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Pharmacokinetic study of isoniazid and pyrazinamide in children: impact of age and nutritional status
  1. Rajeshwar Dayal1,
  2. Yatish Singh1,
  3. Dipti Agarwal2,
  4. Manoj Kumar1,
  5. Soumya Swaminathan3,
  6. Geetha Ramachandran4,
  7. Santosh Kumar5,
  8. Shamrendra Narayan6,
  9. Ankur Goyal7,
  10. A K Hemant Kumar4
  1. 1Department of Pediatrtics, Sarojini Naidu Medical College, Agra, Uttar Pradesh, India
  2. 2Department of Paediatrics, Dr. Ram Manohar Lohia Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
  3. 3Indian Council of Medical Research, New Delhi, India
  4. 4National Institute for Research in Tuberculosis, Chennai, India
  5. 5Department of TB & Chest Diseases, Sarojini Naidu Medical College, Agra, Uttar Pradesh, India
  6. 6Department of Radiology, Dr. Ram Manohar Lohia Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
  7. 7Department of Microbiology, Sarojini Naidu Medical College, Agra, Uttar Pradesh, India
  1. Correspondence to Dr Dipti Agarwal, Faculty Residential Apartment, Dr Ram Manohar Lohia Institute of Medical Sciences, Lucknow 226010, India; drdiptiagarwal{at}yahoo.co.in

Abstract

Objectives To evaluate pharmacokinetics of first-line antitubercular drugs, isoniazid (INH) and pyrazinamide (PZA), with revised WHO dosages and to assess its adequacy in relation to age and nutritional status.

Design Observational study.

Setting This study was conducted at Sarojini Naidu Medical College, Agra, and National Institute for Research in Tuberculosis, Chennai.

Patients 40 subjects diagnosed with tuberculosis were registered in the study and started on daily first-line antitubercular regimen based on the revised WHO guidelines.

Interventions Blood samples were collected at 0, 2, 4, 6 and 8 hours from these subjects after 15 days of treatment for drug estimations.

Main outcome measure The measurement of drug concentrations (maximum peak concentration (Cmax) and area under the time –concentration curve (AUC0–8 hours)) for INH and PZA. Appropriate statistical methods were used to evaluate the impact of age and nutritional status on pharmacokinetic variables.

Results For INH, the difference in drug exposures in children <3 years (Cmax 3.18 µg/mL and AUC0–8 hours15.76 µg/mL hour) and children >3 years (Cmax3.05 µg/mL and AUC0–8 hours 14.37 µg/mL hour) was not significant (P=0.94, P=0.81, respectively). The drug levels in children with low body mass index (BMI) (Cmax3.08 µg/mL; AUC0–8 hours14.81 µg/mL hour) were also comparable with their normal counterparts (Cmax3.09 µg/mL, P=0.99; AUC0–8 hours 14.69 µg/mL hour, P=0.82). PZA drug exposures obtained in children less than 3 years (Cmax29.22 µg/mL, AUC0–8 hours 155.45 µg/mL hour) were significantly lower compared with drug levels in children above 3 years (Cmax 37.12 µg/mL, P=0.03; AUC 202.63 µg/mL hour, P value=0.01). Children with low BMI had significantly lower drug concentrations (Cmax 31.90 µg/mL, AUC0–8 hours167.64 µg/mL hour) when compared with normal counterparts (Cmax 37.60 µg/mL, P=0.02; AUC0–8 hours 208.77 µg/mL hour, P=0.01).

Conclusions The revised WHO drug dosages were found to be adequate for INH with respect to age and nutritional status, whereas PZA showed significantly lower drug levels in children <3 years and in malnourished children.

  • tuberculosis
  • children
  • pharmacokinetics
  • antituberculosis drugs
  • malnutrition

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Footnotes

  • Contributors RD and SS conceived the idea of the study. YS, DA, SN, SK and AG were involved in data collection. DA, GR and MK were involved in final interpretation of the result. GR and AKHK supervised the pharmacokinetic study of the samples and edited the manuscript. DA, YS and SN wrote the first draft of the manuscript. The final manuscript was approved by all authors.

  • Funding This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

  • Patient consent Parental/guardian consent obtained.

  • Ethics approval Institute’s ethical committee, Sarojini Naidu Medical College, Agra India.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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