Pharmacology of orismilast, a potent and selective PDE4 inhibitor
Clinical Summary
View sourceWhat was studied
Evaluated orismilast’s PDE selectivity/potency and anti-inflammatory effects across in vitro PDE1–11 and PDE4 splice-variant assays, ex vivo human whole blood/PBMC cytokine assays (with apremilast as comparator), and an in vivo murine chronic oxazolone ear inflammation model dosed orally at 10 or 30 mg/kg.
Key findings
Orismilast potently inhibited PDE4B/D variants (IC50 3–16 nmol/L) with lower potency for PDE4C2 (104 nmol/L), and more strongly suppressed TNFα than apremilast in PBMC (IC50 10 vs 52 nmol/L; n=3 donors) and whole blood (30 vs 432 nmol/L; n=8–9). In mice, 10 and 30 mg/kg reduced ear thickness over time (p<0.0001), with 30 mg/kg showing AUC 3.4 day×mm versus dexamethasone 2 mg/kg at 2.7 day×mm, and both doses lowered ear-tissue IL-1β, IL-4, IL-5, TNFα, IFNγ, and mKC; mean serum levels were 423 and 1009 ng/mL at 10 and 30 mg/kg.
Study limitations
Findings are preclinical; the chronic oxazolone murine model may not mirror human psoriasis, atopic dermatitis, or hidradenitis suppurativa. Ex vivo assays used few human donors (PBMC n=3; whole blood n=8–9; broad cytokine panel n=4). Studies were industry-sponsored with multiple author conflicts of interest reported.
Clinical implications
No change in clinical practice. These preclinical data support continued clinical testing of oral orismilast as a selective PDE4 inhibitor with broad cytokine suppression; await results from patient trials.
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