Isoniazid pharmacokinetics, pharmacodynamics, and dosing in South African infants

Jennifer J. Kiser, Rui Zhu, David Z. D'Argenio, Mark F. Cotton, Raziya Bobat, George D. McSherry, Shabir A. Madhi, Vincent J. Carey, Heiner I. Seifart, Cedric J. Werely, Courtney V Fletcher

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

AIMS: There are limited data on isoniazid (INH) pharmacokinetics in infants and young children and, therefore, uncertainty on appropriate dosing. METHODS: Pharmacokinetic data were obtained from perinatally HIV-exposed South African infants aged 3-24 months receiving INH 10-20 mg·kg·d orally for Mycobacterium tuberculosis prophylaxis. INH pharmacokinetic parameters were characterized using a population pharmacokinetic approach. Dosing simulations were performed to evaluate weight-based INH doses in children based on N-acetyltransferase 2 enzyme (NAT2) genotype, age, maximum concentrations (Cmax) ≥3 mg/L, and area under the curve (AUC0-24) ≥10.52 mg·h/L. RESULTS: In 151 infants (53% female, 48% HIV positive) receiving a mean INH dose of 14.5 mg·kg·d, mean (±SD) Cmax at 3, 6, and 23 months of age were 10.0 (3.5), 8.6 (2.6), and 9.3 (3.8) mg/L, respectively, mean (±SD) AUC0-24 were 53.6 (26.8), 42 (19.9), and 44 (30.7) mg·h/L, respectively, and mean (±SD) half-lives were 2.1 (0.7), 1.9 (0.6), and 1.8 (0.9) hours, respectively. A trimodal apparent oral clearance of INH as a function of the NAT2 genotype was apparent as early as 3 months. INH was well tolerated. At an average INH dose of 14.5 mg·kg·d, 99% of infants aged 3-24 months have an INH Cmax ≥3 mg/L, and 98% have an INH AUC0-24 ≥10.52 mg·h/L. CONCLUSIONS: INH at an average dose of 14.5 mg/kg once daily was well tolerated in infants and achieved INH Cmax values ≥3 mg/L and AUC0-24 values ≥10.52 mg·h/L.

Original languageEnglish (US)
Pages (from-to)446-451
Number of pages6
JournalTherapeutic Drug Monitoring
Volume34
Issue number4
DOIs
StatePublished - Aug 1 2012

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Isoniazid
Pharmacokinetics
Acetyltransferases
Genotype
HIV
Enzymes
Mycobacterium tuberculosis
Uncertainty
Area Under Curve
Weights and Measures
Population

Keywords

  • children
  • dosing
  • infants
  • isoniazid
  • pharmacokinetics

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Cite this

Isoniazid pharmacokinetics, pharmacodynamics, and dosing in South African infants. / Kiser, Jennifer J.; Zhu, Rui; D'Argenio, David Z.; Cotton, Mark F.; Bobat, Raziya; McSherry, George D.; Madhi, Shabir A.; Carey, Vincent J.; Seifart, Heiner I.; Werely, Cedric J.; Fletcher, Courtney V.

In: Therapeutic Drug Monitoring, Vol. 34, No. 4, 01.08.2012, p. 446-451.

Research output: Contribution to journalArticle

Kiser, JJ, Zhu, R, D'Argenio, DZ, Cotton, MF, Bobat, R, McSherry, GD, Madhi, SA, Carey, VJ, Seifart, HI, Werely, CJ & Fletcher, CV 2012, 'Isoniazid pharmacokinetics, pharmacodynamics, and dosing in South African infants', Therapeutic Drug Monitoring, vol. 34, no. 4, pp. 446-451. https://doi.org/10.1097/FTD.0b013e31825c4bc3
Kiser, Jennifer J. ; Zhu, Rui ; D'Argenio, David Z. ; Cotton, Mark F. ; Bobat, Raziya ; McSherry, George D. ; Madhi, Shabir A. ; Carey, Vincent J. ; Seifart, Heiner I. ; Werely, Cedric J. ; Fletcher, Courtney V. / Isoniazid pharmacokinetics, pharmacodynamics, and dosing in South African infants. In: Therapeutic Drug Monitoring. 2012 ; Vol. 34, No. 4. pp. 446-451.
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AU - D'Argenio, David Z.

AU - Cotton, Mark F.

AU - Bobat, Raziya

AU - McSherry, George D.

AU - Madhi, Shabir A.

AU - Carey, Vincent J.

AU - Seifart, Heiner I.

AU - Werely, Cedric J.

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N2 - AIMS: There are limited data on isoniazid (INH) pharmacokinetics in infants and young children and, therefore, uncertainty on appropriate dosing. METHODS: Pharmacokinetic data were obtained from perinatally HIV-exposed South African infants aged 3-24 months receiving INH 10-20 mg·kg·d orally for Mycobacterium tuberculosis prophylaxis. INH pharmacokinetic parameters were characterized using a population pharmacokinetic approach. Dosing simulations were performed to evaluate weight-based INH doses in children based on N-acetyltransferase 2 enzyme (NAT2) genotype, age, maximum concentrations (Cmax) ≥3 mg/L, and area under the curve (AUC0-24) ≥10.52 mg·h/L. RESULTS: In 151 infants (53% female, 48% HIV positive) receiving a mean INH dose of 14.5 mg·kg·d, mean (±SD) Cmax at 3, 6, and 23 months of age were 10.0 (3.5), 8.6 (2.6), and 9.3 (3.8) mg/L, respectively, mean (±SD) AUC0-24 were 53.6 (26.8), 42 (19.9), and 44 (30.7) mg·h/L, respectively, and mean (±SD) half-lives were 2.1 (0.7), 1.9 (0.6), and 1.8 (0.9) hours, respectively. A trimodal apparent oral clearance of INH as a function of the NAT2 genotype was apparent as early as 3 months. INH was well tolerated. At an average INH dose of 14.5 mg·kg·d, 99% of infants aged 3-24 months have an INH Cmax ≥3 mg/L, and 98% have an INH AUC0-24 ≥10.52 mg·h/L. CONCLUSIONS: INH at an average dose of 14.5 mg/kg once daily was well tolerated in infants and achieved INH Cmax values ≥3 mg/L and AUC0-24 values ≥10.52 mg·h/L.

AB - AIMS: There are limited data on isoniazid (INH) pharmacokinetics in infants and young children and, therefore, uncertainty on appropriate dosing. METHODS: Pharmacokinetic data were obtained from perinatally HIV-exposed South African infants aged 3-24 months receiving INH 10-20 mg·kg·d orally for Mycobacterium tuberculosis prophylaxis. INH pharmacokinetic parameters were characterized using a population pharmacokinetic approach. Dosing simulations were performed to evaluate weight-based INH doses in children based on N-acetyltransferase 2 enzyme (NAT2) genotype, age, maximum concentrations (Cmax) ≥3 mg/L, and area under the curve (AUC0-24) ≥10.52 mg·h/L. RESULTS: In 151 infants (53% female, 48% HIV positive) receiving a mean INH dose of 14.5 mg·kg·d, mean (±SD) Cmax at 3, 6, and 23 months of age were 10.0 (3.5), 8.6 (2.6), and 9.3 (3.8) mg/L, respectively, mean (±SD) AUC0-24 were 53.6 (26.8), 42 (19.9), and 44 (30.7) mg·h/L, respectively, and mean (±SD) half-lives were 2.1 (0.7), 1.9 (0.6), and 1.8 (0.9) hours, respectively. A trimodal apparent oral clearance of INH as a function of the NAT2 genotype was apparent as early as 3 months. INH was well tolerated. At an average INH dose of 14.5 mg·kg·d, 99% of infants aged 3-24 months have an INH Cmax ≥3 mg/L, and 98% have an INH AUC0-24 ≥10.52 mg·h/L. CONCLUSIONS: INH at an average dose of 14.5 mg/kg once daily was well tolerated in infants and achieved INH Cmax values ≥3 mg/L and AUC0-24 values ≥10.52 mg·h/L.

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