Biology Reference
In-Depth Information
rifampicin, and phenytoin decrease theophylline plasma concentrations. In addition,
smoking increases theophylline clearance (by inducing CYP1A2). All these inter-
ferences from concomitant drugs and smoking behavior complicate dosing, and, as a
corollary, individual dose titration and plasma level monitoring are almost imperative
measures in many cases (Boswell-Smith et al.
2006
).
Even when theophylline was given at comparably low doses, as these were
suggested for anti-inflammatory effects in asthmatics (Lim et al.
2001
) or patients
with COPD (Culpitt et al.
2002
), about 13% of patients in a large trial of almost
4,000 patients had theophylline plasma concentrations in a range indicative of a
higher risk for the occurrence of marked side effects (Ohta et al.
2004
).
2.7.2 Other Oral PDE4 Inhibitors
Though the therapeutic index of second-generation PDE4 inhibitors was improved
compared to rolipram, the development of many drugs including filaminast, lirimi-
last, piclamilast, CDP840, CI-1018, D-4418, IC485, L-826,141, SCH 351391, and
V11294A has been discontinued because of a lack of efficacy, probably as the
maximum tolerated dose was still in the lowest therapeutic or even subtherapeutic
range (Giembycz
2008
).
Apremilast (CC-10004, Celgene) (7) is another potent and selective, oral PDE4
inhibitor (IC
50
at PDE4B of 33 nM, no selectivity among PDE4A-PDE4D sub-
types) (Schafer et al.
2010
), which initially may have been developed for asthma or
COPD but recently has shown favorable efficacy in clinical trials on psoriasis and
psoriatric arthritis. In preclinical studies, apremilast confirmed the expected in vitro
anti-inflammatory profile of a PDE4 inhibitor. Yet more interestingly, apremilast
showed efficacy in mouse models of psoriasis (Schafer et al.
2010
) and rheumatoid
arthritis (McCann et al.
2010
).
In a small open-label, single-arm clinical study, 20 mg apremilast once daily
over 4 weeks improved the psoriasis area and severity index (PASI) in 74% of
patients with severe plaque-type psoriasis (Gottlieb et al.
2008
). In those patients
responding to apremilast with reduced epidermal thickness, the number of T-cells
and CD11c-positive (dendritic) cells in dermis and epidermis, as well as total NOS
in skin biopsies, was all suppressed. LPS-induced TNF-
a
release in ex vivo stimu-
lated whole-blood samples taken 2 h after the first intake of apremilast showed
25-70% inhibition in 9 of 11 patients. In this context, half-maximum inhibition of
LPS-induced TNF-
a
release in human whole blood in vitro by apremilast was at
316 nM and the maximum plasma concentration
C
max
in that clinical study was at
450 nM. Apparently, results from the ex vivo experiment were in line with
expectations from comparing the potency in the in vitro experiment with the
C
max
value.
The promising clinical results were recently confirmed in larger randomized,
double-blind, placebo-controlled trials in patients with moderate-to-severe psoriasis
or psoriatic arthritis. In the plaque-type psoriasis trial, apremilast (30 mg BID, p.o.)
met the primary end point of a 75% reduction of their PASI score (PASI-75) in 41%
