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Fixed parameters were the IC 50 , F u , and
. The previously determined in vitro
IC 50(rof) of 0.7 nM and IC 50(rofNO) of 2 nM were used for these calculations
(Hatzelmann and Schudt 2001 ). The dosing interval
t
was 24 h with a once-daily
dosing. The free fractions of the PDE4 inhibitors were 1% for roflumilast and 3%
for roflumilast N-oxide (Fig. 4 ) (Bethke et al. 2007 ).
t
Fig. 4 The concept of total PDE4 inhibitory activity
No clinically relevant pharmacokinetic interactions were observed between
roflumilast and commonly coprescribed drugs such as salbutamol (Bethke et al.
2006 ), formoterol, or budesonide (De Mey et al. 2006b ; Hermann et al. 2007a ).
No relevant drug interactions have been observed between roflumilast and
inhibitors of its main metabolizing enzyme CYP 3A4 (ketoconazole, erythromycin,
increase of tPDE4i by 9% each) nor with competitive substrates of CYP 3A4
(midazolam) (Lahu et al. 2008 ; Lahu et al. 2009 ; Nassr et al. 2007a ). Coadminis-
tration of roflumilast with a potent CYP 1A2 inhibitor (fluvoxamine) increased the
exposure of roflumilast by a factor of 2.6 and of roflumilast N-oxide by a factor of
1.5, respectively (von Richter et al. 2007 ). Coadministration of roflumilast and
the typical cytochrome P450 enzyme inducer rifampicin reduced the exposure to
roflumilast ( C max , AUC by 68 and 79%, respectively) and the N-oxide ( C max , AUC
by 30 and 56%, respectively) (Nassr et al. 2009 ). Smoking is known to induce
CYP 1A2 and roflumilast is (also) metabolized by this enzyme, but no effects of
smoking status on the pharmacokinetics of roflumilast and roflumilast N-oxide
have been observed in healthy adults (Bethke et al. 2001b ), though population-
pharmacokinetic data revealed a 20% decrease of exposure (Lahu et al. 2010 ).
The potential of roflumilast to interact with narrow therapeutic margin drugs
such as digoxin (Eckermann et al. 2011 ), warfarin (McCracken et al. 2011 ), or
theophylline (B
ohmer et al. 2011 ) has also been studied. No clinically relevant
pharmacokinetic interaction was found.
Subjects taking roflumilast in fed state have a significantly reduced maximum
exposure ( C max decreased from 6.52 to 3.86 m gl 1 ) to roflumilast, but the maxi-
mum plasma concentration of the active metabolite remains constant (Hauns et al.
2006 ). The time to reach the peak plasma concentration ( T max increase from 0.96
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