Population Pharmacokinetic-Pharmacodynamic (popPK/PD) Relationship of Orismilast, A Potent and Selective PDE4B/D Inhibitor, in Atopic Dermatitis

Introduction: Orismilast is a novel oral selective inhibitor of phosphodiesterase 4B and 4D subtypes (PDE4B/D) in clinical development for treatment of atopic dermatitis (AD) and other inflammatory skin conditions. Herein, we describe a pharmacokinetic/pharmacodynamic (PK/PD) analysis comparing predicted exposure data of orismilast and apremilast in AD patients and place these data in the context of their IL-13 secretion data generated in a human whole-blood assay. Methods: A PK/PD assessment of orismilast and apremilast in AD was performed. In a human whole blood assay, the levels needed to inhibit IL-13 production were measured for orismilast and apremilast head-to-head. These data were then contextualized with simulated exposure of clinically relevant doses of the two drugs. Results: The analysis shows that orismilast has potential to significantly inhibit IL-13 production at all three clinical doses trialed in AD (20 mg bid, 30 mg bid, and 40 mg bid) as the drug has a predicted Caverage plasma concentration exceeding the IL-13 IC90 value of the human whole-blood assay and a predicted Cmin above the IL-13 IC50 value. Apremilast, in contrast, is predicted to reach Caverage plasma concentrations below the IL-13 IC50 value for both doses (30 mg bid and 40 mg bid) and only exceeding the IL-13 IC50 value at peak concentrations for the highest dose. Conclusion: The outcome of the analysis supports the observed clinical effect of orismilast in patients with AD and could explain the lack of efficacy of apremilast in the same indication.