Topical Roflumilast Cream Results in Higher Skin Concentrations


The mean plasma Ctrough of roflumilast was 1.78 ng/mL, and 9.86 ng/mL for roflumilast N-oxide after 8 weeks of treatment.

Topical Roflumilast Cream Results in Higher Skin Concentrations

Archie W. Thurston Jr., PhD

A new analysis has quantified the pharmacokinetics of roflumilast cream for patients with chronic plaque psoriasis.

A team, led by Archie W. Thurston Jr., PhD, Toxicology Solutions, defined the pharmacokinetic profile of roflumilast delivered topically from a phase 1 maximal usage study, as well as data from phase 2 and phase 3 studies.

The Patients

The majority of patients with chronic plaque psoriasis are treated with topical medications. However, the current stable of treatments lack a balance of efficacy with long-term safety and tolerability.

One potential option could be roflumilast cream 0.3%, a highly potent phosphodiesterase 4 (PDE4) inhibitor approved by the US Food and Drug Administration (FDA) earlier this year for the treatment of patients with plaque psoriasis.

The Data

In the study, the team examined pharmacokinetic data for roflumilast and roflumilast N-oxide, an active metabolite, from a phase 1 and safety maximal usage study of roflumilast cream 0.3% applied once daily for 14 days in patients with plaque psoriasis affecting body surface area of at least 20% (n = 26).

The investigators obtained serial plasma samples on day 1 and 15 to determine the maximum plasma concentration (Cmax) and the area under the concentration-time curve (AUC). They also assessed plasma concentrations at week 3, 4, and 5 for terminal half-life (t½).

The concentrations for both roflumilast and roflumilast N-oxide in skin were also assessed on day 28 for 14 patients with psoriasis in a phase 1/2a study of once-daily roflumilast cream 0.5% and 0.15% for 28 days.

Finally, they assessed the systemic exposure (Ctrough and AUC) of roflumilast and roflumilast N-oxide in two phase III trials (DERMIS-1, n = 245; DERMIS-2, n = 250) of roflumilast cream 0.3% for 8 weeks at week 4 and 8.

The bioavailability of roflumilast cream 0.3% following topical administration was 1.5%. However, unlike the results after oral dosing, the plasma concentration-time curve was flat, with a peak-to-trough ratio of 1.2, while roflumilast N-oxide concentrations were 8-fold higher than roflumilast concentrations.

The t½ in adult patients was 4.0 days for roflumilast and 4.6 days for roflumilast N-oxide after the last dose administered and the steady state was reached by day 15. A steady state was reached by day 15 and the concentrations of roflumilast in skin were on average 126- and 61.8-fold higher than corresponding mean plasma Ctrough following administration of roflumilast cream 0.15% and 0.5% daily for 28 days.

However, the team was only able to quantify roflumilast N-oxide in 1 skin sample (n = 27).

After 8 weeks of treatment in DERMIS-1, the mean plasma Ctrough of roflumilast was 1.78 ng/mL, and 9.86 ng/mL for roflumilast N-oxide. For DERMIS-2, the mean plasma Ctrough was 1.72 ng/mL and 10.2 ng/mL, respectively.

Finally 30.8% (n = 8) of the maximal usage study (mean BSA: 27.5%) experienced adverse events, all of which were mild or moderate. There were no reports of diarrhea, headache, insomnia, or application-site pain and no patients discontinued treatment because of adverse events.

“Topical administration of roflumilast cream 0.3% results in concentrations in skin 126- and 61.8-fold higher relative to plasma, which are much higher than expected to be achievable with oral dosing,” the authors wrote. “PDE4 inhibition in the skin is likely due to roflumilast as compared with its active metabolite, as there is no significant conversion to roflumilast N-oxide in the skin. Consistent with reservoir formation and retention of drug in the stratum corneum, roflumilast is slowly released from the skin (t½ 4 days) and peak-to-trough ratio is 1.2.”

The study, “Pharmacokinetics of Roflumilast Cream in Chronic Plaque Psoriasis: Data from Phase I to Phase III Studies,” was published online in the American Journal of Clinical Dermatology.

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