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

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

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.

Conflict of interest statement

Z.L., M.L., and B.N.S. were employees of Sanofi at the time of the study and held stock and/or stock options in the company. M.K., Y.T., J.E.M., Y.L., Q.L., and C.O‐R. are employees of Sanofi and may hold stock and/or stock options in the company. A.R., J.D.H., J.D.D., A.T.D., P.K., and M.A. are employees and shareholders of Regeneron Pharmaceuticals, Inc. S.H. has nothing to disclose.

© 2020 Regeneron Pharmaceuticals, Inc. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.

Figures

Figure 1
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 AUClast/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 AUClast/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. AUClast indicates area under the concentration‐time curve to time of last measurable concentration; IV, intravenous; SC, subcutaneous; SD, standard deviation.
Figure 1
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 AUClast/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 AUClast/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. AUClast indicates area under the concentration‐time curve to time of last measurable concentration; IV, intravenous; SC, subcutaneous; SD, standard deviation.
Figure 2
Figure 2
Influence of body weight and ethnicity on pharmacokinetics of dupilumab: AUClast 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 dupilumaba (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. AUClast indicates area under the concentration‐time curve to time of last measurable concentration; SC, subcutaneous. Standard error around the mean is presented.
Figure 3
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.

References

    1. Gandhi NA, Bennett BL, Graham NM, et al. Targeting key proximal drivers of type 2 inflammation in disease. Nat Rev Drug Discov. 2016;15(1):35‐50.
    1. Dellon ES. Epidemiology of eosinophilic esophagitis. Gastroenterol Clin North Am. 2014;43(2):201‐218.
    1. Peters SP, Ferguson G, Deniz Y, et al. Uncontrolled asthma: a review of the prevalence, disease burden and options for treatment. Respir Med. 2006;100(7):1139‐1151.
    1. Bieber T. Atopic dermatitis. N Engl J Med. 2008;358(14):1483‐1494.
    1. Passali D, Cingi C, Cambi J, et al. A survey on chronic rhinosinusitis: opinions from experts of 50 countries. Eur Arch Otorhinolaryngol. 2016;273(8):2097‐2109.
    1. Lucendo AJ, Molina‐Infante J, Á Arias, et al. Guidelines on eosinophilic esophagitis: evidence‐based statements and recommendations for diagnosis and management in children and adults. United Eur Gastroenterol J. 2017;5(3):335‐358.
    1. Drucker AM, Wang AR, Li WQ, et al. The burden of atopic dermatitis: summary of a report for the National Eczema Association. J Invest Dermatol. 2017;137(1):26‐30.
    1. Simpson, EL , Bieber T, Eckert L, et al. Patient burden of moderate to severe atopic dermatitis (AD): insights from a phase 2b clinical trial of dupilumab in adults. J Am Acad Dermatol. 2016;74(3):491‐498.
    1. Fokkens WJ, Lund VJ, Mullol J, et al. European position paper on rhinosinusitis and nasal polyps 2012. Rhinology. 2012;23(Suppl 23):1‐298.
    1. Silverberg JI, Hanifin JM. Adult eczema prevalence and associations with asthma and other health and demographic factors: a US population‐based study. J Allergy Clin Immunol. 2013;132(5):1132‐1138.
    1. Gandhi N, Pirozzi G, Graham NMH. Commonality of the IL‐4/IL‐13 pathway in atopic diseases. Expert Rev Clin Immunol. 2017;13(5):425‐437.
    1. MacDonald LE, Karow M, Stevens S, et al. Precise and in situ genetic humanization of 6 Mb of mouse immunoglobulin genes. Proc Natl Acad Sci U S A. 2014;111(14):5147‐5152.
    1. Murphy AJ, MacDonald LE, Stevens S, et al. Mice with megabase humanization of their immunoglobulin genes generate antibodies as efficiently as normal mice. Proc Natl Acad Sci U S A. 2014;111(14):5153‐5158.
    1. Beck LA, Thaçi D, Hamilton JD, et al. Dupilumab treatment in adults with moderate‐to‐severe atopic dermatitis. N Engl J Med. 2014;371(2):130‐139.
    1. Thaçi D, Simpson EL, Beck LA, et al. Efficacy and safety of dupilumab in adults with moderate‐to‐severe atopic dermatitis inadequately controlled by topical treatments: a randomised, placebo‐controlled, dose‐ranging phase 2b trial. Lancet. 2016;387(10013):40‐52.
    1. Simpson EL, Bieber T, Guttman‐Yassky E, et al. Two phase 3 trials of dupilumab versus placebo in atopic dermatitis. N Engl J Med. 2016;375(24):2335‐2348.
    1. Blauvelt A, de Bruin‐Weller M, Gooderham M, et al. Long‐term management of moderate‐to‐severe atopic dermatitis with dupilumab and concomitant topical corticosteroids (LIBERTY AD CHRONOS): a 1‐year, randomised, double‐blinded, placebo‐controlled, phase 3 trial. Lancet. 2017;389(10086):2287‐2303.
    1. de Bruin‐Weller M, Thaçi D, Smith CH, et al. Dupilumab with concomitant topical corticosteroid treatment in adults with atopic dermatitis with an inadequate response or intolerance to ciclosporin A or when this treatment is medically inadvisable: a placebo‐controlled, randomized phase III clinical trial (LIBERTY AD CAFÉ). Br J Dermatol. 2018;178(5):1083‐1101.
    1. Cork MJ, Thaçi D, Eichenfield L, et al. Dupilumab in adolescents with uncontrolled moderate‐to‐severe atopic dermatitis: results from a phase IIa open‐label and subsequent phase III open‐label extension trial. Br J Dermatol. 2020;182(1):85‐96.
    1. Simpson EL, Paller AS, Siegfried EC, et al. Efficacy and safety of dupilumab in adolescents with uncontrolled moderate to severe atopic dermatitis: a phase 3 randomized clinical trial. JAMA Dermatol. 2020;156(1):44‐56. 10.1001/jamadermatol.2019.3336
    1. Wenzel S, Ford L, Pearlman D, et al. Dupilumab in persistent asthma with elevated eosinophil levels. N Engl J Med. 2013;368(26):2455‐2466.
    1. Wenzel S, Castro M, Corren J, et al. Dupilumab efficacy and safety in adults with uncontrolled persistent asthma despite use of medium‐to‐high‐dose inhaled corticosteroids plus a long‐acting β2 agonist: a randomised double‐blind placebo‐controlled pivotal phase 2b dose‐ranging trial. Lancet. 2016;388(10039):31‐44.
    1. Rabe KF, Nair P, Brusselle G, et al. Efficacy and safety of dupilumab in glucocorticoid‐dependent severe asthma. N Engl J Med. 2018;378(26):2475‐2485.
    1. Castro M, Corren J, Pavord ID, et al. Dupilumab efficacy and safety in moderate‐to‐severe uncontrolled asthma. N Engl J Med. 2018;378(26):2486‐2496.
    1. Bachert C, Mannent L, Naclerio RM, et al. Effect of subcutaneous dupilumab on nasal polyp burden in patients with chronic sinusitis and nasal polyposis: a randomized clinical trial. JAMA. 2016;315(5):469‐479.
    1. Bachert C, Han JK, Desrosiers M, et al. Dupilumab efficacy and safety in severe chronic rhinosinusitis with nasal polyps in the randomised phase 3 trials LIBERTY NP SINUS‐24 and LIBERTY NP SINUS‐52. Lancet. 2019;394(10209):1638‐1650.
    1. Hirano I, Dellon ES, Hamilton JD, et al. Dupilumab efficacy in adults with active eosinophilic esophagitis: a randomized placebo‐controlled phase 2 trial. Gastroenterology. 2020;158(1):111‐122.e10.
    1. Kovalenko P, DiCioccio AT, Davis JD, et al. Exploratory population PK analysis of dupilumab, a fully human monoclonal antibody against IL‐4Rα, in atopic dermatitis patients and normal volunteers. CPT Pharmacometrics Syst Pharmacol. 2016;5(11):617‐624.
    1. Dua P, Hawkins E, van der Graaf PH. A tutorial on target‐mediated drug disposition (TMDD) models. CPT Pharmacometrics Syst Pharmacol. 2015;4(6):324‐337.
    1. Zuber CE, Galizzi JP, Harada N, Durand I, Banchereau J. Interleukin‐4 receptors on human blood mononuclear cells. Cell Immunol. 1990;129(2):329‐340.
    1. D'Ippolito D, Dupilumab Pisano M. (Dupixent): an interleukin‐4 receptor antagonist for atopic dermatitis. P T. 2018;43(9):532‐535.
    1. Davis JD, Bansal A, Hassman D, et al. Evaluation of potential disease‐mediated drug‐drug interaction in patients with moderate‐to‐severe atopic dermatitis receiving dupilumab. Clin Pharmacol Ther. 2018;104(6):1146‐1154.
    1. Food and Drug Administration (US FDA). Center for Drug Evaluation and Research . Clinical pharmacology and biopharmaceutics review, dupilumab biologics license application number 761055Orig1s000. July 29, 2016. . Accessed January 23, 2020.
    1. Collins SL, Moore RA, McQuay HJ. The visual analogue pain intensity scale: what is moderate pain in millimetres? Pain. 1997;72(1‐2):95‐97.
    1. Wewers ME, Lowe NK. A critical review of visual analogue scales in the measurement of clinical phenomena. Res Nurs Health. 1990;13(4):227‐236.
    1. Food and Drug Administration (US FDA) . FDA guidance for industry: toxicity grading scale for healthy adult and adolescent volunteers enrolled in preventive vaccine clinical trials. September 2007. . Accessed January 23, 2020.
    1. Liddiard K, Welch JS, Lozach J, Heinz S, Glass CK, Greaves DR. Interleukin‐4 induction of the CC chemokine TARC (CCL17) in murine macrophages is mediated by multiple STAT6 sites in the TARC gene promoter. BMC Mol Biol. 2006;7:45.
    1. He JS, Narayanan S, Subramaniam S, et al. Biology of IgE production: IgE cell differentiation and the memory of IgE responses. Curr Top Microbiol Immunol. 2015;388:1‐19.
    1. Gabrielsson J, Peletier LA. Pharmacokinetic steady‐states highlight interesting target‐mediated disposition properties. AAPS J. 2017;19(3):772‐786.
    1. Mager DE, Jusko WJ. General pharmacokinetic model for drugs exhibiting target‐mediated drug disposition. J Pharmacokinet Pharmacodyn. 2001;28(6):507‐532.
    1. Martinez JM, Brunet A, Hurbin F, DiCioccio AT, Rauch C, Fabre D. Population pharmacokinetic analysis of alirocumab in healthy volunteers or hypercholesterolemic subjects using a Michaelis‐Menten approximation of a target‐mediated drug disposition model‐support for a biologics license application submission: Part I. Clin Pharmacokinet. 2019;58(1):101‐113.
    1. Xu C, Su Y, Paccaly A, Kanamaluru V. Population pharmacokinetics of sarilumab in patients with rheumatoid arthritis. Clin Pharmacokinet. 2019;58(11):1455‐1467.
    1. Meng Z, Ma L, Sheng T, et al. Dupilumab dose selection for a phase 3 study in asthma patients: pharmacokinetic/pharmacodynamic (PK/PD) modelling and clinical trial simulation. In PAGE . Abstracts of the Annual Meeting of the Population Approach Group in Europe. 2017;26:7161 . Accessed January 23, 2020.
    1. Walpole SC, Prieto‐Merino D, Edwards P, Cleland J, Stevens G, Roberts I. The weight of nations: an estimation of adult human biomass. BMC Public Health. 2012;12:439.
    1. Bertau C, Filipe‐Santos O, Wang T, Rojas HE, Granger C, Schwarzenbach F. Evaluation of the impact of viscosity, injection volume, and injection flow rate on subcutaneous injection tolerance. Med Devices (Auckl). 2015;8:473‐484.
    1. Dias C, Abosaleem B, Crispino C, Gao B, Shaywitz A. Tolerability of high‐volume subcutaneous injections of a viscous placebo buffer: a randomized, crossover study in healthy subjects. AAPS PharmSciTech. 2015;16(5):1101‐1107.
    1. Guttman‐Yassky E, Bissonnette R, Ungar B, et al. Dupilumab progressively improves systemic and cutaneous abnormalities in patients with atopic dermatitis. J Allergy Clin Immunol. 2019;143(1):155‐172.

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