Biological products for the treatment of psoriasis: therapeutic targets, pharmacodynamics and disease-drug-drug interaction implications

Abstract

Psoriasis is a chronic inflammatory skin disease condition that involves altered expression of a broad spectrum of proinflammatory cytokines which are associated with activation of T cells and proliferation of keratinocytes. Currently approved biological products for psoriasis treatment fall into two main classes: cytokine modulators and biologics targeting T cells. In psoriatic patients, elevated levels of proinflammatory cytokines are observed. Elevated proinflammatory cytokines can suppress some cytochrome P450 (CYP) enzymes, and the treatment of psoriasis with biological products can reduce proinflammatory cytokine levels. Therefore, the exposure of CYP substrate drugs is anticipated to be affected by the psoriasis disease resulting in a higher exposure than in healthy state (named disease-drug interaction) as well as by the biological treatments due to disease improvements resulting in a decrease in exposure (named disease-drug-drug interaction, disease-DDI). However, the quantitative impact on CYP substrate exposure due to disease or due to treatment with biological products remains to be evaluated. The objective of the current review is to provide an overview of the therapeutic targets and cytokine-related pharmacodynamic effects of biological products in psoriasis treatment with a particular focus on their implications for disease-DDI. The clinical study design considerations for psoriasis disease-DDI evaluation are also discussed.

Fig. 1

Cytokines associated with psoriasis pathogenesis and potential disease-drug-drug interactions. Cytokines reported to modify CYP enzyme formation, and activities were previously reviewed by Huang et al. (16). Pathogenesis of psoriasis involves altered expression of a broad spectrum of proinflammatory and anti-inflammatory cytokines (–15). CYP cytochrome P450; hGH human growth hormone; IFN interferon; IL interleukin; TNF tumor necrosis factor

Fig. 2

Cytokine-mediated disease-DDI in inflammatory disease conditions (e.g., psoriasis). Proinflammatory cytokines are overexpressed under an inflammatory disease condition such as psoriasis. Elevated levels of cytokines down-regulate the formation, stability, and activity of drug-metabolizing enzymes including cytochrome P450 enzymes (CYP), which in turn result in increased exposure of CYP substrate. Following biological treatment and disease condition improvement, the exposure of the CYP substrate is normalized to that in healthy subjects (assuming that maximal treatment effect induces complete normalization of cytokine levels into healthy state). In the event of disease return (relapse) or worsening (rebound) when the biological therapy is discontinued or even during the treatment, reelevated levels of cytokines result in CYP enzymes inhibition and increased exposure of small molecule drugs. In the event of the disease rebound, the exposure of the CYP substrate could be even higher than that before the initiation of the biological treatment due to worsening of the disease (see text). In situations of disease relapse or rebound, and when new therapies are reinitiated, patients who are receiving concomitant CYP substrate, monitoring of the effect or drug concentration is needed, particularly for CYP substrates with narrow therapeutic index where the dose is individually adjusted