PMID- 36422852 OWN - NLM STAT- MEDLINE DCOM- 20230303 LR - 20230303 IS - 1179-1888 (Electronic) IS - 1175-0561 (Print) IS - 1175-0561 (Linking) VI - 24 IP - 2 DP - 2023 Mar TI - Pharmacokinetics of Roflumilast Cream in Chronic Plaque Psoriasis: Data from Phase I to Phase III Studies. PG - 315-324 LID - 10.1007/s40257-022-00741-9 [doi] AB - BACKGROUND: Most patients with chronic plaque psoriasis receive topical treatment; however, available options lack a balance of efficacy with long-term safety and tolerability. Roflumilast cream 0.3% is a highly potent phosphodiesterase 4 (PDE4) inhibitor approved by the US FDA for treatment of psoriasis. OBJECTIVE: The aim of this study was to define the pharmacokinetic (PK) profile of roflumilast delivered topically from a phase I maximal usage study and data from phase II and phase III studies. METHODS: PK data for roflumilast and the active metabolite, roflumilast N-oxide, were determined from a phase I PK 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 (BSA) >/=20% (N = 26). Serial plasma samples were obtained on Days 1 and 15 to determine maximum plasma concentration (C(max)) and area under the concentration-time curve (AUC). Plasma concentrations were also assessed at Weeks 3, 4, and 5 for terminal half-life (t((1/2))). Concentrations of roflumilast and roflumilast N-oxide in skin were assessed at Day 28 for 14 patients with psoriasis in a phase I/IIa study of once-daily roflumilast cream 0.5% and 0.15% for 28 days. Systemic exposure (C(trough) 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 was assessed at Weeks 4 and 8. RESULTS: Bioavailability of roflumilast cream 0.3% after topical administration was 1.5%. Unlike after oral dosing, the plasma concentration-time curve was flat, with a peak-to-trough ratio of 1.2. Roflumilast N-oxide concentrations were eightfold higher than roflumilast concentrations. The t((1/2)) in adult patients was 4.0 days for roflumilast and 4.6 days for roflumilast N-oxide following the last dose administered. Steady state was reached by Day 15. Concentrations of roflumilast in skin were, on average, 126- and 61.8-fold higher than corresponding mean plasma C(trough) following administration of roflumilast cream 0.15% and 0.5% daily for 28 days. Roflumilast N-oxide was quantifiable in only one skin sample (N = 27). Following 8 weeks of treatment in DERMIS-1, mean plasma C(trough) of roflumilast was 1.78 ng/mL, and 9.86 ng/mL for roflumilast N-oxide. In DERMIS-2, mean plasma C(trough) was 1.72 ng/mL and 10.2 ng/mL, respectively. In the maximal usage study (mean BSA: 27.5%), eight patients (30.8%) experienced adverse events (AEs) and all were mild or moderate, with no reports of diarrhea, headache, insomnia, or application-site pain; no patients discontinued treatment due to an AE. CONCLUSION: 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. 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 (t((1/2)) 4 days) and peak-to-trough ratio is 1.2. GOV IDENTIFIERS: NCT04279119, NCT03392168, NCT04211363, NCT04211389. CI - (c) 2022. The Author(s). FAU - Thurston, Archie W Jr AU - Thurston AW Jr AD - Toxicology Solutions, San Diego, CA, USA. FAU - Osborne, David W AU - Osborne DW AD - Arcutis Biotherapeutics, Inc, 3027 Townsgate Road, Suite 300, Westlake Village, CA, 91361, USA. FAU - Snyder, Scott AU - Snyder S AD - Arcutis Biotherapeutics, Inc, 3027 Townsgate Road, Suite 300, Westlake Village, CA, 91361, USA. FAU - Higham, Robert C AU - Higham RC AD - Arcutis Biotherapeutics, Inc, 3027 Townsgate Road, Suite 300, Westlake Village, CA, 91361, USA. FAU - Burnett, Patrick AU - Burnett P AD - Arcutis Biotherapeutics, Inc, 3027 Townsgate Road, Suite 300, Westlake Village, CA, 91361, USA. FAU - Berk, David R AU - Berk DR AD - Arcutis Biotherapeutics, Inc, 3027 Townsgate Road, Suite 300, Westlake Village, CA, 91361, USA. dberk@arcutis.com. LA - eng SI - ClinicalTrials.gov/NCT04279119 SI - ClinicalTrials.gov/NCT03392168 SI - ClinicalTrials.gov/NCT04211363 SI - ClinicalTrials.gov/NCT04211389 PT - Clinical Trial, Phase I PT - Clinical Trial, Phase II PT - Clinical Trial, Phase III PT - Journal Article DEP - 20221124 PL - New Zealand TA - Am J Clin Dermatol JT - American journal of clinical dermatology JID - 100895290 RN - 0 (Aminopyridines) RN - 0 (Phosphodiesterase 4 Inhibitors) RN - 0P6C6ZOP5U (Roflumilast) RN - F08MQ6CZCS (roflumilast N-oxide) SB - IM MH - Adult MH - Humans MH - Aminopyridines MH - *Phosphodiesterase 4 Inhibitors/therapeutic use MH - *Psoriasis/drug therapy PMC - PMC9968262 COIS- Archie W. Thurston Jr is an employee of Toxicology Solutions and a consultant with Arcutis Biotherapeutics, Inc. David R. Berk, David W. Osborne, Scott Snyder, Robert C. Higham, and Patrick Burnett are employees of Arcutis Biotherapeutics, Inc. EDAT- 2022/11/25 06:00 MHDA- 2023/03/03 06:00 PMCR- 2022/11/24 CRDT- 2022/11/24 11:31 PHST- 2022/10/20 00:00 [accepted] PHST- 2022/11/25 06:00 [pubmed] PHST- 2023/03/03 06:00 [medline] PHST- 2022/11/24 11:31 [entrez] PHST- 2022/11/24 00:00 [pmc-release] AID - 10.1007/s40257-022-00741-9 [pii] AID - 741 [pii] AID - 10.1007/s40257-022-00741-9 [doi] PST - ppublish SO - Am J Clin Dermatol. 2023 Mar;24(2):315-324. doi: 10.1007/s40257-022-00741-9. Epub 2022 Nov 24.