Pyrazinamide blood concentrations in children suffering from tuberculosis: a comparative study at two doses

Aims

To evaluate the pharmacokinetics and pharmacodynamic indices of pyrazinamide at doses of 15 and 25 mg kg⁻¹ in children suffering from tuberculosis.

Methods

Twenty children with tuberculosis received pyrazinamide at a single dose of 25 mg kg⁻¹ (group I) and 15 mg kg⁻¹ (group II). Serial blood samples were collected and the drug concentrations were analyzed spectrophotometrically. The pharmacokinetic parameters were calculated and the duration of time for which pyrazinamide concentrations in serum remained above the pyrazinamide inhibitory concentrations of 20 μg ml⁻¹ and 25 μg ml⁻¹ was studied.

Results

The mean peak serum concentration was 42.4 ± 3.3 μg ml⁻¹ (95% CI ± 6.5) and 38.6 ± 3.9 μg ml⁻¹ (95% CI ± 7.7) in groups I and II, respectively. The elimination half-life was 9.3 ± 1.3 h and 10.5 ± 2.3 h (P = 0.6) and clearance was 0.06 ± 0.01 l h⁻¹ kg⁻¹ and 0.04 ± 0.01 l h⁻¹ kg⁻¹ (P = 0.08) in groups I and II, respectively. Pharmacokinetic parameters and PKPD indices were comparable with both the doses.

Conclusions

The study indicates that comparable serum concentrations of pyrazinamide are attained with 25 mg kg⁻¹ and 15 mg kg⁻¹ doses in children. The elimination half-life was longer and volume of distribution greater in children than in the adult population.

What is already known about this subject

• Pyrazinamide is recommended in doses varying from 15 to 40 mg kg⁻¹. The most commonly used average daily dose is 25 mg kg⁻¹. Its use is associated with dose dependent hepatotoxicity.
• Lower doses are not used because of lack of pharmacokinetic data especially in children. There is only one detailed study of pyrazinamide in children at a dose of 35 mg kg⁻¹.

What this study adds

• This is the first study evaluating serum concentrations of pyrazinamide in children at a dose of 15 mg kg⁻¹ which is on the lower side of the recommended dose. The study also compared the serum concentrations and pharmacokinetics achieved with this dose with the widely used dose of 25 mg kg⁻¹ in children suffering from tuberculosis.
• The pharmacokinetics and pharmacodynamic indices of pyrazinamide were comparable with the 25 and 15 mg kg⁻¹ doses.