Table 2.
Population PK parameters of final model and bootstrap validation
| PK parameter | Population mean | RSE (%) | Shrinkage (%) | IPV (%) | RSE (%) | Bootstrap (n = 2000) | ||
|---|---|---|---|---|---|---|---|---|
| Median | 5th | 95th | ||||||
| Ka (h–1) = θ1 × Ka_FOR | ||||||||
| θ1 | 0.52 | 27 | 17.5 | 37 | 38 | 0.52 | 0.39 | 0.7 |
| Limustin, Ka_FOR = 1 + θ13 | ||||||||
| Unknown formulation, Ka_FOR = 1 + θ14 | ||||||||
| θ13 | –0.76 | 6 | - | - | - | –0.76 | –0.83 | –0.69 |
| θ14 | –0.51 | 23 | - | - | - | –0.52 | –0.68 | –0.2 |
| V/F (l) | 24.16 | 39 | 14.7 | 66 | 46- | 23.71 | 14.44 | 37.5 |
| CL/F (l h–1) = θ3 × INFCYP3A5 | ||||||||
| θ3 | 11.98 | 8 | - | - | - | 12.03 | 10.67 | 13.91 |
| If CYP3A5*1/*3, INFCYP3A5 = 1 + θ8 | ||||||||
| If CYP3A5*1/*1, INFCYP3A5 = 1 + θ9 | ||||||||
| θ8 | 0.5 | 38 | - | - | - | 0.5 | 0.13 | 0.77 |
| θ9 | 0.93 | 33 | - | - | - | 0.95 | 0.16 | 2.21 |
| Q/F (l h–1) | 32.49 | 20 | - | - | - | 32.65 | 24.3 | 39.71 |
| VT/F (l) | 383.5 | 34 | - | - | - | 373.79 | 251.71 | 708.49 |
| tlag (h) | 0.39 | 6 | - | - | - | 0.39 | 0.35 | 0.43 |
| F (%) = 100 × FDTOT × FFOR | 100* | - | –0.47 | 38 | 22 | - | - | - |
| FDTOT = e[(θ10 × (Dose–2)]) | ||||||||
| θ10 | –0.3 | 19 | - | - | - | –0.3 | –0.4 | –0.22 |
| FFOR | ||||||||
| Limustin, FFOR = 1 + θ11 | ||||||||
| Unknown formulation, FFOR = 1 + θ12 | ||||||||
| θ11 | –0.53 | 22 | - | - | - | –0.53 | –0.67 | –0.3 |
| θ12 | –0.53 | 16 | - | - | - | –0.51 | –0.66 | –0.34 |
| Residual error [ln (ng ml–1)] | 0.12 | 8 | –0.33 | 35 | 49 | 0.12 | 0.11 | 0.14 |
*
assumed as 100%, was not estimated. CL/F, apparent blood clearance; CYP3A5, genotype of gene coding cytochrome P450-5; F, relative bioavailabilty; FDTOT, effect of the tacrolimus total dose on F; FFOR, effect of FOR on F; FOR, tacrolimus formulation that could be Prograf®, Limustin®, Framebin®, Tenacrine® or unknown; IPV, inter-patient variability; INFCYP3A5, influence of CYP3A5 genotype; KA, absorption first order rate constant; KA_FOR, effect of FOR on KA; Q/F, apparent intercompartmental clearance; RSE, relative standard error; tlag, lag time in absorption; V/F and VT/F, apparent volume of distribution volume of the central and peripheral compartments, respectively.