title: Pharmacokinetics of first-line antituberculosis drugs in HIV-infected children with tuberculosis treated with intermittent regimens in India.
abstract: The objective of this report was to study the pharmacokinetics of rifampin (RMP), isoniazid (INH), and pyrazinamide (PZA) in HIV-infected children with tuberculosis (TB) treated with a thrice-weekly anti-TB regimen in the government program in India. Seventy-seven HIV-infected children with TB aged 1 to 15 years from six hospitals in India were recruited. During the intensive phase of TB treatment with directly observed administration of the drugs, a complete pharmacokinetic study was performed. Drug concentrations were measured by high-performance liquid chromatography. A multivariable regression analysis was done to explore the factors impacting drug levels and treatment outcomes. The proportions of children with subnormal peak concentrations (Cmax) of RMP, INH, and PZA were 97%, 28%, and 33%, respectively. Children less than 5 years old had a lower median Cmax and lower exposure (area under the time-concentration curve from 0 to 8 h [AUC0-8]) of INH (Cmax, 2.5 versus 5.1 μg/ml, respectively [P=0.016]; AUC0-8, 11.1 versus 22.0 μg/ml·h, respectively [P=0.047[) and PZA (Cmax, 34.1 versus 42.3 μg/ml, respectively [P=0.055]; AUC0-8, 177.9 versus 221.7 μg/ml·h, respectively [P=0.05]) than those more than 5 years old. In children with unfavorable versus favorable outcomes, the median Cmax of RMP (1.0 versus 2.8 μg/ml, respectively; P=0.002) and PZA (31.9 versus 44.4 μg/ml, respectively; P=0.045) were significantly lower. Among all factors studied, the PZA Cmax influenced TB treatment outcome (P=0.011; adjusted odds ratio, 1.094; 95% confidence interval, 1.021 to 1.173). A high proportion of children with HIV and TB had a subnormal RMP Cmax. The PZA Cmax significantly influenced treatment outcome. These findings have important clinical implications and emphasize that drug doses in HIV-infected children with TB have to be optimized.
authors.affiliation: National Institute for Research in Tuberculosis, ICMR, Chetpet, Chennai, India.
authors.forename: Geetha
authors.initials: G
authors.lastname: Ramachandran
authors.affiliation: National Institute for Research in Tuberculosis, ICMR, Chetpet, Chennai, India.
authors.forename: A K Hemanth
authors.initials: AK
authors.lastname: Kumar
authors.affiliation: National Institute for Research in Tuberculosis, ICMR, Chetpet, Chennai, India.
authors.forename: P K
authors.initials: PK
authors.lastname: Bhavani
authors.affiliation: National Institute for Research in Tuberculosis, ICMR, Chetpet, Chennai, India.
authors.forename: T
authors.initials: T
authors.lastname: Kannan
authors.affiliation: National Institute for Research in Tuberculosis, ICMR, Chetpet, Chennai, India.
authors.forename: S Ramesh
authors.initials: SR
authors.lastname: Kumar
authors.affiliation: National Institute for Research in Tuberculosis, ICMR, Chetpet, Chennai, India.
authors.forename: N Poorana
authors.initials: NP
authors.lastname: Gangadevi
authors.affiliation: National Institute for Research in Tuberculosis, ICMR, Chetpet, Chennai, India.
authors.forename: V V
authors.initials: VV
authors.lastname: Banurekha
authors.affiliation: National Institute for Research in Tuberculosis, ICMR, Chetpet, Chennai, India.
authors.forename: L
authors.initials: L
authors.lastname: Sekar
authors.affiliation: Government Hospital of Thoracic Medicine, Chennai, India.
authors.forename: N
authors.initials: N
authors.lastname: Ravichandran
authors.affiliation: Government Rajaji Hospital, Madurai, India.
authors.forename: G
authors.initials: G
authors.lastname: Mathevan
authors.affiliation: Indira Gandhi Institute of Child Health, Bengaluru, India.
authors.forename: G N
authors.initials: GN
authors.lastname: Sanjeeva
authors.affiliation: Sarojini Naidu Medical College, Agra, India.
authors.forename: Rajeshwar
authors.initials: R
authors.lastname: Dayal
authors.affiliation: National Institute for Research in Tuberculosis, ICMR, Chetpet, Chennai, India soumyas@nirt.res.in.
authors.forename: Soumya
authors.initials: S
authors.lastname: Swaminathan
mesh_terms: D000293:Adolescent; D000995:Antitubercular Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D007194:India; D007223:Infant; D007538:Isoniazid / Q000493:pharmacokinetics / Q000627:therapeutic use; D008297:Male; D011718:Pyrazinamide / Q000493:pharmacokinetics / Q000627:therapeutic use; D012044:Regression Analysis; D012293:Rifampin / Q000493:pharmacokinetics / Q000627:therapeutic use; D016896:Treatment Outcome; D014376:Tuberculosis / Q000188:drug therapy*
chemical_list: D000995:Antitubercular Agents; D011718:Pyrazinamide; D007538:Isoniazid; D012293:Rifampin