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

Abstract

Dupilumab is a fully human monoclonal antibody directed against the interleukin (IL)-4 receptor α subunit (IL-4Rα) of IL-4 heterodimeric type I and type II receptors that mediate IL-4/IL-13 signaling through this pathway. Blockade of these receptors broadly suppresses type 2 inflammation associated with atopic/allergic diseases, including atopic dermatitis and asthma. Six phase 1 studies investigated the pharmacokinetics, pharmacodynamics, safety, and tolerability of dupilumab in healthy subjects. Two randomized, double-blind, placebo-controlled, sequential studies assessed safety and tolerability of single escalating dupilumab doses administered intravenously or subcutaneously (one included various racial groups, and one included exclusively Japanese subjects); 3 randomized, parallel-group, single-dose studies compared the pharmacokinetic profiles of different dupilumab products and formulations after single subcutaneous doses; and one study assessed dupilumab administered as fast versus slow subcutaneous injections. Dupilumab concentrations in serum were measured in all studies, and total immunoglobulin E (IgE) and thymus- and activation-regulated chemokine (TARC) concentrations were measured in 2 studies as pharmacodynamic markers. Across the phase 1 studies, dupilumab exhibited target-mediated pharmacokinetics consisting of parallel linear and nonlinear elimination, with the target-mediated phase highly dominated by nonlinearity at lower drug concentrations. Systemic exposure and tolerability of dupilumab were consistent irrespective of differences in product, formulation, or racial background. Dupilumab reduced circulating concentrations of total IgE and TARC, indicating blockade of IL-4Rα-mediated signaling. Dupilumab had a favorable safety profile across the wide range of doses administered. Together, these findings support the continued development and use of dupilumab in treatment of type 2 diseases.

Trial registration: ClinicalTrials.gov NCT01015027 NCT01537653 NCT01537640 NCT01484600.

Keywords: dupilumab; healthy subjects; pharmacodynamics; pharmacokinetics; type 2 immune diseases.

Figure 1

Pharmacokinetics of single dupilumab doses. Mean concentration‐time profiles following single IV and SC administration of dupilumab in the ascending‐dose first‐in‐human study (R668‐AS‐0907). Left inset shows the AUC_last/dose ratio following IV dupilumab administration, and right inset after SC dupilumab administration (A). Mean concentration‐time profiles following fast or slow injection of 300 mg SC dupilumab in the R668‐HV‐1108 study (B). Mean concentration‐time profiles following ascending SC dupilumab doses in the TDU12265 study in Japanese healthy subjects (C). The inset shows the AUC_last/dose ratio following administration of the SC dupilumab doses. Horizontal dashed lines represent the lower limit of quantification (LLOQ). Mean values below the LLOQ were excluded. AUC_last indicates area under the concentration‐time curve to time of last measurable concentration; IV, intravenous; SC, subcutaneous; SD, standard deviation.

Figure 1

Pharmacokinetics of single dupilumab doses. Mean concentration‐time profiles following single IV and SC administration of dupilumab in the ascending‐dose first‐in‐human study (R668‐AS‐0907). Left inset shows the AUC_last/dose ratio following IV dupilumab administration, and right inset after SC dupilumab administration (A). Mean concentration‐time profiles following fast or slow injection of 300 mg SC dupilumab in the R668‐HV‐1108 study (B). Mean concentration‐time profiles following ascending SC dupilumab doses in the TDU12265 study in Japanese healthy subjects (C). The inset shows the AUC_last/dose ratio following administration of the SC dupilumab doses. Horizontal dashed lines represent the lower limit of quantification (LLOQ). Mean values below the LLOQ were excluded. AUC_last indicates area under the concentration‐time curve to time of last measurable concentration; IV, intravenous; SC, subcutaneous; SD, standard deviation.

Figure 2

Influence of body weight and ethnicity on pharmacokinetics of dupilumab: AUC_last vs baseline body weight after administration of 300 mg SC dupilumab (A), and concentration‐time profile of functional dupilumab after administration of 150 mg or 300 mg SC dupilumab^a (B) in Japanese and non‐Japanese subjects in the TDU12265 and R668‐AS‐0907 studies. Horizontal dashed line represents the lower limit of quantification (LLOQ). Mean values below the lower limit of quantitation were excluded. AUC_last indicates area under the concentration‐time curve to time of last measurable concentration; SC, subcutaneous. Standard error around the mean is presented.

Figure 3

Total IgE and TARC levels in serum following dupilumab administration. Median percentage changes from baseline in total IgE in R668‐AS‐0907 (A) and TDU12265 (B) and median percentage changes from baseline in TARC in R668‐AS‐0907 (C) and TDU12265 (D). IgE indicates immunoglobulin E; IV, intravenously; SC, subcutaneous; TARC, thymus‐ and activation‐regulated chemokine.