Background: Roflumilast is an oral, selective phosphodiesterase 4 inhibitor with anti-inflammatory effects in\r\nchronic obstructive pulmonary disease (COPD). The addition of roflumilast to long-acting bronchodilators improves\r\nlung function in patients with moderate-to-severe COPD. The present study investigated drug-drug interaction\r\neffects between inhaled formoterol and oral roflumilast.\r\nMethods: This was a single-centre (investigational clinic), open, randomised, multiple-dose, parallel-group study. In\r\nRegimen A, healthy men were treated with roflumilast (500 �µg tablet once daily; Day 2-18) and concomitant\r\nformoterol (24 �µg twice daily; Day 12-18). In Regimen B, healthy men were treated with formoterol (24 �µg twice\r\ndaily; Day 2-18) and concomitant roflumilast (500 �µg once daily; Day 9-18). Steady-state plasma pharmacokinetics\r\nof roflumilast, roflumilast N-oxide and/or formoterol (Cmax and AUC0-t) as well as pharmacodynamics - blood\r\npressure, transthoracic impedance cardiography (ZCG), 12-lead digital electrocardiography, peripheral blood\r\neosinophils, and serum glucose and potassium concentrations - were evaluated through Day 1 (baseline), Day 8\r\n(Regimen B: formoterol alone) or Day 11 (Regimen A: roflumilast alone), and Day 18 (Regimen A and B: roflumilast\r\nplus formoterol). Blood and urine samples were taken for safety assessment at screening, pharmacokinetic profiling\r\ndays and Day 19. Adverse events were monitored throughout the study.\r\nResults: Of the 27 subjects enrolled, 24 were evaluable (12 in each regimen). No relevant pharmacokinetic\r\ninteractions occurred. Neither roflumilast nor formoterol were associated with significant changes in cardiovascular\r\nparameters as measured by ZCG, and these parameters were not affected during concomitant administration.\r\nFormoterol was associated with a slight increase in heart rate and a corresponding shortening of the QT interval,\r\nwithout changes in the heart rate-corrected QTc interval. There were small effects on the other pharmacodynamic\r\nassessments when roflumilast and formoterol were administered individually, but no interactions or safety concerns\r\nwere seen after concomitant administration. No severe or serious adverse events were reported, and no adverse\r\nevents led to premature study discontinuation.\r\nConclusions: No clinically relevant pharmacokinetic or pharmacodynamic interactions were found when oral\r\nroflumilast was administered concomitantly with inhaled formoterol, including no effect on cardiac repolarisation.\r\nRoflumilast was well tolerated
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