Pharmacokinetics of the selective PDE4 inhibitor Roflumilast and its active metabolite Roflumilast N-oxide are not affected by concomitant budesonide, salbutamol, or erythromycin

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Abstract Rationale Roflumilast is a novel, potent, selective phosphodiesterase 4 (PDE4) inhibitor in clinical development for the treatment of COPD and asthma. Patients with these diseases often receive concomitant medications. Therefore, investigation of potential drug interactions is important. Methods Three randomized, open-label studies evaluated potential pharmacokinetic interactions of oral Roflumilast and inhaled budesonide or salbutamol, or oral erythromycin in healthy subjects. Two studies (3-period crossover design) included 12 males in each: subjects received for 7 days (1) Roflumilast 500μg once daily (od), budesonide 400μg twice daily (800μg/day), or both medications together; (2) Roflumilast 500μg od, salbutamol 2×100 μ g three times daily (600μg/day), or both concomitantly. In the third study (a two-period design), 18 males received a single dose of erythromycin-ethylsuccinate 588mg followed by Roflumilast 500μg od for 11 days, and Roflumilast 500μg and erythromycin-ethylsuccinate 588mg on Day 11. Results Point estimates and 90% confidence intervals for AUC 0–24h and C max of Roflumilast and its active metabolite, Roflumilast N-oxide, did not vary with concomitant administration of budesonide, salbutamol, or erythromycin. Neither Roflumilast nor Roflumilast N-oxide had any influence on pharmacokinetics of budesonide or salbutamol. Concomitant Roflumilast and erythromycin reduced AUC and C max of erythromycin to a not clinically relevant extent (24% and 20%) when compared with antibiotic alone. There were no clinically relevant changes in vital signs, ECG, or clinical laboratory parameters. Conclusions There were no pharmacokinetic interactions between Roflumilast or Roflumilast N-oxide and budesonide or salbutamol, and only minor interaction with erythromycin were observed. Therefore, these drugs can be co-administered without dose adjustments. Roflumilast was well tolerated.