as well as
lung parenchymal destruction following exposure to tobacco smoke over several
months. Roflumilast further reduced the lung fibrotic response secondary to
bleomycin in mice and rats. Finally, roflumilast mitigated pulmonary vascular
remodeling and pulmonary hypertension in rats following chronic hypoxia or
monocrotaline (see Hatzelmann et al.
2010
for review). The anti-inflammatory
potential of roflumilast was confirmed in clinical studies. One study administered
roflumilast at the standard dose of 500
m
g per day over 4 weeks to human volunteers
that were then exposed to lipopolysaccharide (LPS) by bronchoscopy-assisted
segmental bronchial challenge (Hohlfeld et al.
2008
). The resulting increase of
neutrophils in the segmental lavage was reduced with roflumilast versus placebo
by 39% (Hohlfeld et al.
2008
). In another study recruiting patients afflicted with
mild-to-moderate COPD, Grootendorst and colleagues (
2007
) found a reduction by
approximately 35% in the number of neutrophils collected in induced sputum
following a 4-week course of oral roflumilast, once daily at 500
m
g per day.
These anti-inflammatory effects may translate into the observed clinical efficacy
in COPD. In four large clinical trials, roflumilast was shown to robustly (1) increase
FEV1 by about 40-80 ml over 1 year, (2) reduce the rate of acute exacerbations in
COPD by 15-21% (1 year), and (3) maintain its favorable effects on lung function
and exacerbation rate when added to bronchodilators such as tiotropium or salme-
terol (Calverley et al.
2009
; Fabbri et al.
2009
; Hanania et al.
2010
). Retrospective
analyses revealed that roflumilast can also reduce exacerbations and improve lung
function when given concomitantly with inhaled corticosteroids in patients with
severe COPD (Calverley et al.
2010
).
