Adequacy of the 10 mg/kg Daily Dose of Antituberculosis Drug Isoniazid in Infants under 6 Months of Age
Por:
López-Ramos MG, Vinent-Genestar J, Aarnoutse R, Colbers A, Velasco E, Martorell-Sampol L, Falcón-Neyra L, Neth O, Prieto L, Guillén S, Baquero-Artigao F, Méndez-Echevarría A, Gómez-Pastrana D, Jiménez AB, Lahoz R, Ramos-Amador JT, Soriano-Arandes A, Santiago B, Rosa Farré Riba, Fortuny-Guasch C, Soy D and Noguera-Julian A
Publicada:
1 feb 2023
Ahead of Print:
30 ene 2023
Resumen:
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.
Filiaciones:
López-Ramos MG:
Pharmacy Department, Hospital Sant Joan de Déu, 08950 Barcelona, Spain
Vinent-Genestar J:
Pharmacy Department, Hospital Sant Joan de Déu, 08950 Barcelona, Spain
Aarnoutse R:
Department of Pharmacy, Radboud University Medical Center, Radboud Institute for Health Sciences, 6525 HB Nijmegen, The Netherlands
Colbers A:
Department of Pharmacy, Radboud University Medical Center, Radboud Institute for Health Sciences, 6525 HB Nijmegen, The Netherlands
Velasco E:
Malalties Infeccioses i Resposta Inflamatòria Sistèmica en Pediatria, Unitat d'Infeccions, Servei de Pediatria, Institut de Recerca Pediàtrica Sant Joan de Déu, 08950 Barcelona, Spain
Martorell-Sampol L:
Molecular Genetics Department, Hospital Sant Joan de Déu, 08950 Barcelona, Spain
Falcón-Neyra L:
Pediatric Infectious Diseases, Rheumatology and Immunology Unit, Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla, 41013 Seville, Spain
Red de Investigación Traslacional en Infectología Pediátrica RITIP, 28029 Madrid, Spain
Neth O:
Pediatric Infectious Diseases, Rheumatology and Immunology Unit, Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla, 41013 Seville, Spain
Red de Investigación Traslacional en Infectología Pediátrica RITIP, 28029 Madrid, Spain
Prieto L:
Red de Investigación Traslacional en Infectología Pediátrica RITIP, 28029 Madrid, Spain
Department of Infectious Diseases, Hospital 12 de Octubre, 28041 Madrid, Spain
Guillén S:
Pediatrics Department, Hospital de Getafe, 28905 Madrid, Spain
Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), 28029 Madrid, Spain
Baquero-Artigao F:
Red de Investigación Traslacional en Infectología Pediátrica RITIP, 28029 Madrid, Spain
Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), 28029 Madrid, Spain
Pediatrics and Infectious Diseases Unit, La Paz University Hospital, 28046 Madrid, Spain
Méndez-Echevarría A:
Red de Investigación Traslacional en Infectología Pediátrica RITIP, 28029 Madrid, Spain
Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), 28029 Madrid, Spain
Pediatrics and Infectious Diseases Unit, La Paz University Hospital, 28046 Madrid, Spain
Gómez-Pastrana D:
Neumología Pediátrica, Servicio de Pediatría, Hospital Universitario Jerez de la Frontera, 11407 Cádiz, Spain
Jiménez AB:
Pediatrics Department, Fundación Jiménez Díaz, 28040 Madrid, Spain
Lahoz R:
Pediatrics Department, Hospital Joan XXIII, 43005 Tarragona, Spain
Ramos-Amador JT:
Red de Investigación Traslacional en Infectología Pediátrica RITIP, 28029 Madrid, Spain
Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), 28029 Madrid, Spain
Servicio de Pediatría, Hospital Clinico San Carlos e Instituto de Investigación Sanitaria del Hospital Clínico San Carlos, 28040 Madrid, Spain
Departamento de Salud Pública y Materno-Infantil, Universidad Complutense de Madrid, 28040 Madrid, Spain
Soriano-Arandes A:
Pediatric Infectious Diseases and Immunodeficiencies Unit-Drassanes Unit, Hospital Vall D'Hebron, 08035 Barcelona, Spain
Santiago B:
Red de Investigación Traslacional en Infectología Pediátrica RITIP, 28029 Madrid, Spain
Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), 28029 Madrid, Spain
Sección Enfermedades Infecciosas Pediátricas, Servicio de Pediatría, Hospital Gregorio Marañón, 28009 Madrid, Spain
Instituto de Investigación Sanitaria Gregorio Marañon, 28009 Madrid, Spain
Rosa Farré Riba:
Pharmacy Department, Hospital Sant Joan de Déu, 08950 Barcelona, Spain
Fortuny-Guasch C:
Malalties Infeccioses i Resposta Inflamatòria Sistèmica en Pediatria, Unitat d'Infeccions, Servei de Pediatria, Institut de Recerca Pediàtrica Sant Joan de Déu, 08950 Barcelona, Spain
Red de Investigación Traslacional en Infectología Pediátrica RITIP, 28029 Madrid, Spain
Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), 28029 Madrid, Spain
Departament de Cirurgia i Especialitats Medicoquirúrgiques, Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona, 08036 Barcelona, Spain
Soy D:
Pharmacy Department, Division of Medicines, Hospital Clinic of Barcelona, University of Barcelona, 08036 Barcelona, Spain
Noguera-Julian A:
Malalties Infeccioses i Resposta Inflamatòria Sistèmica en Pediatria, Unitat d'Infeccions, Servei de Pediatria, Institut de Recerca Pediàtrica Sant Joan de Déu, 08950 Barcelona, Spain
Red de Investigación Traslacional en Infectología Pediátrica RITIP, 28029 Madrid, Spain
Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), 28029 Madrid, Spain
Departament de Cirurgia i Especialitats Medicoquirúrgiques, Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona, 08036 Barcelona, Spain
Passeig Sant Joan de Déu 2, 08950 Esplugues, Spain
Green Submitted, gold
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