title: Pharmacokinetics of isoniazid, rifampicin, pyrazinamide and ethambutol in Indian children.
abstract: BACKGROUND
  The available pharmacokinetic data on anti-tubercular drugs in children raises the concern of suboptimal plasma concentrations attained when doses extrapolated from adult studies are used. Also, there is lack of consensus regarding the effect of malnutrition on pharmacokinetics of anti-tubercular drugs in children. We conducted this study with the aims of determining the plasma concentrations of isoniazid, rifampicin, pyrazinamide and ethambutol achieved with different dosage of the anti-tubercular drugs so as to provide supportive evidence to the revised dosages and to evaluate the effects of malnutrition on the pharmacokinetics of these drugs in children. We also attempted to correlate the plasma concentrations of these drugs with clinical outcome of therapy.
  
  
  METHODS
  Prospective drug estimation study was conducted in two groups of children, age 6 months to 15 years, with tuberculosis, with or without severe malnutrition, receiving different dosage of daily anti- tubercular therapy. The dosage (range) of isoniazid was 5 (4-6) and 10 (7-15) mg/kg in the two groups, respectively, that of rifampicin-10 (8-12) and 15 (10-12) mg/kg, respectively, both the groups received same dose of pyrazinamide (30-35 mg/kg) and ethambutol (20-25 mg/kg). All four drugs were simultaneously estimated by liquid chromatography-mass spectrometry (LC-MS/MS).
  
  
  CONCLUSIONS
  The median (IQR) Cmax of isoniazid increased significantly from 0.6 (0.3,1.2) μg/mL to 3.4 (1.8, 5.0) μg/mL with increase in the dose. Plasma rifampicin concentrations increased only marginally on increasing the dose [median (IQR) Cmax: 10.4 (7.2, 13.9) μg/mL vs. 12.0 (6.1, 24.3) μg/mL, p=0.08]. For ethambutol, 55.9% of the children had inadequate 2-hour concentrations. Two-hour plasma concentrations of at least one drug were low in 59 (92.2%) and 54 (85.7%) children in the two dosing regimen, respectively. We did not observe any effect of malnutrition on pharmacokinetic parameters of the drugs studied. We did not observe an association between low plasma drug concentrations and poor outcome. We may have to be cautious while increasing the doses and strive to asses other factors influencing the drug concentrations and treatment outcomes in children.
authors.affiliation: Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India. aparna.sinha.deb@gmail.com.
authors.forename: Aparna
authors.initials: A
authors.lastname: Mukherjee
authors.affiliation: Department of Ocular Pharmacology, All India Institute of Medical Sciences, New Delhi, India. tvelpandian@hotmail.com.
authors.forename: Thirumurthy
authors.initials: T
authors.lastname: Velpandian
authors.affiliation: Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India. ms2157@rediffmail.com.
authors.forename: Mohit
authors.initials: M
authors.lastname: Singla
authors.affiliation: Department of Ocular Pharmacology, All India Institute of Medical Sciences, New Delhi, India. kunwar.kanhiya@gmail.com.
authors.forename: Kunwar
authors.initials: K
authors.lastname: Kanhiya
authors.affiliation: Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India. skkabra@hotmail.com.
authors.forename: Sushil K
authors.initials: SK
authors.lastname: Kabra
authors.affiliation: Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India. rakesh_lodha@hotmail.com.
authors.forename: Rakesh
authors.initials: R
authors.lastname: Lodha
mesh_terms: D000293:Adolescent; D000995:Antitubercular Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002648:Child; D002675:Child, Preschool; D004977:Ethambutol / Q000008:administration & dosage / Q000493:pharmacokinetics; D005006:Ethnicity; D005260:Female; D006801:Humans; D007194:India; D007223:Infant; D007538:Isoniazid / Q000008:administration & dosage / Q000493:pharmacokinetics; D008297:Male; D011446:Prospective Studies; D011718:Pyrazinamide / Q000008:administration & dosage / Q000493:pharmacokinetics; D012044:Regression Analysis; D012293:Rifampin / Q000008:administration & dosage / Q000493:pharmacokinetics; D053719:Tandem Mass Spectrometry; D016896:Treatment Outcome; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D000995:Antitubercular Agents; D011718:Pyrazinamide; D004977:Ethambutol; D007538:Isoniazid; D012293:Rifampin