Pharmacokinetic study of isoniazid and pyrazinamide in children: impact of age and nutritional status

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 (C max ) and area under the time -concentration curve (AUC 0-8 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 max 3.18 µg/mL and AUC 0-8 hours 15.76 µg/mL hour) and children >3 years (C max 3.05 µg/mL and AUC 0-8 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) (C max 3.08 µg/mL; AUC 0-8 hours 14.81 µg/mL hour) were also comparable with their normal counterparts (C max 3.09 µg/mL, P=0.99; AUC 0-8 hours 14.69 µg/mL hour, P=0.82). PZA drug exposures obtained in children less than 3 years (C max 29.22 µg/mL, AUC 0-8 hours 155.45 µg/mL hour) were significantly lower compared with drug levels in children above 3 years (C max 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 (C max 31.90 µg/mL, AUC 0-8 hours 167.64 µg/mL hour) when compared with normal counterparts (C max 37.60 µg/mL, P=0.02; AUC 0-8 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.