The Oral, Once‐Daily Phosphodiesterase 4 Inhibitor Roflumilast Lacks Relevant Pharmacokinetic Interactions With Inhaled Budesonide

Abstract

This open-label, randomized, 3-period crossover study evaluated the pharmacokinetic interaction potential of roflumilast and budesonide following repeated coadministration to healthy male subjects (N = 12). Treatments consisted of oral roflumilast 500 mug, once daily, orally inhaled budesonide 800 mug, twice daily, and concomitant administration of both treatments for 7 days each. Roflumilast and roflumilast N-oxide in plasma and budesonide serum levels were measured by specific assays. Geometric mean test/reference ratios of steady-state pharmacokinetic parameters were evaluated by analysis of variance. Safety and tolerability were monitored. Pharmacokinetic parameters of roflumilast, roflumilast N-oxide, and budesonide after coadministration of roflumilast and budesonide were similar to those after mono-treatment. Compared with budesonide and roflumilast mono-treatments, slightly lower maximum serum/plasma concentration (C(max)) and area under the curve (AUC) values of roflumilast N-oxide and budesonide (ranging from -8% to -16%) were observed with combined treatment. All test/reference ratios were within predefined equivalence acceptance ranges for roflumilast AUC (0.80, 1.25) and C(max) (0.70, 1.43) and for roflumilast N-oxide and budesonide AUC and C(max) (all 0.67, 1.50). Coadministration of roflumilast and budesonide did not alter the steady-state disposition of each other and did not affect safety and tolerability of either drug.

Pharmacokinetic evaluation of roflumilast

“…The potential pharmacokinetic interactions between roflumilast 500 µg once daily and inhaled budesonide 400 µg b.i.d. (administered by dry powder inhaler) were assessed in 12 healthy subjects (median age, 26 years) in an open-label, three-period, crossover study [46]. The plasma concentration--time profiles of roflumilast alone or in combination with budesonide were very similar, suggesting that the pharmacokinetic characteristics of roflumilast were unaltered by concomitant budesonide.…”

Treatment of Chronic Obstructive Pulmonary Disease with Roflumilast, a New Phosphodiesterase 4 Inhibitor

“…Neither roflumilast nor roflumilast N-oxide by themselves inhibit CYP3A4 or CYP1A2 (40). Other data suggest a low potential for roflumilast to interact adversely with other drugs including montelukast, erythromycin, ketoconazole, budesonide, albuterol, midazolam (40), and antacids containing magnesium hydroxide or aluminium hydroxide (59)(60)(61)(63)(64)(65)(66)(67). This is important to determine because inducers of CYP3A4 and CYP1A2 have the potential to increase the CL of roflumilast thereby lowering its efficacy.…”

“…Correspondingly, agents that are metabolized by the same system could compete with roflumilast and delay its inactivation, in effect raising its level. A number of studies have been performed to evaluate such drug-drug interactions and their potential for adverse reactions (59)(60)(61)(62)(63)(64)(65)(66)(67). The results published so far indicate that there is not a substantial effect of a range of potential agents and conditions on roflumilast levels.…”

Drug interactions

“…These changes were insufficient to cause any change in pharmacodynamics. Hermann et al (2007) have shown that roflumilast does not affect the pharmacokinetics of budesonide, a CYP3A4 substrate, and vice versa. Consistent with the lack of an effect on CYP3A4-dependent metabolism, Nassr et al (2007) did not find any pharmacokinetic Drug Metabolism Reviews Downloaded from informahealthcare.com by MIT Libraries on 11/04/14…”