TABLE 2.
Population PK parameter estimates and post hoc secondary PK parameters from the final population PK model of isoniazid in children with TBMa
| Parameter | Population estimateb (% RSE)c |
95% CIc | % CV for IIVb (% RSE)c |
95% CI for IIVc |
Plasmad | CSFd |
|---|---|---|---|---|---|---|
| Primary PK parameters | ||||||
| F | 1 (fixed) | |||||
| CL/F (liters/h) | 9.43 (6.55) | 8.33–10.7 | 36.8 (10.2) | 30.6–45.7 | ||
| Vc/F (liters) | 3.78 (33.6) | 1.32–6.29 | ||||
| MTT (h) | 0.878 (10.9) | 0.682–1.05 | ||||
| MAT50 (mo) | 12.7 (6.85) | 10.9–14.3 | ||||
| HILL | 4.7 (13.5) | 3.60–6.04 | ||||
| Q/F (liters/h) | 28.0 (21.5) | 18.2–41.3 | 101 (11.7) | 69.6–133 | ||
| Vp/F (liters) | 15.3 (9.60) | 12.6–18.3 | ||||
| QCSF/F (liters/h) | 13.7 (43.6) | 4.45–27.5 | ||||
| fu | 0.9 (fixed) | |||||
| PC | 1.65 (5.24) | 1.48–1.81 | ||||
| Slow acetylators (%) | 56.4 (6.61) | 49.0–63.4 | ||||
| σPlasma | 0.474 (4.18) | 0.402–0.556 | ||||
| σCSF | 0.170 (6.96) | 0.129–0.220 | ||||
| Secondary PK parameters at steady state | ||||||
| Fast and intermediate acetylators | ||||||
| AUC0–24 (mg×h/liter) | 6.35 (2.64–24.2) | 9.42 (3.91–35.9) | ||||
| Cmax (mg/liter) | 2.12 (1.47–5.13) | 3.14 (2.18–7.61) | ||||
| Tmax (h) | 0.942 (0.801–1.19) | 0.955 (0.821–1.19) | ||||
| t1/2 (h) | 2.14 (1.04–6.24) | 2.14 (1.04–6.24) | ||||
| Slow acetylators | ||||||
| AUC0–24 (mg×h/liter) | 12.4 (6.38–21.6) | 18.4 (9.47–32.1) | ||||
| Cmax (mg/liter) | 2.41 (1.88–3.84) | 3.58 (2.79–5.70) | ||||
| Tmax (h) | 1.14 (0.890–4.52) | 1.15 (0.920–4.53) | ||||
| t1/2 (h) | 3.66 (2.08–6.38) | 3.66 (2.08–6.38) | ||||
Abbreviations: F, relative bioavailability; CL/F, oral elimination clearance; Vc/F, volume of distribution of the central compartment; MTT, mean transit absorption time; MAT50, postmenstrual age at which clearance is 50% of the mature clearance; HILL, Hill coefficient for maturation clearance; Q/F, intercompartmental clearance; Vp/F, volume of distribution of peripheral compartment; QCSF/F, intercompartmental clearance between central and CSF compartments; fu, fraction unbound; PC, transfer multiplier between central and CSF compartments describing blood-brain penetration; Slow acetylator, reduction of elimination clearance (percent) in slow acetylator compared to fast acetylator; IIV, interindividual variability; σ, variance of the residual variability, incorporated as an additive error on the logarithmic scale; AUC0–24, area under the concentration-time curve from 0 to 24 h; Cmax, peak concentration; Tmax, time to reach peak concentration; t1/2, terminal elimination half-life.
Computed population mean parameter estimates from NONMEM. Parameter estimates are scaled to typical patient at 10.9 kg and 3 years.
Assessed by sampling importance resampling (SIR).
Median (min-max).