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...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-01-01
|
| Series: | Antibiotics |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2079-6382/12/2/272 |
| _version_ | 1797622745022857216 |
|---|---|
| author | Maria Goretti López-Ramos Joan Vinent Rob Aarnoutse Angela Colbers Eneritz Velasco-Arnaiz Loreto Martorell Lola Falcón-Neyra Olaf Neth Luis Prieto Sara Guillén Fernando Baquero-Artigao Ana Méndez-Echevarría David Gómez-Pastrana Ana Belén Jiménez Rebeca Lahoz José Tomás Ramos-Amador Antoni Soriano-Arandes Begoña Santiago Rosa Farré Clàudia Fortuny Dolors Soy Antoni Noguera-Julian |
| author_facet | Maria Goretti López-Ramos Joan Vinent Rob Aarnoutse Angela Colbers Eneritz Velasco-Arnaiz Loreto Martorell Lola Falcón-Neyra Olaf Neth Luis Prieto Sara Guillén Fernando Baquero-Artigao Ana Méndez-Echevarría David Gómez-Pastrana Ana Belén Jiménez Rebeca Lahoz José Tomás Ramos-Amador Antoni Soriano-Arandes Begoña Santiago Rosa Farré Clàudia Fortuny Dolors Soy Antoni Noguera-Julian |
| author_sort | Maria Goretti López-Ramos |
| collection | DOAJ |
| 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 (<i>n</i> = 1), heterozygous intermediate (<i>n</i> = 12), and homozygous slow (<i>n</i> = 7). INH median (IQR) C<sub>max</sub> and AUC<sub>0–24h</sub> 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<sub>max</sub> values, but a larger INH AUC<sub>0–24h</sub> (<i>p</i> = 0.025) and trends towards a longer half-life (<i>p</i> = 0.055) and slower clearance (<i>p</i> = 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. |
| first_indexed | 2024-03-11T09:14:37Z |
| format | Article |
| id | doaj.art-03f0d4084399450bb0f28a54c3bd5442 |
| institution | Directory Open Access Journal |
| issn | 2079-6382 |
| language | English |
| last_indexed | 2024-03-11T09:14:37Z |
| publishDate | 2023-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antibiotics |
| spelling | doaj.art-03f0d4084399450bb0f28a54c3bd54422023-11-16T18:42:40ZengMDPI AGAntibiotics2079-63822023-01-0112227210.3390/antibiotics12020272Adequacy of the 10 mg/kg Daily Dose of Antituberculosis Drug Isoniazid in Infants under 6 Months of AgeMaria Goretti López-Ramos0Joan Vinent1Rob Aarnoutse2Angela Colbers3Eneritz Velasco-Arnaiz4Loreto Martorell5Lola Falcón-Neyra6Olaf Neth7Luis Prieto8Sara Guillén9Fernando Baquero-Artigao10Ana Méndez-Echevarría11David Gómez-Pastrana12Ana Belén Jiménez13Rebeca Lahoz14José Tomás Ramos-Amador15Antoni Soriano-Arandes16Begoña Santiago17Rosa Farré18Clàudia Fortuny19Dolors Soy20Antoni Noguera-Julian21Pharmacy Department, Hospital Sant Joan de Déu, 08950 Barcelona, SpainPharmacy Department, Hospital Sant Joan de Déu, 08950 Barcelona, SpainDepartment of Pharmacy, Radboud University Medical Center, Radboud Institute for Health Sciences, 6525 HB Nijmegen, The NetherlandsDepartment of Pharmacy, Radboud University Medical Center, Radboud Institute for Health Sciences, 6525 HB Nijmegen, The NetherlandsMalalties Infeccioses i Resposta Inflamatòria Sistèmica en Pediatria, Unitat d’Infeccions, Servei de Pediatria, Institut de Recerca Pediàtrica Sant Joan de Déu, 08950 Barcelona, SpainMolecular Genetics Department, Hospital Sant Joan de Déu, 08950 Barcelona, SpainPediatric Infectious Diseases, Rheumatology and Immunology Unit, Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla, 41013 Seville, SpainPediatric Infectious Diseases, Rheumatology and Immunology Unit, Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla, 41013 Seville, SpainRed de Investigación Traslacional en Infectología Pediátrica RITIP, 28029 Madrid, SpainPediatrics Department, Hospital de Getafe, 28905 Madrid, SpainRed de Investigación Traslacional en Infectología Pediátrica RITIP, 28029 Madrid, SpainRed de Investigación Traslacional en Infectología Pediátrica RITIP, 28029 Madrid, SpainNeumología Pediátrica, Servicio de Pediatría, Hospital Universitario Jerez de la Frontera, 11407 Cádiz, SpainPediatrics Department, Fundación Jiménez Díaz, 28040 Madrid, SpainPediatrics Department, Hospital Joan XXIII, 43005 Tarragona, SpainRed de Investigación Traslacional en Infectología Pediátrica RITIP, 28029 Madrid, SpainPediatric Infectious Diseases and Immunodeficiencies Unit–Drassanes Unit, Hospital Vall D’Hebron, 08035 Barcelona, SpainRed de Investigación Traslacional en Infectología Pediátrica RITIP, 28029 Madrid, SpainPharmacy Department, Hospital Sant Joan de Déu, 08950 Barcelona, SpainMalalties Infeccioses i Resposta Inflamatòria Sistèmica en Pediatria, Unitat d’Infeccions, Servei de Pediatria, Institut de Recerca Pediàtrica Sant Joan de Déu, 08950 Barcelona, SpainPharmacy Department, Division of Medicines, Hospital Clinic of Barcelona, University of Barcelona, 08036 Barcelona, SpainMalalties Infeccioses i Resposta Inflamatòria Sistèmica en Pediatria, Unitat d’Infeccions, Servei de Pediatria, Institut de Recerca Pediàtrica Sant Joan de Déu, 08950 Barcelona, SpainIn 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 (<i>n</i> = 1), heterozygous intermediate (<i>n</i> = 12), and homozygous slow (<i>n</i> = 7). INH median (IQR) C<sub>max</sub> and AUC<sub>0–24h</sub> 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<sub>max</sub> values, but a larger INH AUC<sub>0–24h</sub> (<i>p</i> = 0.025) and trends towards a longer half-life (<i>p</i> = 0.055) and slower clearance (<i>p</i> = 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.https://www.mdpi.com/2079-6382/12/2/272acetylationinfantisoniazidpharmacokineticstransaminasestuberculosis |
| spellingShingle | Maria Goretti López-Ramos Joan Vinent Rob Aarnoutse Angela Colbers Eneritz Velasco-Arnaiz Loreto Martorell Lola Falcón-Neyra Olaf Neth Luis Prieto Sara Guillén Fernando Baquero-Artigao Ana Méndez-Echevarría David Gómez-Pastrana Ana Belén Jiménez Rebeca Lahoz José Tomás Ramos-Amador Antoni Soriano-Arandes Begoña Santiago Rosa Farré Clàudia Fortuny Dolors Soy Antoni Noguera-Julian Adequacy of the 10 mg/kg Daily Dose of Antituberculosis Drug Isoniazid in Infants under 6 Months of Age Antibiotics acetylation infant isoniazid pharmacokinetics transaminases tuberculosis |
| 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 | acetylation infant isoniazid pharmacokinetics transaminases tuberculosis |
| url | https://www.mdpi.com/2079-6382/12/2/272 |
| work_keys_str_mv | AT mariagorettilopezramos adequacyofthe10mgkgdailydoseofantituberculosisdrugisoniazidininfantsunder6monthsofage AT joanvinent adequacyofthe10mgkgdailydoseofantituberculosisdrugisoniazidininfantsunder6monthsofage AT robaarnoutse adequacyofthe10mgkgdailydoseofantituberculosisdrugisoniazidininfantsunder6monthsofage AT angelacolbers adequacyofthe10mgkgdailydoseofantituberculosisdrugisoniazidininfantsunder6monthsofage AT eneritzvelascoarnaiz adequacyofthe10mgkgdailydoseofantituberculosisdrugisoniazidininfantsunder6monthsofage AT loretomartorell adequacyofthe10mgkgdailydoseofantituberculosisdrugisoniazidininfantsunder6monthsofage AT lolafalconneyra adequacyofthe10mgkgdailydoseofantituberculosisdrugisoniazidininfantsunder6monthsofage AT olafneth adequacyofthe10mgkgdailydoseofantituberculosisdrugisoniazidininfantsunder6monthsofage AT luisprieto adequacyofthe10mgkgdailydoseofantituberculosisdrugisoniazidininfantsunder6monthsofage AT saraguillen adequacyofthe10mgkgdailydoseofantituberculosisdrugisoniazidininfantsunder6monthsofage AT fernandobaqueroartigao adequacyofthe10mgkgdailydoseofantituberculosisdrugisoniazidininfantsunder6monthsofage AT anamendezechevarria adequacyofthe10mgkgdailydoseofantituberculosisdrugisoniazidininfantsunder6monthsofage AT davidgomezpastrana adequacyofthe10mgkgdailydoseofantituberculosisdrugisoniazidininfantsunder6monthsofage AT anabelenjimenez adequacyofthe10mgkgdailydoseofantituberculosisdrugisoniazidininfantsunder6monthsofage AT rebecalahoz adequacyofthe10mgkgdailydoseofantituberculosisdrugisoniazidininfantsunder6monthsofage AT josetomasramosamador adequacyofthe10mgkgdailydoseofantituberculosisdrugisoniazidininfantsunder6monthsofage AT antonisorianoarandes adequacyofthe10mgkgdailydoseofantituberculosisdrugisoniazidininfantsunder6monthsofage AT begonasantiago adequacyofthe10mgkgdailydoseofantituberculosisdrugisoniazidininfantsunder6monthsofage AT rosafarre adequacyofthe10mgkgdailydoseofantituberculosisdrugisoniazidininfantsunder6monthsofage AT claudiafortuny adequacyofthe10mgkgdailydoseofantituberculosisdrugisoniazidininfantsunder6monthsofage AT dolorssoy adequacyofthe10mgkgdailydoseofantituberculosisdrugisoniazidininfantsunder6monthsofage AT antoninoguerajulian adequacyofthe10mgkgdailydoseofantituberculosisdrugisoniazidininfantsunder6monthsofage |