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The role of antidrug antibodies in ustekinumab therapy and the impact of methotrexate
OBJECTIVE: We investigated the impact of concomitant MTX on ustekinumab (UST) levels and antidrug antibody (ADA) formation in PsA and evaluated consequences in pharmacodynamics and pharmacokinetics. METHODS: We conducted a post-hoc analysis on 112 PsA serum samples of subjects treated with open-labe...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10691926/ https://www.ncbi.nlm.nih.gov/pubmed/37079726 http://dx.doi.org/10.1093/rheumatology/kead177 |
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author | Mojtahed Poor, Sorwe Henke, Marina Ulshöfer, Thomas Köhm, Michaela Behrens, Frank Burkhardt, Harald Schiffmann, Susanne |
author_facet | Mojtahed Poor, Sorwe Henke, Marina Ulshöfer, Thomas Köhm, Michaela Behrens, Frank Burkhardt, Harald Schiffmann, Susanne |
author_sort | Mojtahed Poor, Sorwe |
collection | PubMed |
description | OBJECTIVE: We investigated the impact of concomitant MTX on ustekinumab (UST) levels and antidrug antibody (ADA) formation in PsA and evaluated consequences in pharmacodynamics and pharmacokinetics. METHODS: We conducted a post-hoc analysis on 112 PsA serum samples of subjects treated with open-label UST and either concomitant MTX (UST/MTX, n = 58) or placebo (UST/pbo, n = 54) obtained in a randomized (1:1), double-blind, multicentre trial. A validated antibody-binding-based multitiered testing was used to detect ADA and ADA with neutralizing capacity (nADA). The impact of MTX on UST immunogenicity was analysed by comparison of UST/pbo with UST/MTX cohorts at different time points. Patient- and disease-related predispositions for ADA formation were investigated with multiple linear regression analysis. Immunogenicity impact on pharmacokinetics, safety and efficacy was determined by cohort comparison between patients with and without ADA formation. RESULTS: Over 52 weeks, 11 UST/pbo- and 19 UST/MTX-treated patients developed ADA (P > 0.05). In the UST/pbo cohort, the visit-dependent UST levels were in the range of 0.047 (0.05) –0.110 (0.07) µg/ml overall, and 0.037 (0.04)–0.091 (0.08) µg/ml in ADA-confirmed subjects. In UST/MTX-treated patients, the UST levels exhibited an intervisit variation in the range of 0.0502 (0.04)–0.106 (0.07) µg/ml overall and 0.029 (0.03)–0.097 (0.07) µg/ml in ADA positive subjects (P > 0.05). At week 52, ADA-confirmed patients did not differ significantly (P > 0.05) in safety or clinical outcomes from ADA-negative patients. CONCLUSION: Concomitant MTX had no significant impact on UST immunogenicity. Furthermore, ADA formation was not associated with impairments in UST safety, efficacy or trough levels. TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov, NCT03148860. |
format | Online Article Text |
id | pubmed-10691926 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-106919262023-12-02 The role of antidrug antibodies in ustekinumab therapy and the impact of methotrexate Mojtahed Poor, Sorwe Henke, Marina Ulshöfer, Thomas Köhm, Michaela Behrens, Frank Burkhardt, Harald Schiffmann, Susanne Rheumatology (Oxford) Basic Science OBJECTIVE: We investigated the impact of concomitant MTX on ustekinumab (UST) levels and antidrug antibody (ADA) formation in PsA and evaluated consequences in pharmacodynamics and pharmacokinetics. METHODS: We conducted a post-hoc analysis on 112 PsA serum samples of subjects treated with open-label UST and either concomitant MTX (UST/MTX, n = 58) or placebo (UST/pbo, n = 54) obtained in a randomized (1:1), double-blind, multicentre trial. A validated antibody-binding-based multitiered testing was used to detect ADA and ADA with neutralizing capacity (nADA). The impact of MTX on UST immunogenicity was analysed by comparison of UST/pbo with UST/MTX cohorts at different time points. Patient- and disease-related predispositions for ADA formation were investigated with multiple linear regression analysis. Immunogenicity impact on pharmacokinetics, safety and efficacy was determined by cohort comparison between patients with and without ADA formation. RESULTS: Over 52 weeks, 11 UST/pbo- and 19 UST/MTX-treated patients developed ADA (P > 0.05). In the UST/pbo cohort, the visit-dependent UST levels were in the range of 0.047 (0.05) –0.110 (0.07) µg/ml overall, and 0.037 (0.04)–0.091 (0.08) µg/ml in ADA-confirmed subjects. In UST/MTX-treated patients, the UST levels exhibited an intervisit variation in the range of 0.0502 (0.04)–0.106 (0.07) µg/ml overall and 0.029 (0.03)–0.097 (0.07) µg/ml in ADA positive subjects (P > 0.05). At week 52, ADA-confirmed patients did not differ significantly (P > 0.05) in safety or clinical outcomes from ADA-negative patients. CONCLUSION: Concomitant MTX had no significant impact on UST immunogenicity. Furthermore, ADA formation was not associated with impairments in UST safety, efficacy or trough levels. TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov, NCT03148860. Oxford University Press 2023-04-20 /pmc/articles/PMC10691926/ /pubmed/37079726 http://dx.doi.org/10.1093/rheumatology/kead177 Text en © The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Basic Science Mojtahed Poor, Sorwe Henke, Marina Ulshöfer, Thomas Köhm, Michaela Behrens, Frank Burkhardt, Harald Schiffmann, Susanne The role of antidrug antibodies in ustekinumab therapy and the impact of methotrexate |
title | The role of antidrug antibodies in ustekinumab therapy and the impact of methotrexate |
title_full | The role of antidrug antibodies in ustekinumab therapy and the impact of methotrexate |
title_fullStr | The role of antidrug antibodies in ustekinumab therapy and the impact of methotrexate |
title_full_unstemmed | The role of antidrug antibodies in ustekinumab therapy and the impact of methotrexate |
title_short | The role of antidrug antibodies in ustekinumab therapy and the impact of methotrexate |
title_sort | role of antidrug antibodies in ustekinumab therapy and the impact of methotrexate |
topic | Basic Science |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10691926/ https://www.ncbi.nlm.nih.gov/pubmed/37079726 http://dx.doi.org/10.1093/rheumatology/kead177 |
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