Roflumilast: Drug Pharmacology and Clinical Efficacy

General Description

Roflumilast cream, a topical treatment for plaque psoriasis, undergoes metabolism primarily via CYP3A4 and CYP1A2, forming roflumilast N-oxide, its major metabolite. Pharmacokinetic studies show low bioavailability (1.5%) and slow absorption, achieving steady state by day 15 with minimal concentration fluctuations. Roflumilast and its metabolite exhibit an extended half-life and accumulate in skin, suggesting localized action with minimal systemic exposure. Clinical trials demonstrate significant efficacy in reducing plaque severity and achieving PASI 75 response in patients, confirming its effectiveness across varying psoriasis severities. Overall, roflumilast cream shows promise as a well-tolerated option, supporting its clinical utility in dermatological practice.

Figure 1. Roflumilast

Drug Pharmacology

Pharmacokinetics

Roflumilast undergoes metabolism primarily via the cytochrome P450 system, specifically CYP3A4 and CYP1A2, resulting in its major metabolite, roflumilast N-oxide. This metabolite, though less potent than roflumilast, exhibits significantly higher concentrations in plasma following topical administration. In a maximal use study, roflumilast cream 0.3% demonstrated low bioavailability (1.5%) and slow absorption, achieving steady state by day 15. The concentration-time curve showed minimal fluctuations, indicative of a flat profile with a peak-to-trough ratio of 1.2. Pharmacokinetic parameters such as Cmax and AUC values were similar in adults and adolescents with moderate plaque psoriasis, suggesting consistent systemic exposure across different age groups.

Long-term Pharmacodynamics

The extended half-life of roflumilast (4.0 days) and roflumilast N-oxide (4.6 days) following topical administration points towards potential reservoir formation within the skin, facilitating slow release into the bloodstream. This observation aligns with the drug's high protein affinity and lipophilic nature, promoting its retention in skin tissues. Biodistribution studies, using punch biopsies, revealed significantly higher concentrations of roflumilast in the skin compared to plasma, further emphasizing its localized action and minimal systemic exposure. Notably, conversion of roflumilast to its N-oxide metabolite was limited within skin samples, underscoring the drug's metabolic behavior in cutaneous tissues.

Special Considerations and Contraindications

Clinical trials investigating hepatic or renal impairment did not proceed with topical roflumilast, but findings from oral formulations suggest increased plasma exposure in patients with mild to moderate hepatic impairment. Consequently, topical roflumilast is contraindicated in individuals with moderate to severe hepatic impairment. Limited data on renal impairment indicate no significant changes in pharmacokinetic profiles. Regarding potential drug interactions, while formal studies for topical roflumilast are lacking, oral formulations have shown increased plasma exposure when co-administered with certain CYP3A4 inhibitors and combination oral contraceptives. Prescribers should exercise caution and review concurrent medications when prescribing roflumilast cream. ¹

Clinical Efficacy

Phase I/II Trials

In initial trials, roflumilast cream demonstrated promising efficacy in treating mild-to-moderate plaque psoriasis. Participants applying roflumilast cream at concentrations of 0.5% and 0.15% experienced significant reductions in Total Plaque Severity Score (TPSS) and Total Plaque Area (TPA) within just 4 weeks compared to vehicle alone. Notably, improvements were evident as early as 2 weeks post-treatment initiation, with no indication of response plateauing by the fourth week. These findings suggest that roflumilast's efficacy may potentially increase with prolonged use, highlighting its progressive benefits in managing plaque psoriasis.

In a subsequent phase IIb trial (NCT03638258), 331 participants with mild-to-moderate plaque psoriasis were randomized to receive roflumilast cream 0.3%, roflumilast cream 0.15%, or vehicle cream daily over 12 weeks. The primary endpoint, achieving clear or almost clear status on the Investigator Global Assessment (IGA) scale by week 6, was met by 28% and 23% of participants in the 0.3% and 0.15% roflumilast groups, respectively, compared to only 8% in the vehicle group (p < 0.001). By week 12, these percentages increased to 38% and 32% for the roflumilast groups, demonstrating sustained efficacy. Moreover, a subset analysis revealed substantial efficacy in treating intertriginous psoriasis, with 73% of patients in the roflumilast 0.3% group achieving significant improvement at 6 weeks compared to 29% in the vehicle group. These results underscore roflumilast's robust efficacy in diverse manifestations of plaque psoriasis, reinforcing its potential as a viable treatment option. ²

Phase III Trials

Two pivotal phase III trials, DERMIS-1 (NCT04211363) and DERMIS-2 (NCT0421138), further validated roflumilast cream's efficacy and safety in a larger cohort of 881 participants with varying severities of plaque psoriasis. Participants were treated daily with roflumilast cream 0.3% or vehicle cream for 12 weeks, with outcomes demonstrating significant reductions in Psoriasis Area and Severity Index (PASI) scores favoring the roflumilast groups. At 8 weeks, 41.6% and 7.6% of roflumilast-treated patients achieved PASI 75 response in the DERMIS-1 trial, compared to 39.0% and 5.3% in the vehicle group (p < 0.001). Notably, patients with intertriginous involvement also showed marked improvement, further supporting roflumilast's efficacy across different psoriasis types. These trials confirm roflumilast cream as an effective and well-tolerated treatment option for plaque psoriasis, reinforcing its potential clinical utility in dermatological practice. ²

Reference

1. Thurston AW, Osborne DW, Snyder S, et al Pharmacokinetics of roflumilast cream in chronic plaque psoriasis: data from phase I to phase III studies. Am J Clin Dermatol. 2023; 24(2): 315–324.

2. Drakos A, Vender R, Torres T. Topical roflumilast for the treatment of psoriasis. Expert Rev Clin Immunol. 2023 Jul-Dec; 19(9): 1053-1062.

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