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

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.

Dupilumab Provides Favorable Safety and Sustained Efficacy for up to 3 Years in an Open-Label Study of Adults with Moderate-to-Severe Atopic Dermatitis

“… Data are expressed as n (%) unless otherwise specified AD atopic dermatitis, BMI body mass index, DLQI Dermatology Life Quality Index, EASI Eczema Area and Severity Index, IGA Investigator’s Global Assessment, NRS Numerical Rating Scale, OLE open-label extension, POEM Patient-Oriented Eczema Measure, q2w every 2 weeks, q4w every 4 weeks, q8w every 8 weeks, qw weekly, SD standard deviation, TCI topical calcineurin inhibitor, TCS topical corticosteroid a Includes patients from NCT01259323 [ 14 , 19 ] ( N = 7); NCT01859988 [ 20 ] ( N = 296); NCT01385657 [ 14 , 19 ] ( N = 12); NCT01548404 [ 14 ] ( N = 51); NCT01639040 [ 14 ] ( N = 17); NCT02260986 [ 10 ] ( N = 581); NCT01979016 [ 18 ] ( N = 44); NCT02210780 [ 15 ] ( N = 168); NCT02277743 [ 12 ] ( N = 353); NCT02407756 [ 16 ] ( N = 5); NCT02395133 [ 22 ] ( N = 415); NCT02277769 [ 12 ] ( N = 402); NCT02755649 [ 11 ] ( N = 313); NCT02647086 [ 17 ] ( N = 13) b These patients completed the treatment and end-of-study periods c Includes reasons of relocation, desire for pregnancy, did not want to discontinue treatment for 12 weeks, work/school conflict, and personal reasons not specified d Includes patients withdrawn from the study, both those receiving treatment at the time of withdrawal and those not receiving treatment during the safety follow-up period e Includes the following dupilumab doses in the parent study: 75 mg qw, 100 mg q4w, 150 mg qw, 200 mg q2w, 200 mg qw, 300 mg q8w, 300 mg q4w, 2 mg/kg, 4 mg/kg f These patients had screen failed in the parent study because the enrollment target was met, but they were permitted to enter the OLE …”

Secukinumab Treatment Does Not Alter the Pharmacokinetics of the Cytochrome P450 3A4 Substrate Midazolam in Patients With Moderate to Severe Psoriasis

“…However, in patients with psoriasis and atopic dermatitis, the situation seems to be different. DDDI studies, such as with the anti‐IL‐4/IL‐13 antibody dupilumab in patients with moderate‐to‐severe atopic dermatitis and with the anti‐IL‐23p19 monoclonal antibodies risankizumab and tildrakizumab in patients with moderate‐to‐severe psoriasis, showed no significant effect on the PK of CYP3A4, CYP2C19, CYP2C9, CYP1A2, or CYP2D6 substrates …”

Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of Dupilumab in Healthy Adult Subjects

“…Serum concentrations of functional dupilumab (which represent antibody molecules with at least 1 available binding site, that is, the sum of free dupilumab [2 available binding sites] and dupilumab present in a 1:1 human IL-4Rα/dupilumab complex) were determined using a validated ELISA method (Regeneron Pharmaceuticals, Inc., Tarrytown, New York). 28,32,33 The lower limit of quantification was 0.078 mg/L. The following PK parameters were determined using noncompartmental methods: arithmetic mean of peak concentration (C max ), median time to C max (t max ), and arithmetic mean (±SD) of area under the concentration-time curve to time of last measurable concentration (AUC last , calculated using actual times).…”

“…31 Furthermore, drug-drug interaction assessments between dupilumab and cytochrome P450 (CYP) substrates (including substrates of CYP3A, CYP2C19, CYP2C9, CYP1A2, and CYP2D6) revealed no significant impact of dupilumab on enzyme activities in patients with moderate to severe AD. 32 This article describes 6 phase 1 studies of dupilumab in healthy adult subjects. The aims of these studies were to assess the safety, tolerability, and PK profiles of dupilumab in healthy adult subjects after single intravenous (IV) or subcutaneous (SC) doses; to examine the influence of body weight and race/ethnicity (Japanese versus non-Japanese populations) on PK in the absence of disease; to confirm the consistency of systemic dupilumab exposure for products derived from various manufacturing and formulation processes; and to describe the pharmacodynamic (PD) responses of biomarkers known to be dependent on IL-4 and IL-13 signaling, including total immunoglobulin E (IgE) and thymus-and activation-regulated chemokine (TARC).…”