Table 2.
Pharmacokinetic and covariate parameters in final population model
| Parameter | Estimate (%SEE) | % Variability a , a (%SEE) | Bootstrap median (95% CI) | Bootstrap median % variability a , a (95% CI) |
|---|---|---|---|---|
| Fraction of dose entering gut compartment, F a | 0.868 (0.0583) | 7.08 (fixed) b , b | 0.882 (0.874–0.890) | 7.08 (fixed) b , b |
| Fraction of F a absorbed via transit compartment | 0.458 (0.336) | 7.08 (fixed) | 0.479 (0.453–0.507) | 7.08 (fixed) |
| Maximum rate of absorption, ka,max (µmol/h) | 91.1 (3.96) | 77.3 (20.6) | 97.6 (85.0–111) | 71.5 (60.6–83.7) |
| Km for saturable absorption (µmol) | 52.7 (0.410) | 7.08 (fixed) | 51.8 (47.8–56.2) | 7.08 (fixed) |
| MTT (h) | 1.44 (3.68) | 71.9 (8.73) | 1.52 (1.43–1.62) | 70.1 (64.2–77.9) |
| Central volume (L) | 588 (2.81) | 68.6 (6.68) | 604 (563–635) | 65.7 (59.9–72.8) |
| Intercompartmental clearance (L/h) | 4.57 (0.449) | 7.08 (fixed) | 3.66 (3.10–4.29) | 7.08 (fixed) |
| Peripheral volume (L) | 159 (0.421) | 7.08 (fixed) | 152 (132–184) | 7.08 (fixed) |
| Zero‐order absorption duration (h) | 3.18 (10.3) | 638 (5.79) | 3.04 (2.52–3.84) | 810 (533–1278) |
| Absorption lag time (h) | 1.74 (0.538) | 7.08 (fixed) | 1.76 (1.69–1.80) | 7.08 (fixed) |
| Rate constant for formation of M2 from gut (/h) | 0.361 (0.479) | 7.08 (fixed) | 0.401 (0.366–0.432) | 7.08 (fixed) |
| Rate constant for formation of M20 from gut (/h) | 0.284 (0.468) | 7.08 (fixed) | 0.306 (0.276–0.339) | 7.08 (fixed) |
| CLint to form M2 in liver (L/h) c , c | 280 (0.436) | BSV of 44.9 (27.1) for healthy and 57.9 (39.5) for patients. WSV of 68.1 (5.12) for patients | 235 (199–284) | BSV of 44.3 (36.1–54.5) for healthy and 56.7 (44.8–71.2) for patients. WSV of 68.7 (59.6–80.7) for patients |
| CLint to form M20 in liver (L/h) c , c | 705 (0.421) | BSV of 44.9 (27.1) for healthy and 57.9 (39.5) for patients. WSV of 68.1 (5.12) for patients | 700 (627–775) | BSV of 44.3 (36.1–54.5) for healthy and 56.7 (44.8–71.2) for patients. WSV of 68.7 (59.6–80.7) for patients |
| CLint of M2 in liver (L/h) | 254 (2.06) | 41.9 (20.3) | 241 (218–271) | 42.2 (32.9–50.4) |
| CLint of M20 in liver (L/h) | 431 (2.00) | 42.5 (18.9) | 454 (417–489) | 42.1 (32.6–51.4) |
| Box‐cox shape for zero‐order duration ETAs | 0.19 (3.16) | – | 0.145 (0.116–0.184) | – |
| Diarrhea effect on Fa d | −0.417 (7.99) | – | −0.0079 (−1.29, 2.65 × 10−7) | – |
| C2 formulation on absorption lag e | 0.846 (2.99) | – | 0.872 (0.618–1.06) | – |
| C3 formulation on absorption lag e | 0.968 (1.82) | – | 0.982 (0.770–1.12) | – |
| Formulation on ka,max f | −0.513 (6.84) | – | −0.487 (−0.587 to −0.376) | – |
| Correlation between variability for MTT and zero‐order duration | 0.474 (16.9) | 0.474 (16.9) | ||
| Correlation between variability in CLint of M2 and M20 | 0.909 (15.6) | 0.908 (0.869–0.927) |
| Residual error | Estimate (%SEE) | Bootstrap median (95% CI) |
|---|---|---|
| Interindividual variability for residual error | 45.7 (17.5) | 44.7 (39.5–51.0) |
| Proportional error parent drug (oral) (%) | 21.7 (3.65) | 20.6 (19.1–22.1) |
| Proportional error M2 (%) | 21.9 (2.74) | 20.7 (19.1–22.1) |
| Proportional error M20 (%) | 13.8 (3.00) | 13.1 (12.3–14.1) |
| Proportional error 13C8‐labeled parent i.v. (%) | 61.6 (12.2) | 62.2 (51.7–71.4) |
| Additive error parent (oral) (µmol/L) | 0.000758 (28.9) | 0.000833 (0.000398–0.00261) |
| Additive error M2 (µmol/L) | 0.00122 (8.11) | 0.00121 (0.000985–0.00154) |
| Additive error M20 (µmol/L) | 0.00154 (10.0) | 0.00158 (0.00113–0.00204) |
ALAG8, absorption lag time; BSV, between subject variability; CI, confidence interval; CLint, intrinsic clearance; CV, coefficient of variation; i.v., intravenous; Ka,max, maximum absorption rate; Km, saturable rate constant; MTT, mean transit time; SEE, standard error of the estimate; TVCL, typical value of the clearance; WSV, within subject variability (no WSV for healthy individuals).
Reported as %CV, calculated by the following equation: , where OMEGA(N) is the NONMEM output for the intersubject variability of the Nth parameter.
Fixed OMEGA to 0.005 to facilitate efficiency of the stochastic approximation expectation maximization algorithm.
Variability incorporated in model on total CLint, which was sum of the typical values of CLint to form M2 and CLint to form M20. CLint = (TVCLint,form,m2 + TVCLint,form,m20)*e(BSV+WSV).
Estimate is on the logit parameter for F a. This translates to a 6% decrease in F a when there is diarrhea.
Absorption lag time (ALAG8) = Typical value (TV)ALAG8*(1+0.846*FORM1)*(1+0.968*FORM2), where FORM1 has a value of zero except for individuals with C2 formulation, and FORM2 has a value of zero except for individuals with the C3 formulation where the values are then set to 1. ALAG8= absorption lag time.
Maximum absorption rate (ka,max) = TVka,max *(1‐0.513*FORM2), where FORM2 has a value of zero except for individuals with the C3 formulation where it is set to 1.