Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of Dupilumab in Healthy Adult Subjects.
Administration, Intravenous
Adolescent
Adult
Aged
Antibodies, Monoclonal, Humanized
/ administration & dosage
Clinical Trials, Phase I as Topic
Dose-Response Relationship, Drug
Female
Humans
Injections, Subcutaneous
Interleukin-4 Receptor alpha Subunit
/ immunology
Male
Middle Aged
Randomized Controlled Trials as Topic
Young Adult
dupilumab
healthy subjects
pharmacodynamics
pharmacokinetics
type 2 immune diseases
Journal
Clinical pharmacology in drug development
ISSN: 2160-7648
Titre abrégé: Clin Pharmacol Drug Dev
Pays: United States
ID NLM: 101572899
Informations de publication
Date de publication:
08 2020
08 2020
Historique:
received:
12
09
2019
accepted:
24
02
2020
pubmed:
30
4
2020
medline:
13
8
2021
entrez:
30
4
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32348036
doi: 10.1002/cpdd.798
pmc: PMC7496261
doi:
Substances chimiques
Antibodies, Monoclonal, Humanized
0
Interleukin-4 Receptor alpha Subunit
0
dupilumab
420K487FSG
Banques de données
ClinicalTrials.gov
['NCT01015027', 'NCT01537653', 'NCT01537640', 'NCT01484600']
Types de publication
Comparative Study
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
742-755Informations de copyright
© 2020 Regeneron Pharmaceuticals, Inc. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.
Références
Cell Immunol. 1990 Sep;129(2):329-40
pubmed: 2383894
Br J Dermatol. 2020 Jan;182(1):85-96
pubmed: 31595499
United European Gastroenterol J. 2017 Apr;5(3):335-358
pubmed: 28507746
J Allergy Clin Immunol. 2013 Nov;132(5):1132-8
pubmed: 24094544
Proc Natl Acad Sci U S A. 2014 Apr 8;111(14):5153-8
pubmed: 24706856
Clin Pharmacokinet. 2019 Nov;58(11):1455-1467
pubmed: 31055792
Lancet. 2019 Nov 2;394(10209):1638-1650
pubmed: 31543428
N Engl J Med. 2018 Jun 28;378(26):2475-2485
pubmed: 29782224
CPT Pharmacometrics Syst Pharmacol. 2015 Jun;4(6):324-37
pubmed: 26225261
J Invest Dermatol. 2017 Jan;137(1):26-30
pubmed: 27616422
N Engl J Med. 2008 Apr 3;358(14):1483-94
pubmed: 18385500
CPT Pharmacometrics Syst Pharmacol. 2016 Nov;5(11):617-624
pubmed: 27778477
Gastroenterol Clin North Am. 2014 Jun;43(2):201-18
pubmed: 24813510
JAMA. 2016 Feb 2;315(5):469-79
pubmed: 26836729
Clin Pharmacol Ther. 2018 Dec;104(6):1146-1154
pubmed: 29498038
Res Nurs Health. 1990 Aug;13(4):227-36
pubmed: 2197679
Eur Arch Otorhinolaryngol. 2016 Aug;273(8):2097-109
pubmed: 26742909
BMC Mol Biol. 2006 Nov 29;7:45
pubmed: 17134490
N Engl J Med. 2018 Jun 28;378(26):2486-2496
pubmed: 29782217
JAMA Dermatol. 2020 Jan 1;156(1):44-56
pubmed: 31693077
J Am Acad Dermatol. 2016 Mar;74(3):491-8
pubmed: 26777100
Lancet. 2016 Jan 2;387(10013):40-52
pubmed: 26454361
N Engl J Med. 2013 Jun 27;368(26):2455-66
pubmed: 23688323
Rhinology. 2012 Mar;50(1):1-12
pubmed: 22469599
BMC Public Health. 2012 Jun 18;12:439
pubmed: 22709383
P T. 2018 Sep;43(9):532-535
pubmed: 30186024
Nat Rev Drug Discov. 2016 Jan;15(1):35-50
pubmed: 26471366
Gastroenterology. 2020 Jan;158(1):111-122.e10
pubmed: 31593702
Curr Top Microbiol Immunol. 2015;388:1-19
pubmed: 25553792
J Allergy Clin Immunol. 2019 Jan;143(1):155-172
pubmed: 30194992
Br J Dermatol. 2018 May;178(5):1083-1101
pubmed: 29193016
N Engl J Med. 2014 Jul 10;371(2):130-9
pubmed: 25006719
Respir Med. 2006 Jul;100(7):1139-51
pubmed: 16713224
N Engl J Med. 2016 Dec 15;375(24):2335-2348
pubmed: 27690741
AAPS PharmSciTech. 2015 Oct;16(5):1101-7
pubmed: 25693652
Expert Rev Clin Immunol. 2017 May;13(5):425-437
pubmed: 28277826
AAPS J. 2017 May;19(3):772-786
pubmed: 28144911
Med Devices (Auckl). 2015 Nov 11;8:473-84
pubmed: 26635489
Lancet. 2017 Jun 10;389(10086):2287-2303
pubmed: 28478972
Clin Pharmacokinet. 2019 Jan;58(1):101-113
pubmed: 29725996
Proc Natl Acad Sci U S A. 2014 Apr 8;111(14):5147-52
pubmed: 24706858
Lancet. 2016 Jul 2;388(10039):31-44
pubmed: 27130691
J Pharmacokinet Pharmacodyn. 2001 Dec;28(6):507-32
pubmed: 11999290
Pain. 1997 Aug;72(1-2):95-7
pubmed: 9272792