Pharmacokinetics and Concentration-Response of Dupilumab in Patients With Seasonal Allergic Rhinitis

Mohamed A Kamal, Yoko Franchetti, Ching-Ha Lai, Christine Xu, Claire Q Wang, Allen R Radin, Meagan P O'Brien, Marcella Ruddy, John D Davis, Mohamed A Kamal, Yoko Franchetti, Ching-Ha Lai, Christine Xu, Claire Q Wang, Allen R Radin, Meagan P O'Brien, Marcella Ruddy, John D Davis

Abstract

Patients with moderate to severe allergic rhinitis may benefit from subcutaneous immunotherapy (SCIT), despite the risk of systemic allergic reaction. Dupilumab is a fully human monoclonal antibody that blocks the shared receptor component for interleukin-4 and interleukin-13, key drivers of the type 2 inflammation seen in allergic rhinitis, thereby inhibiting their signaling. In the LIBERTY Grass AID trial (NCT03558997), 16 weeks of treatment with 300 mg of dupilumab every 2 weeks plus timothy grass (TG) SCIT did not reduce TG allergen challenge nasal symptom scores compared with SCIT only but did improve tolerability of SCIT up-titration in patients with a history of grass pollen-induced seasonal allergic rhinitis. Here, we present the pharmacokinetics of functional serum dupilumab and concentration-response relationships in 52 patients enrolled in this trial. Functional dupilumab concentrations and concentrations of TG-specific IgE and IgG4 were assessed in blood samples collected from dupilumab-only and SCIT + dupilumab-treated groups. Mean functional dupilumab concentrations were similar in both groups and reached a steady state of ≈70-80 mg/L at week 5. One week after the end of treatment, TG-specific IgG4 concentrations were increased in the SCIT + dupilumab group, but not in the dupilumab-only group, over the range of dupilumab concentrations evaluated, whereas no changes were seen for TG-specific IgE concentrations. This study demonstrates that SCIT does not alter functional concentrations of serum dupilumab, and the impact of SCIT on TG-specific immunoglobulins is not affected by functional dupilumab concentrations over the range studied, indicating that maximum response was achieved in all patients.

Keywords: concentration-response relationship; dupilumab; grass allergy; pharmacokinetics; seasonal allergic rhinitis; subcutaneous immunotherapy.

Conflict of interest statement

M.A.K., Y.F., C.‐H.L., C.Q.W., A.R.R., M.P.O., M.R., and J.D.D. are employees and shareholders of Regeneron Pharmaceuticals, Inc. C.X. is an employee and may hold stock and/or stock options in Sanofi.

© 2021 Regeneron Pharmaceuticals, Inc. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.

Figures

Figure 1
Figure 1
Mean (± SD) concentrations of functional dupilumab in serum by nominal time. Concentrations below the LLOQ were set to 0; screening was at −28 days but is presented as week 0. LLOQ, lower limit of quantification; SCIT, subcutaneous immunotherapy; SD, standard deviation.
Figure 2
Figure 2
(a) Change from baseline in serum TG sIgG4 versus individual concentrations of functional dupilumab at week 17 (LOCF). (b) Change from baseline in TG sIgE versus individual concentrations of functional dupilumab at week 17 (LOCF). (c) Change from baseline in log‐transformed value of serum TG sIgG4‐to‐sIgE ratio vs individual concentrations of functional dupilumab at week 17 (LOCF). LOCF was used for missing values; concentrations below the LLOQ were set to 0. LLOQ, lower limit of quantification; LOCF, last observation carried forward; SCIT, subcutaneous immunotherapy; sIgE, serum IgE; TG, timothy grass.

References

    1. Varshney J, Varshney H. Allergic rhinitis: an overview. Indian J Otolaryngol Head Neck Surg. 2015;67(2):143‐149.
    1. Fineman SM. The burden of allergic rhinitis: beyond dollars and cents. Ann Allergy Asthma Immunol. 2002;88(4 suppl 1):2‐7.
    1. Seidman MD, Gurgel RK, Lin SY, et al. Clinical practice guideline: allergic rhinitis. Otolaryngol Head Neck Surg. 2015;152(suppl 1):S1‐S43.
    1. Durham SR, Penagos M. Sublingual or subcutaneous immunotherapy for allergic rhinitis? J Allergy Clin Immunol. 2016;137(2):339‐349.e10.
    1. Amin HS, Liss GM, Bernstein DI. Evaluation of near‐fatal reactions to allergen immunotherapy injections. J Allergy Clin Immunol. 2006;117(1):169‐175.
    1. Kubo M. Mast cells and basophils in allergic inflammation. Curr Opin Immunol. 2018;54:74‐79.
    1. Shamji MH, Kappen J, Abubakar‐Waziri H, et al. Nasal allergen‐neutralizing IgG4 antibodies block IgE‐mediated responses: novel biomarker of subcutaneous grass pollen immunotherapy. J Allergy Clin Immunol. 2019;143(3):1067‐1076.
    1. James LK, Shamji MH, Walker SM, et al. Long‐term tolerance after allergen immunotherapy is accompanied by selective persistence of blocking antibodies. J Allergy Clin Immunol. 2011;127(2):509‐516.e1‐5.
    1. Gandhi NA, 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. Gandhi NA, Bennett BL, Graham NMH, et al. Targeting key proximal drivers of type 2 inflammation in disease. Nat Rev Drug Discov. 2016;15(1):35‐50.
    1. Le Floc'h A, Allinne J, Nagashima K, et al. Dual blockade of IL‐4 and IL‐13 with dupilumab, an IL‐4Rα antibody, is required to broadly inhibit type 2 inflammation. Allergy. 2020;75(5):1188‐1204.
    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. 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, Han JK, Desrosiers M, et al. Efficacy and safety of dupilumab in patients with severe chronic rhinosinusitis with nasal polyps (LIBERTY NP SINUS‐24 and LIBERTY NP SINUS‐52): results from two multicentre, randomised, double‐blind, placebo‐controlled, parallel‐group phase 3 trials. Lancet. 2019;394(10209):1638‐1650.
    1. Hirano I, Dellon ES, Hamilton JD, et al. Efficacy of dupilumab in a phase 2 randomized trial of adults with active eosinophilic esophagitis. Gastroenterology. 2020;158(1):111‐122.e10.
    1. Leynaert B, Neukirch F, Demoly P, Bousquet J. Epidemiologic evidence for asthma and rhinitis comorbidity. J Allergy Clin Immunol. 2000;106(suppl 5):S201‐S205.
    1. Weinstein SF, Katial R, Jayawardena S, et al. Efficacy and safety of dupilumab in perennial allergic rhinitis and comorbid asthma. J Allergy Clin Immunol. 2018;142(1):171–177.el.
    1. Busse WW, Maspero JF, Lu Y, et al. Efficacy of dupilumab on clinical outcomes in patients with asthma and perennial allergic rhinitis. Ann Allergy Asthma Immunol. 2020;125(5):565‐576.e1.
    1. Corren J, Saini SS, Gagnon R, et al. Short‐term subcutaneous allergy immunotherapy and dupilumab are well tolerated in allergic rhinitis: a randomized trial. J Asthma Allergy. 2021;14:1045‐1063.
    1. Kovalenko P, Davis JD, Li M, et al. Base and covariate population pharmacokinetic analyses of dupilumab using phase 3 data. Clin Pharmacol Drug Dev. 2020;9(6):756‐767.
    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. Zidarn M, Košnik M, Šilar M, Bajrović N, Korošec P. Sustained effect of grass pollen subcutaneous immunotherapy on suppression of allergen‐specific basophil response; a real‐life, nonrandomized controlled study. Allergy. 2015;70(5):547‐555.
    1. Pène J, Rousset F, Brière F, et al. IgE production by normal human B cells induced by alloreactive T cell clones is mediated by IL‐4 and suppressed by IFN‐gamma. J Immunol. 1988;141(4):1218‐1224.
    1. Poulsen LK, Hummelshoj L. Triggers of IgE class switching and allergy development. Ann Med. 2007;39(6):440‐456.
    1. Lebman DA, Coffman RL. Interleukin 4 causes isotype switching to IgE in T cell‐stimulated clonal B cell cultures. J Exp Med. 1988;168(3):853‐862.
    1. Corren J, Castro M, O'Riordan T, et al. Dupilumab efficacy in patients with uncontrolled, moderate‐to‐severe allergic asthma. J Allergy Clin Immunol Pract. 2020;8(2):516‐526.
    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.
    1. Kariyawasam HH, James LK, Gane SB. Dupilumab: clinical efficacy of blocking IL‐4/IL‐13 signalling in chronic rhinosinusitis with nasal polyps. Drug Des Devel Ther. 2020;14:1757‐1769.

Source: PubMed

赞助者和合作者

医疗条件

药物干预

3
订阅