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

John D Davis, Ashish Bansal, David Hassman, Bolanle Akinlade, Meng Li, Zhaoyang Li, Brian Swanson, Jennifer D Hamilton, A Thomas DiCioccio, John D Davis, Ashish Bansal, David Hassman, Bolanle Akinlade, Meng Li, Zhaoyang Li, Brian Swanson, Jennifer D Hamilton, A Thomas DiCioccio

Abstract

This open-label drug-drug interaction study assessed whether blockade by dupilumab of interleukin (IL)-4 and IL-13 signaling affects the pharmacokinetics of drugs metabolized by cytochrome P450 (CYP450) enzymes. The pharmacokinetics of five CYP450 substrates given orally (midazolam, omeprazole, S-warfarin, caffeine, and metoprolol, metabolized by CYP3A, CYP2C19, CYP2C9, CYP1A2, and CYP2D6, respectively) were evaluated before and 28 days after initiation of dupilumab treatment (subcutaneous 300 mg weekly) in 14 patients with moderate-to-severe atopic dermatitis. Dupilumab had no clinically relevant effects on the pharmacokinetics of CYP450 substrates, provided substantial clinical benefit, and was generally well tolerated. Only one serious adverse event was reported, an episode of systemic inflammatory response syndrome that resolved after treatment was discontinued. In summary, blockade of IL-4/IL-13 signaling in patients with type 2 inflammation does not appear to significantly affect CYP450 enzyme activities; the use of dupilumab in atopic dermatitis patients is unlikely to influence the pharmacokinetics of CYP450 substrates.

Trial registration: ClinicalTrials.gov NCT02647086.

© 2018 The Authors Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

Figures

Figure 1
Figure 1
Mean (SE) percent change in EASI scores following initiation of dupilumab treatment. EASI, Eczema Area and Severity Index.
Figure 2
Figure 2
Median percent change from baseline (Q1–Q3 range) in serum concentrations of (a) TARC and (b) LDH. LDH, lactate dehydrogenase; TARC, thymus and activation regulated chemokine. [Color figure can be viewed at http://wileyonlinelibrary.com]
Figure 3
Figure 3
Concentration–time curves for the five CYP substrates in plasma before and after dupilumab treatment. Data presented as mean (±SD). SD, standard deviation.
Figure 4
Figure 4
Study design. OLE, open‐label extension; PK, pharmacokinetic.

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