Roflumilast, a once-daily oral phosphodiesterase 4 inhibitor, lacks relevant pharmacokinetic interactions with inhaled salbutamol when co-administered in healthy subjects.
OBJECTIVE
Roflumilast is an oral, once-daily phosphodiesterase 4 inhibitor under investigation for the treatment of chronic obstructive pulmonary disease and asthma. In clinical practice, the drug is likely to be co-administered with inhaled bronchodilating beta2-adrenoceptor agonists. Therefore, this study investigated the pharmacokinetic characteristics of roflumilast and its pharmacodynamically active metabolite roflumilast N-oxide when co-administered with orally inhaled salbutamol in healthy subjects.


METHODS
In this open, randomized clinical study, 12 healthy male subjects received repeated doses of oral roflumilast 500 microg once daily, orally inhaled salbutamol 200 microg 3 times daily, and a combination of both drugs over 7 days according to a 3-period, changeover design with 14 days washout between treatments.


RESULTS
Co-administration of roflumilast and salbutamol did not markedly change roflumilast or roflumilast N-oxide disposition. Point estimates (90% confidence intervals) of area under the curve from 0-24 h (AUC 0-24) and maximum plasma concentration in steady state (Cmax,ss) for roflumilast with salbutamol versus roflumilast alone were 1.05 (0.94, 1.17) and 0.97 (0.84, 1.10); the respective point estimates (90% confidence intervals) for AUC 0-24 and Cmax,ss of roflumilast N-oxide were 0.98 (0.91, 1.06) and 0.98 (0.92, 1.03). Roflumilast co-administration did not alter the pharmacokinetics of steady state salbutamol. The respective point estimates (90% confidence intervals) for AUC 0-6 and Cmax,ss of salbutamol with roflumilast versus salbutamol alone were 1.10 (0.99, 1.21), 1.08 (0.91, 1.28). The combination of both drugs was well tolerated.


CONCLUSIONS
There were no relevant pharmacokinetic interactions between roflumilast and salbutamol at therapeutically effective doses.
Bethke
T D
TD
ALTANA Pharma AG, Konstanz, Germany.
Giessmann
T
T
Westphal
K
K
Weinbrenner
A
A
Hauns
B
B
Hauschke
D
D
David
M
M
Lahu
G
G
Zech
K
K
Hermann
R
R
Siegmund
W
W
D000318:Adrenergic beta-Agonists / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D000328:Adult; D000420:Albuterol / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D000631:Aminopyridines / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D001549:Benzamides / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D001993:Bronchodilator Agents / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D003521:Cyclopropanes / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D004347:Drug Interactions; D006801:Humans; D008297:Male; D010726:Phosphodiesterase Inhibitors / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*
D000318:Adrenergic beta-Agonists; D000631:Aminopyridines; D001549:Benzamides; D001993:Bronchodilator Agents; D003521:Cyclopropanes; D010726:Phosphodiesterase Inhibitors; C424423:Roflumilast; D000420:Albuterol