TABLE 2.
| Final population PK parameter estimates of methotrexate in children with ALL.
| Parameters | NONMEM estimates | SIR median (95%CI) | CV for IIV | SIR median (95%CI) |
|---|---|---|---|---|
| CL (L/h) | 6.9 (2.5) | 6.9 (6.62–7.19) | 17.5 (5.8) | 17.6 (16.0–19.7) |
| VC (L) | 20.7 (4.9) | 20.5 (18.5–22.4) | — | — |
| Q1 (L/h) | 0.255 (7.4) | 0.258 (0.232–0.285) | 26.2 (17.2) | 26.2 (18.4–33.6) |
| VP1 (L) | 41.0 (11.4) | 42.1 (34.4–51.3) | — | — |
| Q2 (L/h) | 0.217 (8.7) | 0.224 (0.193–0.260) | — | — |
| VP2 (L) | 3.17 (9.8) | 3.28 (2.75–3.88) | — | — |
| SCr on CL (%) | −0.97 (4.7) | −0.96 (−0.91 to −1.00) | — | — |
| σ | 0.354 (4.3) | 0.350 (0.336–0.366) | — | — |
CL is elimination clearance. VC is the central volume of distribution. Q is the inter-compartmental clearance. VP is the peripheral volume of distribution. σ is the additive residue error on the log scale.
Population estimates in Table 2 are given for a “typical” child with body weight of 19 kg. Body weight, was implemented as a fixed allometric function on all clearance and volume of distribution parameters using exponent of 0.75 and 1.0, respectively.
The coefficients of variation for inter-individual variability (IIV) were calculated as 100 × (evariance)1/2. The relative standard errors (%RSE) were calculated as 100 × (standard deviation/mean).
The SCr was implemented on CL as a linear function [CL = CLtypical × ((SCr-26) × 0.0097)].
SIR: Sampling importance resampling approach. The uncertainty was derived from the SIR, with options of 2,000 samples and 1,000 resamples.