Table 2.
Pharmacokinetic parameter estimates from the final model, and median parameter estimates with 95% CIs from the PsN SIR package
| Parameter (unit) | Description | NONMEM | SIR‐resultsa | ||
|---|---|---|---|---|---|
| Mean θ estimate | %RSE | Median | 95% CI | ||
| S‐ketamine | |||||
| CLINT,H,SK (L/h) | Intrinsic hepatic clearance | 301 | 14.2 | 304 | [260, 352] |
| CLINT,GW,SK (L/h) | Intrinsic gut wall clearance | 1.19 | 39.5 | 1.22 | [0.66, 1.98] |
| K a,SK (/h) | Absorption rate constant | 1.76 | 16.1 | 1.78 | [1.47, 2.11] |
| V C,SK (L) | Volume of central compartment | 14.4 | 43.1 | 14.4 | [5.90, 22.5] |
| V PER1,SK (L) | Volume of first peripheral compartment | 102 | 8.0 | 102 | [92.5, 111] |
| Q PER1,SK (L/h) | Central to first peripheral compartment clearance | 287 | 11.3 | 288 | [250, 331] |
| V PER2,SK (L) | Volume of second peripheral compartment | 180 | 3.8 | 180 | [167, 190] |
| Q PER2,SK (L/h) | Central to second peripheral compartment clearance | 22.4 | 6.0 | 22.3 | [20.8, 24.1] |
| IIV on CLINT,H,SK | Interindividual variability on CLINT,H,SK | 0.25 | 11.9 | 0.26 | [0.17, 0.37] |
| IIV on CLINT,GW,SK | Interindividual variability on CLINT,GW,SK | 2.1 | 22.4 | 2.0 | [1.11, 3.67] |
| IIV on K a,SK | Interindividual variability on K a,SK | 0.42 | 17.9 | 0.44 | [0.29, 0.66] |
| IIV on V PER1,SK | Interindividual variability on V PER1,SK | 0.045 | 22.3 | 0.046 | [0.022, 0.076] |
| RVSK,PLAC | Proportional residual error with placebo | 0.086 | 2.1 | 0.086 | [0.079, 0.093] |
| RVSK,TICLO | Proportional residual error with ticlopidine | 0.065 | 33 | 0.065 | [0.048, 0.09] |
| Norketamine | |||||
| CLINT,H,NK (L/h) | Intrinsic hepatic clearanceb | 73.5 | 7.8 | 73.4 | [67.6, 79.9] |
| CLINT,GW,NK (L/h) | Intrinsic gut wall clearanceb | 44.4 | 35.8 | 46.5 | [29.7, 71.2] |
| V C,NK (L) | Volume of central compartmentb | 88.4 | 4.8 | 88 | [82.6, 93.5] |
| Q PER1,NK (L/h) | Central to first peripheral compartment clearanceb | 19.9 | 12.3 | 20.1 | [17.3, 22.8] |
| V PER1,NK (L) | Volume of first peripheral compartmentb | 88.9 | 5.6 | 88.8 | [81.7, 96.5] |
| IIV on CLINT,H,NK | Interindividual variability on CLINT,H,NK | 0.10 | 15.1 | 0.10 | [0.07, 0.15] |
| RVNK,PLAC | Proportional residual error with placebo | 0.062 | 2.4 | 0.062 | [0.057, 0.068] |
| RVNK,TICLO | Proportional residual error with ticlopidine | 0.064 | 31 | 0.067 | [0.050, 0.090] |
| Ticlopidine | |||||
| CLINT,H,TIC (L/h) | Intrinsic hepatic clearance | 1505 | 27.9 | 1490 | [1148, 1820] |
| CLINT,GW,TIC (L/h) | Intrinsic gut wall clearance | 0 (FIXED) | – | – | – |
| K a,TIC (/h) | Absorption rate constant | 3.3 (FIXED) | – | – | – |
| V C,TIC (L) | Volume of central compartment | 50.3 | 13.9 | 50.8 | [43.9, 57.7] |
| V PER1,TIC (L) | Volume of first peripheral compartment | 191 | 67 | 208.7 | [130, 393] |
| Q PER1,TIC (L/h) | Central to first peripheral compartment clearance | 26.3 | 24.4 | 25.8 | [20.9, 32.0] |
| IIV on CLINT,H,TIC | Interindividual variability on CLINT,H,TIC | 0.12 | 76.2 | 0.13 | [0.06, 0.28] |
| RVTICLO | Proportional residual variability | 0.066 | 9.5 | 0.067 | [0.053, 0.083] |
CI, confidence interval; GW, gut wall; H, hepatic; NK, S‐norketamine; PLAC, placebo; RSE, relative standard error; SK, S‐ketamine; TICLO, ticlopidine.
a
SIR procedure was executed with 20,000 final proposal samples and 2,000 resamples.
b
Should be considered as apparent rather than absolute values, as F met was set to 1 but true value of F met = 0.80 in humans for S‐ketamine to norketamine metabolism.