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Adequacy of the 10 mg/kg Daily Dose of Antituberculosis Drug Isoniazid in Infants under 6 Months of Age

In 2010, the WHO recommended an increase in the daily doses of first-line anti-tuberculosis medicines in children. We aim to characterize the pharmacokinetics of the once-daily isoniazid (INH) dose at 10 mg/kg of body weight in infants <6 months of age. We performed a multicenter pharmacokinetic...

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Autores principales: López-Ramos, Maria Goretti, Vinent, Joan, Aarnoutse, Rob, Colbers, Angela, Velasco-Arnaiz, Eneritz, Martorell, Loreto, Falcón-Neyra, Lola, Neth, Olaf, Prieto, Luis, Guillén, Sara, Baquero-Artigao, Fernando, Méndez-Echevarría, Ana, Gómez-Pastrana, David, Jiménez, Ana Belén, Lahoz, Rebeca, Ramos-Amador, José Tomás, Soriano-Arandes, Antoni, Santiago, Begoña, Farré, Rosa, Fortuny, Clàudia, Soy, Dolors, Noguera-Julian, Antoni
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9952805/
https://www.ncbi.nlm.nih.gov/pubmed/36830184
http://dx.doi.org/10.3390/antibiotics12020272
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author López-Ramos, Maria Goretti
Vinent, Joan
Aarnoutse, Rob
Colbers, Angela
Velasco-Arnaiz, Eneritz
Martorell, Loreto
Falcón-Neyra, Lola
Neth, Olaf
Prieto, Luis
Guillén, Sara
Baquero-Artigao, Fernando
Méndez-Echevarría, Ana
Gómez-Pastrana, David
Jiménez, Ana Belén
Lahoz, Rebeca
Ramos-Amador, José Tomás
Soriano-Arandes, Antoni
Santiago, Begoña
Farré, Rosa
Fortuny, Clàudia
Soy, Dolors
Noguera-Julian, Antoni
author_facet López-Ramos, Maria Goretti
Vinent, Joan
Aarnoutse, Rob
Colbers, Angela
Velasco-Arnaiz, Eneritz
Martorell, Loreto
Falcón-Neyra, Lola
Neth, Olaf
Prieto, Luis
Guillén, Sara
Baquero-Artigao, Fernando
Méndez-Echevarría, Ana
Gómez-Pastrana, David
Jiménez, Ana Belén
Lahoz, Rebeca
Ramos-Amador, José Tomás
Soriano-Arandes, Antoni
Santiago, Begoña
Farré, Rosa
Fortuny, Clàudia
Soy, Dolors
Noguera-Julian, Antoni
author_sort López-Ramos, Maria Goretti
collection PubMed
description In 2010, the WHO recommended an increase in the daily doses of first-line anti-tuberculosis medicines in children. We aim to characterize the pharmacokinetics of the once-daily isoniazid (INH) dose at 10 mg/kg of body weight in infants <6 months of age. We performed a multicenter pharmacokinetic study in Spain. The N-acetyltransferase 2 gene was analyzed to determine the acetylation status. Samples were analyzed using a validated UPLC-UV assay. A non-compartmental pharmacokinetic analysis was performed. Twenty-three pharmacokinetic profiles were performed in 20 infants (8 females) at a median (IQR) age of 19.0 (12.6–23.3) weeks. The acetylator statuses were homozygous fast (n = 1), heterozygous intermediate (n = 12), and homozygous slow (n = 7). INH median (IQR) C(max) and AUC(0–24h) values were 4.8 (3.7–6.7) mg/L and 23.5 (13.4–36.7) h*mg/L and the adult targets (>3 mg/L and 11.6–26.3 h*mg/L) were not reached in three and five cases, respectively. The age at assessment or acetylator status had no impact on C(max) values, but a larger INH AUC(0–24h) (p = 0.025) and trends towards a longer half-life (p = 0.055) and slower clearance (p = 0.070) were observed in homozygous slow acetylators. Treatment was well tolerated; mildly elevated alanine aminotransferase levels were observed in three cases. In our series of young infants receiving isoniazid, no major safety concerns were raised, and the target adult levels were reached in most patients.
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spelling pubmed-99528052023-02-25 Adequacy of the 10 mg/kg Daily Dose of Antituberculosis Drug Isoniazid in Infants under 6 Months of Age López-Ramos, Maria Goretti Vinent, Joan Aarnoutse, Rob Colbers, Angela Velasco-Arnaiz, Eneritz Martorell, Loreto Falcón-Neyra, Lola Neth, Olaf Prieto, Luis Guillén, Sara Baquero-Artigao, Fernando Méndez-Echevarría, Ana Gómez-Pastrana, David Jiménez, Ana Belén Lahoz, Rebeca Ramos-Amador, José Tomás Soriano-Arandes, Antoni Santiago, Begoña Farré, Rosa Fortuny, Clàudia Soy, Dolors Noguera-Julian, Antoni Antibiotics (Basel) Article In 2010, the WHO recommended an increase in the daily doses of first-line anti-tuberculosis medicines in children. We aim to characterize the pharmacokinetics of the once-daily isoniazid (INH) dose at 10 mg/kg of body weight in infants <6 months of age. We performed a multicenter pharmacokinetic study in Spain. The N-acetyltransferase 2 gene was analyzed to determine the acetylation status. Samples were analyzed using a validated UPLC-UV assay. A non-compartmental pharmacokinetic analysis was performed. Twenty-three pharmacokinetic profiles were performed in 20 infants (8 females) at a median (IQR) age of 19.0 (12.6–23.3) weeks. The acetylator statuses were homozygous fast (n = 1), heterozygous intermediate (n = 12), and homozygous slow (n = 7). INH median (IQR) C(max) and AUC(0–24h) values were 4.8 (3.7–6.7) mg/L and 23.5 (13.4–36.7) h*mg/L and the adult targets (>3 mg/L and 11.6–26.3 h*mg/L) were not reached in three and five cases, respectively. The age at assessment or acetylator status had no impact on C(max) values, but a larger INH AUC(0–24h) (p = 0.025) and trends towards a longer half-life (p = 0.055) and slower clearance (p = 0.070) were observed in homozygous slow acetylators. Treatment was well tolerated; mildly elevated alanine aminotransferase levels were observed in three cases. In our series of young infants receiving isoniazid, no major safety concerns were raised, and the target adult levels were reached in most patients. MDPI 2023-01-30 /pmc/articles/PMC9952805/ /pubmed/36830184 http://dx.doi.org/10.3390/antibiotics12020272 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
López-Ramos, Maria Goretti
Vinent, Joan
Aarnoutse, Rob
Colbers, Angela
Velasco-Arnaiz, Eneritz
Martorell, Loreto
Falcón-Neyra, Lola
Neth, Olaf
Prieto, Luis
Guillén, Sara
Baquero-Artigao, Fernando
Méndez-Echevarría, Ana
Gómez-Pastrana, David
Jiménez, Ana Belén
Lahoz, Rebeca
Ramos-Amador, José Tomás
Soriano-Arandes, Antoni
Santiago, Begoña
Farré, Rosa
Fortuny, Clàudia
Soy, Dolors
Noguera-Julian, Antoni
Adequacy of the 10 mg/kg Daily Dose of Antituberculosis Drug Isoniazid in Infants under 6 Months of Age
title Adequacy of the 10 mg/kg Daily Dose of Antituberculosis Drug Isoniazid in Infants under 6 Months of Age
title_full Adequacy of the 10 mg/kg Daily Dose of Antituberculosis Drug Isoniazid in Infants under 6 Months of Age
title_fullStr Adequacy of the 10 mg/kg Daily Dose of Antituberculosis Drug Isoniazid in Infants under 6 Months of Age
title_full_unstemmed Adequacy of the 10 mg/kg Daily Dose of Antituberculosis Drug Isoniazid in Infants under 6 Months of Age
title_short Adequacy of the 10 mg/kg Daily Dose of Antituberculosis Drug Isoniazid in Infants under 6 Months of Age
title_sort adequacy of the 10 mg/kg daily dose of antituberculosis drug isoniazid in infants under 6 months of age
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9952805/
https://www.ncbi.nlm.nih.gov/pubmed/36830184
http://dx.doi.org/10.3390/antibiotics12020272
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