Population Pharmacokinetics and Exposure‐Response Analyses to Guide Dosing of Icatibant in Pediatric Patients With Hereditary Angioedema

Elevated bradykinin levels are responsible for the development of clinical symptoms in patients with hereditary angioedema (HAE). Icatibant is a bradykinin type 2 receptor antagonist indicated for the acute treatment of HAE attacks. A population modeling and simulation approach was used to examine s...

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Autores principales: Wang, Yi, Jomphe, Claudia, Marier, Jean‐Francois, Martin, Patrick
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7984404/
https://www.ncbi.nlm.nih.gov/pubmed/33091166
http://dx.doi.org/10.1002/jcph.1768
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author Wang, Yi
Jomphe, Claudia
Marier, Jean‐Francois
Martin, Patrick
author_facet Wang, Yi
Jomphe, Claudia
Marier, Jean‐Francois
Martin, Patrick
author_sort Wang, Yi
collection PubMed
description Elevated bradykinin levels are responsible for the development of clinical symptoms in patients with hereditary angioedema (HAE). Icatibant is a bradykinin type 2 receptor antagonist indicated for the acute treatment of HAE attacks. A population modeling and simulation approach was used to examine sources of variability impacting icatibant pharmacokinetics (PK) and provide guidance on icatibant dosing in pediatric patients with HAE. An exposure‐response analysis was performed for the time to onset of symptom relief (TOSR). Data from 141 adults (133 healthy, 8 with HAE) who received subcutaneous icatibant 30 mg and 31 pediatric patients with HAE who received 0.4 mg/kg (capped at 30 mg) were included in the analysis. Icatibant PK was described by a 2‐compartment model with linear elimination. Complete absorption of icatibant was expected within 1 hour of dosing. The apparent clearance and central volume of distribution were 15.4 L/h and 20.4 L, respectively. Icatibant PK was mainly dependent on body weight. The mean TOSR was very short (1.38 hours). A flat exposure‐response was observed, confirming that the relationship plateaued at the level of exposure observed in pediatric patients. Simulations confirmed that weight band–based dosing regimens (10 mg [12‐25 kg], 15 mg [26‐40 kg], 20 mg [41‐50 kg], 25 mg [51‐65 kg], and 30 mg [>65 kg]) resulted in exposure similar to the 0.4‐mg/kg dose. This analysis showed that icatibant undergoes rapid absorption, reaches levels required for therapeutic response, and promptly relieves HAE symptoms. A weight band–based dosing regimen is appropriate in pediatric patients with HAE.
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spelling pubmed-79844042021-03-25 Population Pharmacokinetics and Exposure‐Response Analyses to Guide Dosing of Icatibant in Pediatric Patients With Hereditary Angioedema Wang, Yi Jomphe, Claudia Marier, Jean‐Francois Martin, Patrick J Clin Pharmacol Pediatric Pharmacology Elevated bradykinin levels are responsible for the development of clinical symptoms in patients with hereditary angioedema (HAE). Icatibant is a bradykinin type 2 receptor antagonist indicated for the acute treatment of HAE attacks. A population modeling and simulation approach was used to examine sources of variability impacting icatibant pharmacokinetics (PK) and provide guidance on icatibant dosing in pediatric patients with HAE. An exposure‐response analysis was performed for the time to onset of symptom relief (TOSR). Data from 141 adults (133 healthy, 8 with HAE) who received subcutaneous icatibant 30 mg and 31 pediatric patients with HAE who received 0.4 mg/kg (capped at 30 mg) were included in the analysis. Icatibant PK was described by a 2‐compartment model with linear elimination. Complete absorption of icatibant was expected within 1 hour of dosing. The apparent clearance and central volume of distribution were 15.4 L/h and 20.4 L, respectively. Icatibant PK was mainly dependent on body weight. The mean TOSR was very short (1.38 hours). A flat exposure‐response was observed, confirming that the relationship plateaued at the level of exposure observed in pediatric patients. Simulations confirmed that weight band–based dosing regimens (10 mg [12‐25 kg], 15 mg [26‐40 kg], 20 mg [41‐50 kg], 25 mg [51‐65 kg], and 30 mg [>65 kg]) resulted in exposure similar to the 0.4‐mg/kg dose. This analysis showed that icatibant undergoes rapid absorption, reaches levels required for therapeutic response, and promptly relieves HAE symptoms. A weight band–based dosing regimen is appropriate in pediatric patients with HAE. John Wiley and Sons Inc. 2020-10-22 2021-04 /pmc/articles/PMC7984404/ /pubmed/33091166 http://dx.doi.org/10.1002/jcph.1768 Text en © 2020 Takeda Pharmaceutical Company Limited. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology This is an open access article under the terms of the http://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
Wang, Yi
Jomphe, Claudia
Marier, Jean‐Francois
Martin, Patrick
Population Pharmacokinetics and Exposure‐Response Analyses to Guide Dosing of Icatibant in Pediatric Patients With Hereditary Angioedema
title Population Pharmacokinetics and Exposure‐Response Analyses to Guide Dosing of Icatibant in Pediatric Patients With Hereditary Angioedema
title_full Population Pharmacokinetics and Exposure‐Response Analyses to Guide Dosing of Icatibant in Pediatric Patients With Hereditary Angioedema
title_fullStr Population Pharmacokinetics and Exposure‐Response Analyses to Guide Dosing of Icatibant in Pediatric Patients With Hereditary Angioedema
title_full_unstemmed Population Pharmacokinetics and Exposure‐Response Analyses to Guide Dosing of Icatibant in Pediatric Patients With Hereditary Angioedema
title_short Population Pharmacokinetics and Exposure‐Response Analyses to Guide Dosing of Icatibant in Pediatric Patients With Hereditary Angioedema
title_sort population pharmacokinetics and exposure‐response analyses to guide dosing of icatibant in pediatric patients with hereditary angioedema
topic Pediatric Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7984404/
https://www.ncbi.nlm.nih.gov/pubmed/33091166
http://dx.doi.org/10.1002/jcph.1768
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