Biological Products for the Treatment of Psoriasis: Therapeutic Targets, Pharmacodynamics and Disease-Drug-Drug Interaction Implications

Abstract

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 cytokinerelated 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.

Physiologically Based Pharmacokinetic Model to Assess the Influence of Blinatumomab‐Mediated Cytokine Elevations on Cytochrome P450 Enzyme Activity

“…Hence, a dedicated clinical DDI study in patient populations with a meaningful sample size may not be practical. Using the PBPK model to assess the effects of elevated cytokine levels on suppression of CYP450 enzymes was a viable approach for risk assessment for blinatumomab, and potentially for other therapeutics or diseases that influence cytokine levels . For example, some patients treated with CD19‐targeting chimeric antigen receptor (CAR) T‐cell therapy had a 75‐fold increase over pretreatment baseline levels in two of the seven measured cytokines .…”

“…For example, some patients treated with CD19‐targeting chimeric antigen receptor (CAR) T‐cell therapy had a 75‐fold increase over pretreatment baseline levels in two of the seven measured cytokines . Similarly, in patients with psoriasis, mean systemic IL‐6 concentrations were elevated 1.3–12.1‐fold compared with matched controls …”

Evaluation of Potential Disease‐Mediated Drug–Drug Interaction in Patients With Moderate‐to‐Severe Atopic Dermatitis Receiving Dupilumab

“…Although DDI studies are often conducted in healthy volunteers, this study enrolled patients with moderate‐to‐severe AD. Patients with moderate‐to‐severe disease would be expected to have the most pronounced inflammation, and thus the greatest potential for cytokine effects on CYP450 activity . The within‐subject design was expected to minimize confounding due to interpatient variability in baseline CYP450 enzyme activity, as each patient served as their own control.…”

“…In AD patients with elevated IL‐4/IL‐13 concentrations in circulation, any cell type expressing a functional receptor has the potential for activation of the pathway, including liver cells. If IL‐4/IL‐13 down‐ or upregulate CYP450 activity, the metabolism of CYP450 enzyme substrates could be altered in these patients (disease–drug interaction) . The frequent occurrence of multiple comorbid Type 2 diseases, such as comorbid asthma and AD, suggests systemic inflammation is likely present in atopic patients.…”

“…If IL-4/IL-13 down-or upregulate CYP450 activity, the metabolism of CYP450 enzyme substrates could be altered in these patients (disease-drug interaction). 34 The frequent occurrence of multiple comorbid Type 2 diseases, such as comorbid asthma and AD, suggests systemic inflammation is likely present in atopic patients. Blockade of IL-4/IL-13 signaling by an IL-4Ra antagonist such as dupilumab would be expected to dampen systemic inflammation and reverse any modulatory effect of IL-4/IL-13 on CYP450 activity in patients with AD (disease drug-drug interaction (disease-DDI)), if the Type 2 cytokines regulate the enzymes.…”