Pharmacokinetics and Pharmacodynamics of JNJ-55920839, an Antibody Targeting Interferon α/ω, in Healthy Subjects and Subjects with Mild-to-Moderate Systemic Lupus Erythematosus.
Administration, Intravenous
Adult
Antibodies, Monoclonal, Humanized
/ pharmacokinetics
Area Under Curve
Biological Availability
Double-Blind Method
Female
Healthy Volunteers
Humans
Infusions, Intravenous
Injections, Subcutaneous
Interferon-alpha
/ antagonists & inhibitors
Lupus Erythematosus, Systemic
/ drug therapy
Male
Middle Aged
Placebos
Journal
Clinical drug investigation
ISSN: 1179-1918
Titre abrégé: Clin Drug Investig
Pays: New Zealand
ID NLM: 9504817
Informations de publication
Date de publication:
Dec 2020
Dec 2020
Historique:
accepted:
07
10
2020
pubmed:
22
10
2020
medline:
27
1
2021
entrez:
21
10
2020
Statut:
ppublish
Résumé
The interferon (IFN) pathway has been correlated with clinical and serological markers of disease activity in patients with systemic lupus erythematosus (SLE). The pharmacokinetics and pharmacodynamics of JNJ-55920839, a fully human immunoglobulin G1κ antibody targeting IFNα/ω, were investigated. In a double-blind, first-in-human study, Part A enrolled 48 healthy adults who received a single dose of placebo/JNJ-55920839 between 0.3 and 15 mg/kg intravenous (IV) or at 1 mg/kg subcutaneous (SC). Part B enrolled 26 adults with SLE who received placebo or JNJ-55920839 10 mg/kg IV 6 times biweekly. Pharmacokinetic parameters were calculated by noncompartmental analysis (NCA) and estimated by nonlinear mixed-effects modeling. JNJ-55920839 pharmacokinetics following a single IV infusion exhibited a biphasic disposition in healthy subjects. Maximum plasma concentration (C Pharmacokinetic and pharmacodynamic analyses of the data from this study demonstrated that there was biphasic disposition in both healthy subjects and subjects with SLE, CL was faster in subjects with SLE, and increases in total IFNα/ω levels were observed in both healthy subjects and subjects with SLE after treatment with JNJ-55920839, thus further development is supported. The study is registered at ClinicalTrials.gov NCT02609789.
Sections du résumé
BACKGROUND
BACKGROUND
The interferon (IFN) pathway has been correlated with clinical and serological markers of disease activity in patients with systemic lupus erythematosus (SLE).
OBJECTIVE
OBJECTIVE
The pharmacokinetics and pharmacodynamics of JNJ-55920839, a fully human immunoglobulin G1κ antibody targeting IFNα/ω, were investigated.
METHODS
METHODS
In a double-blind, first-in-human study, Part A enrolled 48 healthy adults who received a single dose of placebo/JNJ-55920839 between 0.3 and 15 mg/kg intravenous (IV) or at 1 mg/kg subcutaneous (SC). Part B enrolled 26 adults with SLE who received placebo or JNJ-55920839 10 mg/kg IV 6 times biweekly. Pharmacokinetic parameters were calculated by noncompartmental analysis (NCA) and estimated by nonlinear mixed-effects modeling.
RESULTS
RESULTS
JNJ-55920839 pharmacokinetics following a single IV infusion exhibited a biphasic disposition in healthy subjects. Maximum plasma concentration (C
CONCLUSION
CONCLUSIONS
Pharmacokinetic and pharmacodynamic analyses of the data from this study demonstrated that there was biphasic disposition in both healthy subjects and subjects with SLE, CL was faster in subjects with SLE, and increases in total IFNα/ω levels were observed in both healthy subjects and subjects with SLE after treatment with JNJ-55920839, thus further development is supported. The study is registered at ClinicalTrials.gov NCT02609789.
Identifiants
pubmed: 33085033
doi: 10.1007/s40261-020-00978-4
pii: 10.1007/s40261-020-00978-4
doi:
Substances chimiques
Antibodies, Monoclonal, Humanized
0
Interferon-alpha
0
JNJ-55920839
0
Placebos
0
Banques de données
ClinicalTrials.gov
['NCT02609789']
Types de publication
Clinical Trial, Phase I
Journal Article
Randomized Controlled Trial
Langues
eng
Sous-ensembles de citation
IM
Pagination
1127-1136Références
Furie R, Khamashta M, Merrill JT, Werth VP, Kalunian K, Brohawn P, et al. Anifrolumab, an anti-interferon-alpha receptor monoclonal antibody, in moderate-to-severe systemic lupus erythematosus. Arthritis Rheumatol. 2017;69(2):376–86. https://doi.org/10.1002/art.39962 .
doi: 10.1002/art.39962
pubmed: 28130918
pmcid: 5299497
Kirou KA, Lee C, George S, Louca K, Peterson MG, Crow MK. Activation of the interferon-alpha pathway identifies a subgroup of systemic lupus erythematosus patients with distinct serologic features and active disease. Arthritis Rheumatol. 2005;52(5):1491–503. https://doi.org/10.1002/art.21031 .
doi: 10.1002/art.21031
Thanou A, Merrill JT. New trials in lupus and where are we going. Curr Rheumatol Rep. 2018;20(6):34. https://doi.org/10.1007/s11926-018-0745-1 .
doi: 10.1007/s11926-018-0745-1
pubmed: 29725880
Bennett L, Palucka AK, Arce E, Cantrell V, Borvak J, Banchereau J, et al. Interferon and granulopoiesis signatures in systemic lupus erythematosus blood. J Exp Med. 2003;197(6):711–23. https://doi.org/10.1084/jem.20021553 .
doi: 10.1084/jem.20021553
pubmed: 12642603
pmcid: 2193846
Baechler EC, Batliwalla FM, Karypis G, Gaffney PM, Ortmann WA, Espe KJ, et al. Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus. Proc Natl Acad Sci USA. 2003;100(5):2610–5. https://doi.org/10.1073/pnas.0337679100 .
doi: 10.1073/pnas.0337679100
pubmed: 12604793
Hoffman RW, Merrill JT, Alarcon-Riquelme MM, Petri M, Dow ER, Nantz E, et al. Gene expression and pharmacodynamic changes in 1,760 systemic lupus erythematosus patients from two Phase III trials of BAFF blockade with tabalumab. Arthritis Rheumatol. 2017;69(3):643–54. https://doi.org/10.1002/art.39950 .
doi: 10.1002/art.39950
pubmed: 27723281
pmcid: 6585752
Karageorgas TP, Tseronis DD, Mavragani CP. Activation of type I interferon pathway in systemic lupus erythematosus: association with distinct clinical phenotypes. J Biomed Biotechnol. 2011;2011:273907. https://doi.org/10.1155/2011/273907 .
doi: 10.1155/2011/273907
pubmed: 22162633
pmcid: 3227532
Dall’era MC, Cardarelli PM, Preston BT, Witte A, Davis JC Jr. Type I interferon correlates with serological and clinical manifestations of SLE. Ann Rheum Dis. 2005;64(12):1692–7. https://doi.org/10.1136/ard.2004.033753 .
doi: 10.1136/ard.2004.033753
pubmed: 15843451
pmcid: 1755300
Niewold TB, Hua J, Lehman TJ, Harley JB, Crow MK. High serum IFN-alpha activity is a heritable risk factor for systemic lupus erythematosus. Genes Immun. 2007;8(6):492–502. https://doi.org/10.1038/sj.gene.6364408 .
doi: 10.1038/sj.gene.6364408
pubmed: 17581626
pmcid: 2702174
Kalunian KC, Merrill JT, Maciuca R, McBride JM, Townsend MJ, Wei X, et al. A Phase II study of the efficacy and safety of rontalizumab (rhuMAb interferon-alpha) in patients with systemic lupus erythematosus (ROSE). Ann Rheum Dis. 2016;75(1):196–202. https://doi.org/10.1136/annrheumdis-2014-206090 .
doi: 10.1136/annrheumdis-2014-206090
pubmed: 26038091
Jordan J, Cessaroni M, Schreiter J, Huang C, Chevrier M, Benson J. II-21: Interfering with interferon in lupus: hitting the sweet spot with CNTO 6358. Lupus Sci Med. 2016;3. https://doi.org/10.1136/lupus-2016-000179.51.
Jordan J, Benson J, Chatham WW, Furie R, Stohl W, Wei JCC et al. First-in-human study of JNJ-55920839 in healthy volunteers and systemic lupus erythematosus patients: a randomised placebo-controlled phase 1 trial. Lancet Rheumatology. 2020;Accepted.
Petri M, Orbai AM, Alarcon GS, Gordon C, Merrill JT, Fortin PR, et al. Derivation and validation of the systemic lupus international collaborating clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum. 2012;64(8):2677–86. https://doi.org/10.1002/art.34473 .
doi: 10.1002/art.34473
pubmed: 22553077
pmcid: 3409311
Ovacik M, Lin K. Tutorial on monoclonal antibody pharmacokinetics and its considerations in early development. Clin Transl Sci. 2018;11(6):540–52. https://doi.org/10.1111/cts.12567 .
doi: 10.1111/cts.12567
pubmed: 29877608
pmcid: 6226118
McBride JM, Jiang J, Abbas AR, Morimoto A, Li J, Maciuca R, et al. Safety and pharmacodynamics of rontalizumab in patients with systemic lupus erythematosus: results of a phase I, placebo-controlled, double-blind, dose-escalation study. Arthritis Rheum. 2012;64(11):3666–76. https://doi.org/10.1002/art.34632 .
doi: 10.1002/art.34632
pubmed: 22833362
Narwal R, Roskos LK, Robbie GJ. Population pharmacokinetics of sifalimumab, an investigational anti-interferon-alpha monoclonal antibody, in systemic lupus erythematosus. Clin Pharmacokinet. 2013;52(11):1017–27. https://doi.org/10.1007/s40262-013-0085-2 .
doi: 10.1007/s40262-013-0085-2
pubmed: 23754736
pmcid: 3824374
Bai S, Jorga K, Xin Y, Jin D, Zheng Y, Damico-Beyer LA, et al. A guide to rational dosing of monoclonal antibodies. Clin Pharmacokinet. 2012;51(2):119–35. https://doi.org/10.2165/11596370-000000000-00000 .
doi: 10.2165/11596370-000000000-00000
pubmed: 22257150
Anderson BJ, Holford NH. Mechanism-based concepts of size and maturity in pharmacokinetics. Annu Rev Pharmacol Toxicol. 2008;48:303–32. https://doi.org/10.1146/annurev.pharmtox.48.113006.094708 .
doi: 10.1146/annurev.pharmtox.48.113006.094708
pubmed: 17914927
Wang W, Prueksaritanont T. Prediction of human clearance of therapeutic proteins: simple allometric scaling method revisited. Biopharm Drug Dispos. 2010;31(4):253–63. https://doi.org/10.1002/bdd.708 .
doi: 10.1002/bdd.708
pubmed: 20437464
Lauwerys BR, Ducreux J, Houssiau FA. Type I interferon blockade in systemic lupus erythematosus: where do we stand? Rheumatology (Oxford). 2014;53(8):1369–76. https://doi.org/10.1093/rheumatology/ket403 .
doi: 10.1093/rheumatology/ket403
pubmed: 24344319
Zheng B, Yu XQ, Greth W, Robbie GJ. Population pharmacokinetic analysis of sifalimumab from a clinical phase IIb trial in systemic lupus erythematosus patients. Br J Clin Pharmacol. 2016;81(5):918–28. https://doi.org/10.1111/bcp.12864 .
doi: 10.1111/bcp.12864
pubmed: 26659791
pmcid: 4834601