A quantitative systems pharmacology model for certolizumab pegol treatment in moderate-to-severe psoriasis
Background: Psoriasis is a chronic immune-mediated inflammatory systemic disease with skin manifestations characterized by erythematous, scaly, itchy and/or painful plaques resulting from hyperproliferation of keratinocytes. Certolizumab pegol [CZP], a PEGylated antigen binding fragment of a humaniz...
| Autores: | , , , , , , , , , , , , |
|---|---|
| Formato: | artículo |
| Fecha de publicación: | 2023 |
| País: | España |
| Recursos: | Servizo Galego de Saúde (SERGAS) |
| Repositorio: | RUNA. Repositorio da Consellería de Sanidade e Sergas |
| OAI Identifier: | oai:runa.sergas.gal:20.500.11940/21000 |
| Acesso em linha: | https://portalcientifico.sergas.gal//documentos/6546eced32348009d228e87d http://hdl.handle.net/20.500.11940/21000 |
| Access Level: | acceso abierto |
| Palavra-chave: | Humans Certolizumab Pegol Network Pharmacology Psoriasis Antibodies, Monoclonal, Humanized Immunoglobulin Fab Fragments Chronic Disease AS Ferrol CHUF |
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A quantitative systems pharmacology model for certolizumab pegol treatment in moderate-to-severe psoriasis |
| title |
A quantitative systems pharmacology model for certolizumab pegol treatment in moderate-to-severe psoriasis |
| spellingShingle |
A quantitative systems pharmacology model for certolizumab pegol treatment in moderate-to-severe psoriasis Coto-Segura, P. Humans Certolizumab Pegol Network Pharmacology Psoriasis Antibodies, Monoclonal, Humanized Immunoglobulin Fab Fragments Chronic Disease AS Ferrol CHUF |
| title_short |
A quantitative systems pharmacology model for certolizumab pegol treatment in moderate-to-severe psoriasis |
| title_full |
A quantitative systems pharmacology model for certolizumab pegol treatment in moderate-to-severe psoriasis |
| title_fullStr |
A quantitative systems pharmacology model for certolizumab pegol treatment in moderate-to-severe psoriasis |
| title_full_unstemmed |
A quantitative systems pharmacology model for certolizumab pegol treatment in moderate-to-severe psoriasis |
| title_sort |
A quantitative systems pharmacology model for certolizumab pegol treatment in moderate-to-severe psoriasis |
| dc.creator.none.fl_str_mv |
Coto-Segura, P. Segú-Vergés, C. Martorell, A. Moreno-Ramírez, D. Jorba, G. Junet, V. Guerri, F. Daura, X. Oliva, B. Cara, C. Suárez Magdalena, Olaya Abraham, S. Mas, J.M. |
| author |
Coto-Segura, P. |
| author_facet |
Coto-Segura, P. Segú-Vergés, C. Martorell, A. Moreno-Ramírez, D. Jorba, G. Junet, V. Guerri, F. Daura, X. Oliva, B. Cara, C. Suárez Magdalena, Olaya Abraham, S. Mas, J.M. |
| author_role |
author |
| author2 |
Segú-Vergés, C. Martorell, A. Moreno-Ramírez, D. Jorba, G. Junet, V. Guerri, F. Daura, X. Oliva, B. Cara, C. Suárez Magdalena, Olaya Abraham, S. Mas, J.M. |
| author2_role |
author author author author author author author author author author author author |
| dc.subject.none.fl_str_mv |
Humans Certolizumab Pegol Network Pharmacology Psoriasis Antibodies, Monoclonal, Humanized Immunoglobulin Fab Fragments Chronic Disease AS Ferrol CHUF |
| topic |
Humans Certolizumab Pegol Network Pharmacology Psoriasis Antibodies, Monoclonal, Humanized Immunoglobulin Fab Fragments Chronic Disease AS Ferrol CHUF |
| description |
Background: Psoriasis is a chronic immune-mediated inflammatory systemic disease with skin manifestations characterized by erythematous, scaly, itchy and/or painful plaques resulting from hyperproliferation of keratinocytes. Certolizumab pegol [CZP], a PEGylated antigen binding fragment of a humanized monoclonal antibody against TNF-alpha, is approved for the treatment of moderate-to-severe plaque psoriasis. Patients with psoriasis present clinical and molecular variability, affecting response to treatment. Herein, we utilized an in silico approach to model the effects of CZP in a virtual population (vPop) with moderate-to-severe psoriasis. Our proof-of-concept study aims to assess the performance of our model in generating a vPop and defining CZP response variability based on patient profiles. Methods: We built a quantitative systems pharmacology (QSP) model of a clinical trial-like vPop with moderate-to-severe psoriasis treated with two dosing schemes of CZP (200 mg and 400 mg, both every two weeks for 16 weeks, starting with a loading dose of CZP 400 mg at weeks 0, 2, and 4). We applied different modelling approaches: (i) an algorithm to generate vPop according to reference population values and comorbidity frequencies in real-world populations; (ii) physiologically based pharmacokinetic (PBPK) models of CZP dosing schemes in each virtual patient; and (iii) systems biology-based models of the mechanism of action (MoA) of the drug. Results: The combination of our different modelling approaches yielded a vPop distribution and a PBPK model that aligned with existing literature. Our systems biology and QSP models reproduced known biological and clinical activity, presenting outcomes correlating with clinical efficacy measures. We identified distinct clusters of virtual patients based on their psoriasis-related protein predicted activity when treated with CZP, which could help unravel differences in drug efficacy in diverse subpopulations. Moreover, our models revealed clusters of MoA solutions irrespective of the dosing regimen employed. Conclusion: Our study provided patient specific QSP models that reproduced clinical and molecular efficacy features, supporting the use of computational methods as modelling strategy to explore drug response variability. This might shed light on the differences in drug efficacy in diverse subpopulations, especially useful in complex diseases such as psoriasis, through the generation of mechanistically based hypotheses. |
| publishDate |
2023 |
| dc.date.none.fl_str_mv |
2023 |
| dc.type.none.fl_str_mv |
info:eu-repo/semantics/article |
| format |
article |
| dc.identifier.none.fl_str_mv |
https://portalcientifico.sergas.gal//documentos/6546eced32348009d228e87d http://hdl.handle.net/20.500.11940/21000 |
| url |
https://portalcientifico.sergas.gal//documentos/6546eced32348009d228e87d http://hdl.handle.net/20.500.11940/21000 |
| dc.language.none.fl_str_mv |
Inglés |
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Inglés |
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http://creativecommons.org/licenses/by/4.0/ info:eu-repo/semantics/openAccess |
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http://creativecommons.org/licenses/by/4.0/ |
| eu_rights_str_mv |
openAccess |
| dc.source.none.fl_str_mv |
reponame:RUNA. Repositorio da Consellería de Sanidade e Sergas instname:Servizo Galego de Saúde (SERGAS) |
| instname_str |
Servizo Galego de Saúde (SERGAS) |
| reponame_str |
RUNA. Repositorio da Consellería de Sanidade e Sergas |
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RUNA. Repositorio da Consellería de Sanidade e Sergas |
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1869403409692491776 |
| spelling |
A quantitative systems pharmacology model for certolizumab pegol treatment in moderate-to-severe psoriasisCoto-Segura, P.Segú-Vergés, C.Martorell, A.Moreno-Ramírez, D.Jorba, G.Junet, V.Guerri, F.Daura, X.Oliva, B.Cara, C.Suárez Magdalena, OlayaAbraham, S.Mas, J.M.HumansCertolizumab PegolNetwork PharmacologyPsoriasisAntibodies, Monoclonal, HumanizedImmunoglobulin Fab FragmentsChronic DiseaseAS FerrolCHUFBackground: Psoriasis is a chronic immune-mediated inflammatory systemic disease with skin manifestations characterized by erythematous, scaly, itchy and/or painful plaques resulting from hyperproliferation of keratinocytes. Certolizumab pegol [CZP], a PEGylated antigen binding fragment of a humanized monoclonal antibody against TNF-alpha, is approved for the treatment of moderate-to-severe plaque psoriasis. Patients with psoriasis present clinical and molecular variability, affecting response to treatment. Herein, we utilized an in silico approach to model the effects of CZP in a virtual population (vPop) with moderate-to-severe psoriasis. Our proof-of-concept study aims to assess the performance of our model in generating a vPop and defining CZP response variability based on patient profiles. Methods: We built a quantitative systems pharmacology (QSP) model of a clinical trial-like vPop with moderate-to-severe psoriasis treated with two dosing schemes of CZP (200 mg and 400 mg, both every two weeks for 16 weeks, starting with a loading dose of CZP 400 mg at weeks 0, 2, and 4). We applied different modelling approaches: (i) an algorithm to generate vPop according to reference population values and comorbidity frequencies in real-world populations; (ii) physiologically based pharmacokinetic (PBPK) models of CZP dosing schemes in each virtual patient; and (iii) systems biology-based models of the mechanism of action (MoA) of the drug. Results: The combination of our different modelling approaches yielded a vPop distribution and a PBPK model that aligned with existing literature. Our systems biology and QSP models reproduced known biological and clinical activity, presenting outcomes correlating with clinical efficacy measures. We identified distinct clusters of virtual patients based on their psoriasis-related protein predicted activity when treated with CZP, which could help unravel differences in drug efficacy in diverse subpopulations. Moreover, our models revealed clusters of MoA solutions irrespective of the dosing regimen employed. Conclusion: Our study provided patient specific QSP models that reproduced clinical and molecular efficacy features, supporting the use of computational methods as modelling strategy to explore drug response variability. This might shed light on the differences in drug efficacy in diverse subpopulations, especially useful in complex diseases such as psoriasis, through the generation of mechanistically based hypotheses.The study was funded by UCB Pharma and Anaxomics Biotech. Copy-editing was funded by UCB Pharma. Article processing fees were provided by UCB Pharma. Public funders provided support for some of the authors' salaries: VJ has received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 765158 (COSMIC; www.cosmic-h2020.eu); GJ has received funding from the European Union's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie Grant Agreement No. 765912; FG has received funding from the European Union's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie Grant Agreement No. 813545. The funder UCB Biopharma was not involved in the study design, collection, analysis, interpretation of data, the writing of this article, or the decision to submit it for publication.2023info:eu-repo/semantics/articlehttps://portalcientifico.sergas.gal//documentos/6546eced32348009d228e87dhttp://hdl.handle.net/20.500.11940/21000reponame:RUNA. Repositorio da Consellería de Sanidade e Sergasinstname:Servizo Galego de Saúde (SERGAS)Ingléshttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:runa.sergas.gal:20.500.11940/210002026-06-12T08:40:47Z |
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15.812429 |