Biology Reference
In-Depth Information
inhaled PDE4 inhibitor GSK256066 in development for asthma and COPD and
finally roflumilast, the first PDE4 inhibitor approved and currently marketed as an
oral, once-daily remedy for severe COPD was marked by large progress in chemical
optimization based on improved understanding of PDE4 biology and drug-like
properties determining the appropriate pharmacokinetic profile. In this chapter
aspects of the pharmacology and clinical efficacy of PDE4 inhibitors, which have
been in clinical development over the years are summarized with specific emphasis
on their clinical pharmacokinetic properties.
Keywords Apremilast
GSK256066
PDE4 Inhibitors
Pharmacokinetics
Roflu-
milast
1
Introduction
Phosphodiesterase 4 (PDE4) is abundantly expressed in a broad array of cells
governing inflammatory responses and structural remodeling. Over the last two
decades, an ever-increasing amount of evidence from cellular and animal studies
indicated potential benefits from selective PDE4 inhibitors in numerous ailments.
Among them were respiratory disorders such as chronic obstructive pulmonary
disease (COPD), asthma, or idiopathic pulmonary fibrosis. The major clinical
breakthrough with PDE4 inhibitors was in COPD, a chronic respiratory disorder
mostly developing over decades in about 20-30% of tobacco smokers, regardless
of later smoking cessation. COPD is characterized by a chronic, progressive loss in
lung function associated with sudden acute exacerbations. Major disease mechan-
isms in COPD involve a characteristic pulmonary inflammatory response, structural
remodeling encompassing lung parenchymal destruction (emphysema), and small
airway peribronchial fibrosis, as well as malfunction of the mucociliary apparatus
(Barnes and Rennard
2008
; Hogg and Timens
2009
).
Interestingly, in large clinical trials the once-daily (500
m
g per day), oral PDE4
inhibitor Roflumilast significantly improved lung function and reduced the rate
of acute exacerbations in patients with severe COPD (Calverley et al.
2009
),
especially when added to long-acting bronchodilators such as salmeterol or tiotro-
pium (Fabbri et al.
2009
). In contrast, the clinical effects of oral PDE4 inhibitors are
not associated with acute bronchodilation (Harbinson et al.
1997
; Engelstaetter
et al.
2002
; Grootendorst et al.
2003
). On the basis of its clinical effectiveness in
COPD, roflumilast has recently received market authorization by the European
Medicinal's Agency as the first-in-class PDE4 inhibitor for the maintenance treat-
ment of severe COPD associated with chronic bronchitis in adult patients with
a history of frequent exacerbations as an add-on to bronchodilator treatment.
Besides affecting the lungs, there is increasing awareness of extrapulmonary
components of COPD, reflected as systemic inflammation and comorbidities
(Agusti and Soriano
2008
; Barnes and Celli
2009
). The idea may be proposed that
oral PDE4 inhibitors by virtue of their anti-inflammatory potential and their ability
