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.
RCT Entities:
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.
Authors: E Rey; D Gendrel; J M Treluyer; A Tran; A Pariente-Khayat; P d'Athis; G Pons Journal: Fundam Clin Pharmacol Date: 2001-10 Impact factor: 2.748
Authors: H S Schaaf; D P Parkin; H I Seifart; C J Werely; P B Hesseling; P D van Helden; J S Maritz; P R Donald Journal: Arch Dis Child Date: 2005-06 Impact factor: 3.791
Authors: D P Parkin; S Vandenplas; F J Botha; M L Vandenplas; H I Seifart; P D van Helden; B J van der Walt; P R Donald; P P van Jaarsveld Journal: Am J Respir Crit Care Med Date: 1997-05 Impact factor: 21.405
Authors: Rui Zhu; Jennifer J Kiser; Heiner I Seifart; Cedric J Werely; Charles D Mitchell; David Z D'Argenio; Courtney V Fletcher Journal: J Clin Pharmacol Date: 2011-05-10 Impact factor: 3.126
Authors: Gregory L Kearns; Susan M Abdel-Rahman; Sarah W Alander; Douglas L Blowey; J Steven Leeder; Ralph E Kauffman Journal: N Engl J Med Date: 2003-09-18 Impact factor: 91.245
Authors: P R Donald; F A Sirgel; A Venter; D P Parkin; H I Seifart; B W van de Wal; C Werely; P D van Helden; J S Maritz Journal: Clin Infect Dis Date: 2004-10-25 Impact factor: 9.079
Authors: Ellen M McDonagh; Sotiria Boukouvala; Eleni Aklillu; David W Hein; Russ B Altman; Teri E Klein Journal: Pharmacogenet Genomics Date: 2014-08 Impact factor: 2.089
Authors: R Court; M T Chirehwa; L Wiesner; N de Vries; J Harding; T Gumbo; G Maartens; H McIlleron Journal: Int J Tuberc Lung Dis Date: 2019-10-01 Impact factor: 2.373
Authors: Sylvia M LaCourse; Daniel Leon; Nuttada Panpradist; Barbra A Richardson; Elizabeth Maleche-Obimbo; Jerphason Mecha; Daniel Matemo; Jaclyn N Escudero; John Kinuthia; Barry Lutz; Grace John-Stewart Journal: Pediatr Infect Dis J Date: 2021-01 Impact factor: 2.129