Table 2.
Final Population Pharmacokinetic Parameter Estimates for Linezolid in Plasma and Lumbar CSF
| Parameter | Estimate (95% CI) [RSE, %]a |
|---|---|
| CLmax: maximal clearance, L/hb | 7.25 (6.09–8.86) [9.93] |
| k m: Michaelis-Menten constant, mg/L | 27.2 (16.0–46.4) [29.1] |
| V: volume of distribution, Lb | 40.8 (37.9–43.6) [3.65] |
| F: bioavailability | 1 fixed |
| MTT: mean transit time, h | 0.211 (.112–.342) [28.6] |
| NN: No. of absorption transit compartments | 5.68 (2.36–11.8) [43.5] |
| k a: absorption rate constant, h−1 | 1.21 (.831–1.76) [19.6] |
| Plasma | |
| Proportional error, % | 21.5 (18.8–24.7) [7.06] |
| Additive error, mg/Lc | 0.173 (.0379–.355) [47.1] |
| BSV: between-subject variability in CLmax, % | 9.60 (3.44–13.9) [51.9] |
| BVV: between-visit variability in CLmax, % | 20.3 (15.3–26.9) [30.7] |
| BOV: between-occasion variability in ka, % | 87.9 (66.4–110) [25.9] |
| BOV in MTT, % | 110 (75.8–144) [32.8] |
| k plasma-CSF: equilibration rate constant to CSF, h−1d | 0.198 (.0849–.340) [33.7] |
| PPCmax: maximal pseudo-partition coefficient to CSF | 0.365 (.238–.566) [23.2] |
| CSF proteinmax: CSF protein at which PPCmax is reached, mg/mLe | 1.18 (.730–1.90) [24.4] |
| CSF | |
| Proportional error, % | 91.5 (63.3–151) [23.4] |
| Additive error, mg/Lc | 0.02 fixed |
Abbreviations: CSF, cerebrospinal fluid; RSE, relative SE.
a95% CIs and RSEs were computed with sampling/importance resampling on the final model.
bCLmax and V were allometrically scaled, so the values reported here refer to the typical participant (ie, a median fat-free mass of 45 kg).
cThe estimated additive component of the error was not significantly different from its lower boundary of 20% of the lower limit of quantitation, so it was fixed to this value.
dCorresponds to an equilibration half-life of 3.5 hours (95% CI, 2.04–8.16 hours).
eFor CSF protein < CSF proteinmax (ie, the breakpoint): PPCi = PPCmax · [slope · (CSF protein – breakpoint)], where the breakpoint was an estimated 1.18 mg/mL and the slope was 0.847. The slope was calculated from the following equation: slope = (amplitude – intercept) / (breakpoint – 0), where the intercept and amplitude were fixed to 0 and 1, respectively. For CSF protein ≥ CSF proteinmax: PPCi = PPCmax. The PPC-CSF protein relationship is depicted in Figure 2, and more details are provided in the supplementary file.