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.
