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


CONCLUSIONS
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.


OBJECTIVE
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 microg ml(-1) and 25 microg ml(-1) was studied.


RESULTS
The mean peak serum concentration was 42.4 +/- 3.3 microg ml(-1) (95% CI +/- 6.5) and 38.6 +/- 3.9 microg 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.
Gupta
Pooja
P
Department of Pharmacology, All India Institute of Medical Sciences, New Delhi, India. drgupta.pooja@gmail.com
Roy
Vandana
V
Sethi
Gulshan Rai
GR
Mishra
Tarun Kumar
TK
D000995:Antitubercular Agents / Q000008:administration & dosage* / Q000097:blood*; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D011718:Pyrazinamide / Q000008:administration & dosage* / Q000097:blood*; D014376:Tuberculosis / Q000097:blood* / Q000188:drug therapy*
D000995:Antitubercular Agents; D011718:Pyrazinamide