TABLE 2.
Final population pharmacokinetic model parameter estimates for isoniazid, pyrazinamide, and ethambutol
| Parameter description | Typical value (95% CI) fora: |
||
|---|---|---|---|
| Isoniazid | Pyrazinamide | Ethambutol | |
| CL for rapid NAT2 acetylators (liters/h)b | 97.1 (68.6–144) | ||
| CL for intermediate NAT2 acetylators (liters/h)b | 75.7 (59.4–95.8) | 3.39 (2.96–3.87) | 60.2 (53.7–68.5) |
| CL for slow NAT2 acetylators (liters/h)b | 29.0 (24.3–34.8) | ||
| V1 (liters)b,c | 130 (106-162) | 43.8 (39.7–47.2) | 268 (154–419) |
| Q (liters/h)b,c | 12.4 (5.64–31.3) | 174 (71.7–385) | |
| Vp (liters)b,c | 28.5 (10.8–50.1) | 334 (217–490) | |
| MTT (h)c | 1.21 (0.953–1.51) | 0.934 (0.565–1.17) | 2.15 (1.84–2.51) |
| NNc | 8.01 (3.95–14.9) | 3.78 (2.24–7.71) | 6.23 (3.21–11.6) |
| Bioavailability (F) | 1 fixed | 1 fixed | 1 fixed |
| Proportional error (%) | 22.2 (15.2–30.4) | 9.19 (6.99–14.4) | 23.3 (17.8–33) |
| Additive error (mg/liter) | 0.045 (0.035–0.062) | 0.011 (0.002–0.019) | 0.03e fixed |
| BSV of clearance (%CV)d | 12.7 (1.37–30.8) | 25.4 (17.1–40.3) | 4.69 (0.379–20.4) |
| BOV of mean transit time (%CV)d | 56.7 (43.3–78.0) | 71.9 (41.2–125) | 24.1 (15.9–36.0) |
| BOV of bioavailability (%CV)d | 36.7 (27.0–48.7) | 13.6 (5.81–18.7) | 20.1 (10.6–32.2) |
95% confidence intervals were obtained by the sampling importance resampling technique using PsN software.
Allometric scaling was used for the clearance (CL) by fat-free mass (FFM), intercompartmental clearance (Q), central volume of distribution (V1), and peripheral volume of distribution (Vp) (by weight); typical values are reported for the median FFM and median weight as reported in Table 1.
Prior values (uncertainty) were added to the parameter estimates, as follows: for isoniazid, the Q (16.1 liters/h [50%]), Vp (16.5 liters [50%]), absorption mean transit time (MTT) (0.924 h [50%]), and number of transit compartments (NN) (2.73 [50%]); for pyrazinamide, the MTT (0.84 h [30%]) and NN (2.6 [50%]); and for ethambutol, the V1 (266 liters [50%]), Vp (687 liters [50%]), Q (109 liters/h [50%]), MTT (2.54 h [50%]), and NN (11.1 [50%]).
Between-subject variability (BSV) and between-occasion variability (BOV) were assumed to be log-normally distributed and are reported as approximate %CVs.
The estimate of the additive error was not statistically significant from its lower bound (LLOQ/2); thus, it was fixed to that value.