Purpose

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.

Methods

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.

Results

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.

Conclusions

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.

中文翻译：

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评估软局部 PDE4 抑制剂的皮肤药代动力学和药效学效应：开放式微灌注和皮肤活检

目的

研究两种局部 PDE4 抑制剂在 AD 患者中的临床疗效差异，使用皮肤开放流微灌注和 cAMP 作为新鲜人皮肤外植体的药效学读数。

方法

将临床制剂应用于完整或屏障破坏的人皮肤外植体，并对皮肤活检样品和真皮间质液进行取样以测量药物浓度。此外，在皮肤活检中确定了 cAMP 水平，作为目标参与的衡量标准。

结果

使用 LEO 29102 观察到 cAMP 水平升高，而使用 LEO 39652 未获得目标参与的证据。在屏障受损的皮肤中，LEO 29102 的 dISF 浓度为 2100 nM，而 LEO 39652 的 dISF 浓度仅为 33 nM。对于这两种化合物，在皮肤打孔中测量的浓度活组织检查比 dISF 浓度高 7-33 倍。

结论

dISF 中未结合的药物浓度低，再加上 LEO 39652 在屏障受损的人类皮肤外植体中的最小靶点参与支持 LEO 39652 在 AD 患者中缺乏临床疗效可能是由于靶点的药物可用性不足。我们得出结论，dOFM 与药效靶标参与生物标志物是建立皮肤 PK/PD 关系的强大技术，应谨慎使用皮肤活检。