LEO-29102

To investigate the difference in clinical efficacy in AD patients between two topical PDE4 inhibitors using dermal open flow microperfusion and cAMP as a pharmacodynamic read-out in fresh human skin explants.

Clinical formulations were applied to intact or barrier disrupted human skin explants and both skin biopsy samples and dermal interstitial fluid was sampled for measuring drug concentration. Furthermore, cAMP levels were determined in the skin biopsies as a measure of target engagement.

Elevated cAMP levels were observed with LEO 29102 while no evidence of target engagement was obtained with LEO 39652. In barrier impaired skin the dISF concentration of LEO 29102 was 2100 nM while only 33 nM for LEO 39652. For both compounds the concentrations measured in skin punch biopsies were 7-33-fold higher than the dISF concentrations.

Low unbound drug concentration in dISF in combination with minimal target engagement of LEO 39652 in barrier impaired human skin explants supports that lack of clinical efficacy of LEO 39652 in AD patients is likely due to insufficient drug availability at the target. We conclude that dOFM together with a pharmacodynamic target engagement biomarker are strong techniques for establishing skin PK/PD relations and that skin biopsies should be used with caution.

In the present study, the SD concept is part of the more general recognition that drug design needs to fully integrate metabolic con-siderations from the very beginning as metabolites contribute significantly to the overall activity and toxicity profile of the original drug and focus not on improving activity alone, but on improving the activity/toxicity ratio.This is usually characterized by the therapeutic index, typically defined as the ratio between the half-maximal toxic and effec-tive doses: TI = TD50/ED50.These ideas are the main underlying principles of retrometabolic drug design, which incorporates both SD and chem. delivery system (CDS) design.For most drugs, several metabolites are formed following administration, and they can contribute significantly not just to the overall activity, but also to toxicity and side effects.This can lead to complex time-profiles as illustrated in Figure 1(a), which shows the case of a hypothetical drug D that is present together with its active, toxic, and inactive metabolites.In light of these, the SD approach, which provides general drug design strategies, has particular potential.Because it often starts from a known active structure and focuses on designing safer drugs by decreasing side effects and toxicity, the likelihood of success is increased, especially considering the perspective highlighted by Sir James Black: the most fruitful basis for the discovery of a new drug is to start with an old drug.