Abstract
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 C(average) plasma concentration exceeding the IL-13 IC(90) value of the human whole-blood assay and a predicted C(min) above the IL-13 IC(50) value. Apremilast, in contrast, is predicted to reach C(average) plasma concentrations below the IL-13 IC(50) value for both doses (30 mg bid and 40 mg bid) and only exceeding the IL-13 IC(50) 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.