The Targeted Oral, Once‐Daily Phosphodiesterase 4 Inhibitor Roflumilast and the Leukotriene Receptor Antagonist Montelukast Do Not Exhibit Significant Pharmacokinetic Interactions

Abstract

This nonrandomized, fixed-sequence, 3-period study investigated potential pharmacokinetic interactions between the leukotriene receptor antagonist montelukast, approved for the treatment of asthma, and roflumilast, an oral, once-daily phosphodiesterase 4 inhibitor in clinical development for asthma and chronic obstructive pulmonary disease. Pharmacokinetic interactions are of interest because both drugs may be coadministered and share a common metabolic pathway via cytochrome P450 3A. Single-dose montelukast (10 mg, po) was administered alone in period 1, followed by repeated once-daily roflumilast alone (500 microg, po) for 12 days (period 2). In period 3, 500 microg qd roflumilast was coadministered with 10 mg qd montelukast for 8 days. Different pharmacokinetic parameters were evaluated for montelukast alone, for steady-state roflumilast and its pharmacologically active metabolite roflumilast N-oxide alone, for single-dose montelukast when coadministered with steady-state roflumilast, and for steady-state roflumilast and its N-oxide metabolite when coadministered with steady-state montelukast. The AUC and Cmax of montelukast were modestly increased by 9% and 8%, respectively, when single-dose montelukast was coadministered with steady-state roflumilast. The pharmacokinetics of roflumilast and roflumilast N-oxide in steady state remained unchanged when repeat-dose montelukast was coadministered at steady-state. Concomitant administration of both drugs was well tolerated. These findings suggest that no dose adjustment is warranted for either drug when roflumilast and montelukast are coadministered.

Pharmacologically Active Drug Metabolites: Impact on Drug Discovery and Pharmacotherapy

“…The contribution of the N-oxide metabolite was modeled to be greater than the parent, and interestingly, based on comparisons of healthy volunteers and COPD patients, this contribution was modeled to be even greater in the patients. Using exposure values from Böhmer et al, (2009) Sibutramine offers an interesting example of two active metabolites and an instance wherein the parent drug probably contributes little effect. It was used as a weight-loss agent, although safety problems led to its removal from clinical practice.…”

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.…”

Roflumilast combined with montelukast versus montelukast alone as add-on treatment in patients with moderate-to-severe asthma

“…B€ ohmer et al 27 reported that the pharmacokinetics of roflumilast and roflumilast N-oxide (its active metabolite) in steady state remain unchanged when montelukast is coadministered at steady state and that both drugs are well tolerated. Thus no dose adjustment for either drug is necessary when roflumilast and montelukast are coadministered.…”