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

Li, Zhaoyang; Radin, Allen; Li, Meng; Hamilton, Jennifer D.; Kajiwara, Miyuki; Davis, John D.; Takahashi, Yoshinori; Hasegawa, Setsuo; Ming, Jeffrey E.; DiCioccio, A. Thomas; Li, Yongtao; Kovalenko, Pavel; Lu, Qiang; Ortemann‐Renon, Catherine; Ardeleanu, Marius; Swanson, Brian N.

doi:10.1002/cpdd.798

Cited by 46 publications

(61 citation statements)

References 43 publications

(72 reference statements)

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“…The study was conducted in healthy individuals, as they demonstrate similar dupilumab PK as patients with AD and other type 2 inflammatory diseases. 16,17 The primary objective of the study was to compare the systemic exposure of dupilumab after a single dose of dupilumab 200 mg SC when administered by AI relative to PFS-S. The secondary objective was to determine the safety and tolerability of a single injection of dupilumab 200 mg when administered by the 2 different devices.…”

Section: Methodsmentioning

confidence: 99%

“…dupilumab PK, with lower exposure observed at higher body weight. [16][17][18] Dupilumab is currently available for SC administration as a prefilled syringe with a needle shield (PFS-S) and an autoinjector (AI) device in 200-and 300-mg dose strengths. Drug delivery by the AI (also known as a prefilled pen) has been shown, for other drugs, to be preferred by some patients, and can be administered by patients or caregivers, and thus may increase compliance over long treatment durations.…”

mentioning

confidence: 99%

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Pharmacokinetics of Subcutaneous Dupilumab Injection With an Autoinjector Device or Prefilled Syringe

Cohen

Zhang

Xia

et al. 2022

Clinical Pharm in Drug Dev

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Dupilumab, a human monoclonal antibody against interleukin‐4 receptor alpha, has demonstrated efficacy and an acceptable safety profile in adult and pediatric patients with moderate‐to‐severe atopic dermatitis (AD) and other type 2 inflammatory diseases. Dupilumab is available in 200‐ and 300‐mg strengths as a prefilled syringe with a needle shield (PFS‐S), and more recently as an autoinjector (AI) device. This study was designed to assess the pharmacokinetic (PK) comparability of a single subcutaneous (SC) dose of dupilumab 200 mg, delivered by 2 different devices, AI (test) versus PFS‐S (reference). A total of 130 healthy male and female participants were enrolled in this phase 1 parallel design study, with 128 evaluable for PK. Following dupilumab 200‐mg SC injection, dupilumab exposure in serum was similar for both AI and PFS‐S. The geometric mean ratios of PK parameters with 90% confidence intervals were 1.08 (0.97‐1.21) for maximum serum concentration (Cmax) and 1.11 (0.96‐1.28) for area under the serum concentration–time curve until the last quantifiable concentration (AUClast). Dupilumab administration by both devices was well tolerated, and there were no serious adverse events, or severe treatment‐emergent adverse events experienced during the study. Overall, exposure to dupilumab 200 mg was comparable when administered via the AI or PFS‐S devices in healthy male and female study participants.

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Pharmacokinetics of Subcutaneous Dupilumab Injection With an Autoinjector Device or Prefilled Syringe

Cohen

Zhang

Xia

et al. 2022

Clinical Pharm in Drug Dev

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“…Dupilumab achieves signaling inhibition of IL-4 by blocking both types of receptors and IL-13 signaling by blocking type 2 receptors. As a result, it causes the dual inhibition of the IL-4/IL-13 signaling pathway, producing a reduction in epidermal hyperplasia, modification in the lesional skin appearance, modulation of genes related to epidermal pathology in AD, and inhibition of the release of proinflammatory cytokines, chemokines, and IgE [19][20][21].…”

Section: Molecular Structure and Mechanism Of Actionmentioning

confidence: 99%

“…The steady-state concentration ranged from 173 ± 75.9 μg/mL to 193 ± 77.0 μg/mL for 300 mg injected weekly and from 73.3 ± 40.0 μg/mL to 79.9 ± 41.4 μg/ mL for 300 mg injected every other week. Dupilumab is metabolized by degradation into smaller peptides and amino acids with the same pathways as endogenous IgG [20,21].…”

Section: Pharmacokineticsmentioning

confidence: 99%

“…Early results showed that there is a significant increase in the serum concentrations of IL-4 and IL-13 following dupilumab administration, indicating IL-4Rα blockade [20]. There has also been a recently published study assessing the pharmacodynamics of dupilumab showing statistically significant decreases in total serum IgE, serum thymus, and activation-regulated chemokine (TARC) [21]. TARC is a correlation factor of disease activity as well as the blood eosinophil count.…”

Section: Pharmacodynamicsmentioning

confidence: 99%

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Efficacy and safety of dupilumab in adult moderate-to-severe atopic dermatitis: An update narrative literature review

Kreouzi¹,

Theodorakis²,

Thomaidou³

2022

Our Dermatol Online

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Background: Adult atopic dermatitis (AD) is defined as a continuum of childhood AD or the development of the disease in adulthood, accounting for 7.7–59.7% of adult AD cases varying in severity and manifestations. The symptomatology of moderate-to-severe adult AD may significantly impact the overall health and quality of life of the patient. The “classic” topical treatments used in mild-to-moderate cases, such as emollients and topical corticosteroids, are usually not adequate to control the symptoms of most of the patients with moderate-to-severe disease. For many years these patients were managed with systemic corticosteroids and immunomodulators, leading to substantial side effects with questionable efficacy. The introduction of dupilumab, the first biologic agent approved by the Food and Drug Administration for use in adult moderate-to-severe AD, has commenced a new era in the management of AD. This narrative literature review addresses the question of how patients with moderate-to-severe AD may achieve a recession or improvement in the overall progression of the disease with the use of dupilumab in both an efficient and safe way. Material and Methods: A search in the PubMed, Embase, and Cochrane databases was conducted using the following combination of MeSH terms: “dupilumab” AND “atopic” (“dermatitis” OR “eczema”). The searches were limited to RCTs written in the English language published before January 25, 2021. The literature used included phase II and III RCTs examining the efficacy and/or safety of dupilumab compared to placebo or other treatments in adults with moderate-to-severe AD. Moderate-to-severe AD was defined by an IGA score of 3 (moderate) or 4 (severe) and EASI 16 or higher at screening and baseline. Additionally, we searched the website clinicaltrials.gov for any unpublished or ongoing RCTs. The search was done independently by two authors in all databases and followed by the exclusion of duplicates. Results: Upon reviewing all randomized controlled trials, dupilumab was found to be an effective and safe option for managing adult moderate-to-severe AD with long-term therapeutic effects. Conclusion: The best results for maintaining long-term disease recession were achieved with the combination of dupilumab and topical corticosteroids.

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Association of Serum Dupilumab Levels at 16 Weeks With Treatment Response and Adverse Effects in Patients With Atopic Dermatitis

et al. 2022

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ImportanceThe registered dose of dupilumab for adult patients with atopic dermatitis (AD) is 300 mg every other week. At present, it is unknown whether serum dupilumab levels are associated with treatment response or adverse effects.ObjectivesTo evaluate serum dupilumab levels at 16 weeks of treatment and to explore the association of serum dupilumab levels with treatment response and adverse effects in patients with AD.Design, Setting, and ParticipantsThis clinical, prospective, observational cohort study used data from the prospective BioDay Registry including adult patients with AD who started dupilumab treatment and for whom a serum sample was available at 16 weeks of treatment. All patients were treated according to the BioDay protocol in the University Medical Center Utrecht in the Netherlands. Patients received a loading dose of dupilumab 600 mg subcutaneously, followed by 300 mg every other week. Patients who had a dose adjustment or discontinued treatment before 16 weeks of treatment were excluded. Data analyses were performed from January to June 2022.Main Outcomes and MeasuresDisease severity of AD was assessed at baseline and at weeks 16 and 52 using the Eczema Area and Severity Index (EASI). Treatment response was defined as the percent reduction in EASI score vs the baseline score (eg, EASI 90 indicated a 90% reduction) and as an absolute EASI cutoff score of 7 or lower (controlled AD). Adverse effects were recorded during the first year. At 16 weeks, dupilumab serum levels and treatment responses were measured and analyzed. Multivariate logistic regression modeling was used to determine the prediction of response (EASI 90; EASI ≤7) and adverse effects at 52 weeks, with serum dupilumab levels at 16 weeks in the presence of the covariates age and sex.ResultsAmong the total of 295 patients with AD (mean [SD] age, 41.5 [15.9] years; 170 [57.6%] men), the median (IQR [range]) drug level was 86.6 μg/mL (64.6-110.0 μg/mL [10.1-382.0 μg/mL]) at 16 weeks of treatment. No significant differences were found in serum dupilumab levels between responder statuses (EASI, &lt;50, 50, 75, or 90) at week 16. Multivariate logistic regression analysis showed nonsignificant odds ratios (ORs) for serum dupilumab levels at 16 weeks regarding prediction of long-term response (EASI ≥90: OR, 0.96 [95% CI, 0.90-1.04; P = .34] and EASI ≤7: OR, 1.03 [95% CI, 0.93-1.14; P = .55]) and adverse effects (OR, 1.01 [95% CI, 0.95-1.07; P = .83]).Conclusion and RelevanceThis prospective clinical cohort study found a broad range of serum dupilumab levels at 16 weeks of treatment and no association with treatment response and adverse effects during first year of treatment. Response may be dependent on target availability of the interleukin-4 receptor subunit α, with an interpatient variability producing heterogeneity in response.

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

Cited by 46 publications

References 43 publications

Pharmacokinetics of Subcutaneous Dupilumab Injection With an Autoinjector Device or Prefilled Syringe

Pharmacokinetics of Subcutaneous Dupilumab Injection With an Autoinjector Device or Prefilled Syringe

Efficacy and safety of dupilumab in adult moderate-to-severe atopic dermatitis: An update narrative literature review

Association of Serum Dupilumab Levels at 16 Weeks With Treatment Response and Adverse Effects in Patients With Atopic Dermatitis

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