Population pharmacokinetics of rifampicin, pyrazinamide and isoniazid in children with tuberculosis: in silico evaluation of currently recommended doses.
OBJECTIVE
To describe the population pharmacokinetics of rifampicin, pyrazinamide and isoniazid in children and evaluate the adequacy of steady-state exposures.


METHODS
We used previously published data for 76 South African children with tuberculosis to describe the population pharmacokinetics of rifampicin, pyrazinamide and isoniazid. Monte Carlo simulations were used to predict steady-state exposures in children following doses in fixed-dose combination tablets in accordance with the revised guidelines. Reference exposures were derived from an ethnically similar adult population with tuberculosis taking currently recommended doses.


RESULTS
The final models included allometric scaling of clearance and volume of distribution using body weight. Maturation was included for clearance of isoniazid and clearance and absorption transit time of rifampicin. For a 2-year-old child weighing 12.5 kg, the estimated typical oral clearances of rifampicin and pyrazinamide were 8.15 and 1.08 L/h, respectively. Isoniazid typical oral clearance (adjusted for bioavailability) was predicted to be 4.44, 11.6 and 14.6 L/h for slow, intermediate and fast acetylators, respectively. Higher oral clearance values in intermediate and fast acetylators also resulted from 23% lower bioavailability compared with slow acetylators.


CONCLUSIONS
Simulations based on our models suggest that with the new WHO dosing guidelines and utilizing available paediatric fixed-dose combinations, children will receive adequate rifampicin exposures when compared with adults, but with a larger degree of variability. However, pyrazinamide and isoniazid exposures in many children will be lower than in adults. Further studies are needed to confirm these findings in children administered the revised dosages and to optimize pragmatic approaches to dosing.
Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
Simbarashe P
SP
Zvada
Paolo
P
Denti
Peter R
PR
Donald
H Simon
HS
Schaaf
Stephanie
S
Thee
James A
JA
Seddon
Heiner I
HI
Seifart
Peter J
PJ
Smith
Helen M
HM
McIlleron
Ulrika S H
US
Simonsson
D000995:Antitubercular Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002648:Child; D002675:Child, Preschool; D001330:Electronic Data Processing; D005260:Female; D006801:Humans; D007223:Infant; D007538:Isoniazid / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008297:Male; D015233:Models, Statistical; D011718:Pyrazinamide / Q000008:administration & dosage / Q000493:pharmacokinetics*; D012293:Rifampin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D013019:South Africa; D014376:Tuberculosis / Q000188:drug therapy*
D000995:Antitubercular Agents; D011718:Pyrazinamide; D007538:Isoniazid; D012293:Rifampin
NONMEM; anti-Mycobacterium; modelling and simulation; paediatrics; pharmacometrics