Population pharmacokinetics of rifampicin, pyrazinamide and isoniazid in children with tuberculosis: in silico evaluation of currently recommended doses

Abstract

Objectives: To describe the population pharmacokinetics of rifampicin, pyrazinamide and isoniazid in children and evaluate the adequacy of steady-state exposures.

Patients and 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.

Keywords: NONMEM; anti-Mycobacterium; modelling and simulation; paediatrics; pharmacometrics.

Figure 1.

Maturation of oral clearance (CL) and mean transit time (MTT) of rifampicin and CL of isoniazid in a typical patient with post-natal age. The plot is not adjusted for covariate effects or allometric scaling.

Figure 2.

VPCs for the final models of rifampicin, pyrazinamide and isoniazid. The lower, middle and upper lines are the 5th percentile, median and 95th percentile of the observed data, respectively. The shaded areas are the 95% CIs for the 5th percentile, median and 95th percentile of the simulated data.

Figure 3.

Box plot of simulated steady-state AUC of rifampicin across different age and weight bands, obtained adhering as closely as possible to the revised guidelines in dose per unit weight according to WHO 2010 dosing guidelines. Each box shows the 25th–75th percentile of simulated AUC and the symbol ‘x’ shows data falling outside 1.5 times the IQR (25th–75th). The lower, middle and upper broken lines are the derived 5th percentile (9.0 mg · h/L), median (30.7 mg · h/L) and 95th percentile (52.4 mg · h/L) of the adult AUC, respectively. The grey shaded area is the 25th–75th (21.9–39.5 mg · h/L) percentile of the adult AUC.

Figure 4.

Box plot of simulated steady-state AUC of pyrazinamide across different age and weight bands, obtained adhering as closely as possible to the revised guidelines in dose per unit weight according to WHO 2010 dosing guidelines. Each box shows the 25th–75th percentile of simulated AUC and the symbol ‘x’ shows data falling outside 1.5 times the IQR (25th–75th). The lower, middle and upper broken lines are the derived 5th percentile (244.0 mg · h/L), median (427.0 mg · h/L) and 95th percentile (675.0 mg · h/L) of the adult AUC, respectively. The grey shaded area is the 25th–75th (346–547 mg · h/L) percentile of the adult AUC.

Figure 5.

Box plot of simulated steady-state AUC of isoniazid in slow (S), intermediate (I) and fast (F) acetylators across different age and weight bands, obtained adhering as closely as possible to the revised guidelines in dose per unit weight according to WHO 2010 dosing guidelines. Each box shows the 25th–75th percentile of simulated AUC and the symbol ‘x’ shows data falling outside 1.5 times the IQR (25th–75th). The lower, middle and upper broken lines are the derived 5th percentile (9.8 mg · h/L), median (23.4 mg · h/L) and 95th percentile (55.6 mg · h/L) of the adult AUC, respectively. The grey shaded area is the 25th–75th (15.6–35.5 mg · h/L) percentile of the adult AUC.