Isoniazid pharmacokinetics, pharmacodynamics, and dosing in South African infants

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dc.contributor.authorKiser J.J.
dc.contributor.authorZhu R.
dc.contributor.authorD'Argenio D.Z.
dc.contributor.authorCotton M.F.
dc.contributor.authorBobat R.
dc.contributor.authorMcSherry G.D.
dc.contributor.authorMadhi S.A.
dc.contributor.authorCarey V.J.
dc.contributor.authorSeifart H.I.
dc.contributor.authorWerely C.J.
dc.contributor.authorFletcher C.V.
dc.date.accessioned2012-08-02T09:13:51Z
dc.date.available2012-08-02T09:13:51Z
dc.date.issued2012
dc.descriptionArticle
dc.description.abstractAIMS: 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. Copyright © 2012 by Lippincott Williams & Wilkins.
dc.identifier.citationTherapeutic Drug Monitoring
dc.identifier.citation34
dc.identifier.citation4
dc.identifier.citation446
dc.identifier.citation451
dc.identifier.issn1634356
dc.identifier.other10.1097/FTD.0b013e31825c4bc3
dc.identifier.urihttp://hdl.handle.net/10019.1/21921
dc.subjectchildren
dc.subjectdosing
dc.subjectinfants
dc.subjectisoniazid
dc.subjectpharmacokinetics
dc.titleIsoniazid pharmacokinetics, pharmacodynamics, and dosing in South African infants
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