Indications
Oral roflumilast is primarily indicated to mitigate the risk of exacerbations in patients with severe chronic obstructive pulmonary disease (COPD), particularly those with chronic bronchitis and a history of exacerbations. In its topical form, roflumilast cream is approved for the treatment of plaque psoriasis, including in intertriginous regions, and is also used for managing mild to moderate atopic dermatitis in patients aged six years and older. Additionally, the topical foam formulation is authorized for treating seborrheic dermatitis in individuals nine years of age and above.
Pharmacodynamics
Roflumilast exerts its therapeutic effects by inhibiting phosphodiesterase-4 (PDE4), leading to an increase in cyclic adenosine monophosphate (cAMP) in target cells. Both roflumilast and its active metabolite, roflumilast N-oxide, demonstrate high selectivity for PDE4, showing minimal activity against other phosphodiesterases such as PDEs 1, 2, 3, 5, and 7. This selective inhibition results in the modulation of inflammatory responses, which is beneficial in managing conditions like COPD and psoriasis.
Absorption
After administering a 500 microgram dose orally, roflumilast achieves a bioavailability of approximately 80%. When taken in the fasted state, peak plasma concentrations occur within 0.5 to 2 hours. However, in the fed state, the maximum concentration (Cmax) is diminished by 40%, while the time to reach this concentration (Tmax) is extended by one hour, although the overall absorption remains unaffected. For topical applications in adults, the mean systemic exposure for roflumilast and its N-oxide metabolite is 72.7 ± 53.1 and 628 ± 648 h·ng/mL, respectively. In adolescents, these values are slightly lower, recorded at 25.1 ± 24.0 and 140 ± 179 h·ng/mL, respectively.
Metabolism
Roflumilast undergoes metabolic conversion to its active metabolite, roflumilast N-oxide, primarily via the cytochrome P450 enzymes CYP3A4 and CYP1A2. Although the N-oxide metabolite possesses less potency in inhibiting PDE4 compared to its parent compound, its plasma area under the curve (AUC) is substantially greater, approximately tenfold, contributing to its overall pharmacological efficacy.
Mechanism of Action
Roflumilast, along with its active metabolite roflumilast N-oxide, functions as an inhibitor of phosphodiesterase 4 (PDE4), a key enzyme involved in the breakdown of cyclic 3',5'-adenosine monophosphate (cyclic AMP) within cells. By inhibiting PDE4 activity, these compounds lead to increased levels of intracellular cyclic AMP. Although the precise mechanisms through which roflumilast achieves its therapeutic effects are not fully understood, this action is fundamental to its role.
