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Caplacizumab Model‐Based Dosing Recommendations in Pediatric Patients With Acquired Thrombotic Thrombocytopenic Purpura
Acquired thrombotic thrombocytopenic purpura (aTTP) is a rare and life‐threatening autoimmune thrombotic microangiopathy. Caplacizumab, evaluated in phase II and III studies in adults, shortens the time to platelet count response and reduces aTTP exacerbations, has a favorable safety profile, and ca...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9255589/ https://www.ncbi.nlm.nih.gov/pubmed/34699078 http://dx.doi.org/10.1002/jcph.1991 |
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author | Bergstrand, Martin Hansson, Emma Delaey, Bernard Callewaert, Filip De Passos Sousa, Rui Sargentini‐Maier, Maria Laura |
author_facet | Bergstrand, Martin Hansson, Emma Delaey, Bernard Callewaert, Filip De Passos Sousa, Rui Sargentini‐Maier, Maria Laura |
author_sort | Bergstrand, Martin |
collection | PubMed |
description | Acquired thrombotic thrombocytopenic purpura (aTTP) is a rare and life‐threatening autoimmune thrombotic microangiopathy. Caplacizumab, evaluated in phase II and III studies in adults, shortens the time to platelet count response and reduces aTTP exacerbations, has a favorable safety profile, and can potentially reduce refractoriness and mortality associated with aTTP. Since no children with aTTP were enrolled in these clinical trials, caplacizumab has been initially approved for use only in adult patients with aTTP (10 mg). Pediatric dosing recommendations were developed using model‐based simulations. A semimechanistic pharmacokinetic/pharmacodynamic population model has been developed describing the interaction between caplacizumab and von Willebrand factor antigen (vWF:Ag) following intravenous and subcutaneous administration of caplacizumab in different adult populations, at various dose levels, using nonlinear mixed‐effects modeling. Based on the allometrically scaled pharmacokinetic/pharmacodynamic model, different dosing regimens were simulated in 8000 children (aged 2‐18 years). Simulated caplacizumab exposures and vWF:Ag levels across different age categories were compared to an adult reference group. A simulated daily dose of 5 mg in children weighing <40 kg and of 10 mg in children weighing ≥40 kg resulted in similar exposures and vWF:Ag suppression across age and weight groups. Despite the lack of pediatric clinical data, the results of this modeling and simulation analysis constituted the basis for the European extension of indication for caplacizumab (10 mg) to adolescents aged >12 years and with a body weight ≥40 kg. This represents a rare case in which regulatory authorities have deemed a modeling and simulation study robust enough to approve a variation of indication. |
format | Online Article Text |
id | pubmed-9255589 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-92555892022-07-08 Caplacizumab Model‐Based Dosing Recommendations in Pediatric Patients With Acquired Thrombotic Thrombocytopenic Purpura Bergstrand, Martin Hansson, Emma Delaey, Bernard Callewaert, Filip De Passos Sousa, Rui Sargentini‐Maier, Maria Laura J Clin Pharmacol Pediatric Pharmacology Acquired thrombotic thrombocytopenic purpura (aTTP) is a rare and life‐threatening autoimmune thrombotic microangiopathy. Caplacizumab, evaluated in phase II and III studies in adults, shortens the time to platelet count response and reduces aTTP exacerbations, has a favorable safety profile, and can potentially reduce refractoriness and mortality associated with aTTP. Since no children with aTTP were enrolled in these clinical trials, caplacizumab has been initially approved for use only in adult patients with aTTP (10 mg). Pediatric dosing recommendations were developed using model‐based simulations. A semimechanistic pharmacokinetic/pharmacodynamic population model has been developed describing the interaction between caplacizumab and von Willebrand factor antigen (vWF:Ag) following intravenous and subcutaneous administration of caplacizumab in different adult populations, at various dose levels, using nonlinear mixed‐effects modeling. Based on the allometrically scaled pharmacokinetic/pharmacodynamic model, different dosing regimens were simulated in 8000 children (aged 2‐18 years). Simulated caplacizumab exposures and vWF:Ag levels across different age categories were compared to an adult reference group. A simulated daily dose of 5 mg in children weighing <40 kg and of 10 mg in children weighing ≥40 kg resulted in similar exposures and vWF:Ag suppression across age and weight groups. Despite the lack of pediatric clinical data, the results of this modeling and simulation analysis constituted the basis for the European extension of indication for caplacizumab (10 mg) to adolescents aged >12 years and with a body weight ≥40 kg. This represents a rare case in which regulatory authorities have deemed a modeling and simulation study robust enough to approve a variation of indication. John Wiley and Sons Inc. 2021-11-29 2022-03 /pmc/articles/PMC9255589/ /pubmed/34699078 http://dx.doi.org/10.1002/jcph.1991 Text en © 2021 Sanofi. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology https://creativecommons.org/licenses/by-nc/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. |
spellingShingle | Pediatric Pharmacology Bergstrand, Martin Hansson, Emma Delaey, Bernard Callewaert, Filip De Passos Sousa, Rui Sargentini‐Maier, Maria Laura Caplacizumab Model‐Based Dosing Recommendations in Pediatric Patients With Acquired Thrombotic Thrombocytopenic Purpura |
title | Caplacizumab Model‐Based Dosing Recommendations in Pediatric Patients With Acquired Thrombotic Thrombocytopenic Purpura |
title_full | Caplacizumab Model‐Based Dosing Recommendations in Pediatric Patients With Acquired Thrombotic Thrombocytopenic Purpura |
title_fullStr | Caplacizumab Model‐Based Dosing Recommendations in Pediatric Patients With Acquired Thrombotic Thrombocytopenic Purpura |
title_full_unstemmed | Caplacizumab Model‐Based Dosing Recommendations in Pediatric Patients With Acquired Thrombotic Thrombocytopenic Purpura |
title_short | Caplacizumab Model‐Based Dosing Recommendations in Pediatric Patients With Acquired Thrombotic Thrombocytopenic Purpura |
title_sort | caplacizumab model‐based dosing recommendations in pediatric patients with acquired thrombotic thrombocytopenic purpura |
topic | Pediatric Pharmacology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9255589/ https://www.ncbi.nlm.nih.gov/pubmed/34699078 http://dx.doi.org/10.1002/jcph.1991 |
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