Table 2.
Population pharmacokinetic parameter estimates of models for TAC and MMF.
| Parameter | Base model | Final model | ||
|---|---|---|---|---|
| Population mean value (%RSE) | IIV CV% (%RSE) | Population mean value (%RSE) | IIV CV% (%RSE) | |
| Tacrolimus | ||||
| CL TAC (L/h) | 28.5 (19%) | 31.3% (13%) | 21.9 (16%) | 24.4% (14%) |
| V TAC (L) | 102 (15%) | 46.8% (16%) | 103 (15%) | 45.5% (18%) |
| Ka TAC (h−1) | 1.78 FIX | — | 1.78 FIX | — |
| k23 (h−1) | 0.863 (47%) | — | 0.803 (44%) | — |
| k32 (h−1) | 0.641 (48%) | — | 0.583 (51%) | — |
| Lag time (h) | 0.59 FIX | — | 0.59 FIX | — |
| CYP3A5 on CL TAC | — | — | 1.49 (9%) | — |
| σ add TAC | 0.687 (34%) | — | 0.585 (48%) | — |
| σ prop TAC | 0.203 (13%) | — | 0.211 (14%) | — |
| Mycophenolic acid | ||||
| CL MPA (L/h) | 2.94 (9%) | 24.8% (15%) | 3.27 (10%) | 25.8% (17%) |
| V MPA (L) | 22.9 (33%) | 42.9% (18%) | 23.2 (33%) | 42.9% (19%) |
| Ka MPA (h−1) | 2.29 FIX | — | 2.29 FIX | — |
| k56 (h−1) | 1.71 (24%) | — | 1.75 (23%) | — |
| k65 (h−1) | 0.0081 (17%) | — | 0.0089 (18%) | — |
| k70 (h−1) | 0.0958 (21%) | — | 0.103 (18%) | — |
| V MPAG (L) | 1.82 (17%) | — | 1.76 (15%) | — |
| f MPA | 0.85 FIX | — | 0.85 FIX | — |
| EHC (%) | 0.367 FIX | — | 0.367 FIX | — |
| k84 (h−1) | 18.4 FIX | — | 18.4 FIX | — |
| MTIME1 | 7.96 FIX | — | 7.96 FIX | — |
| MTIME2 | 1 FIX | — | 1 FIX | — |
| V AcMPAG (L) | 13.9 FIX | — | 13.9 FIX | — |
| k90 (h−1) | 0.407 FIX | — | 0.407 FIX | — |
| UGT2B7 on k 59 | — | — | 0.812 (10%) | — |
| SLCO1B3 on V MPAG (L) | — | — | 1.2 (10%) | — |
| σ prop MPA | 0.507 (7%) | — | 0.515 (7%) | — |
| σ prop MPAG | 0.221 (8%) | — | 0.216 (8%) | — |
| σ add AcMPAG | 0.0719 (25%) | — | 0.0647 (23%) | — |
| σ prop AcMPAG | 0.284 (9%) | — | 0.268 (8%) | — |
| Interaction | 0.0732 (39%) | — | 0.06 (35%) | — |
IIV, interindividual variability; CV, coefficient of variation; RSE, relative standard error; F, fraction of the dose absorbed; CL, clearance; TAC, tacrolimus; V, volume of distribution; Ka, first-order absorption rate constant; k23, k32, k56, and k65, intercompartment rate constants; MPA, mycophenolic acid; k70 and k90, eliminated rate constants; CYP3A5, CYP3A5 expressers (CYP3A5*1/*1 or CYP3A5*1/*3 carriers); fMPA, fraction of MPA which metabolized to MPAG; EHC, enterohepatic circulation; k84, gallbladder emptying rate constant; MTIME1, meal time; MTIME2, Gallbladder emptying duration; MPAG, MPA 7-O-glucuronide; AcMPAG, MPA acyl glucuronide; SLCO1B3, SLCO1B3 rs4149117 T carrier; UGT2B7, UGT2B7 rs7439366 T carrier; σprop, proportional residual error; σadd, additive residual error.