Table 2.
Pharmacokinetics parameter estimations
| Parameter | Without Effect Dose | Final Model (CV in %) | Bootstrap (95th Percentile) |
|---|---|---|---|
| TLAG (h) | 0.21 (2) | 0.21 (2) | 0.21 (0.15 to 0.26) |
| ka (hours−1) | 3.9 (10) | 3.9 (10) | 3.8 (2.5 to 5.0) |
| Vc (L) | 54 (11) | 68 (14) | 70 (52 to 98) |
| CL (L/h) | 13.6 (6) | 17.0 (9) | 16.8 (13.9 to 20.2) |
| Vp (L) | 222 (9) | 229 (9) | 244 (202 to 326) |
| Q (L/h) | 37 (7) | 38 (7) | 38 (32 to 53) |
| Residual error | 0.45 (2) | 0.45 (2) | 0.44 (0.42 to 0.47) |
| Calcineurin inhibitor effect | |||
| θCsA of CL | 1.37 (9) | 1.13 (11) | 1.16 (0.93 to 1.40) |
| θCsA of Vc | 0.91 (15) | 0.72 (18) | 0.73 (0.50 to 0.97) |
| Time dependency | |||
| CsA: θΔ of CL | 0.90 (11) | 0.87 (11) | 0.90 (0.74 to 1.14) |
| CsA: θrate of CL (day−1) | 0.018 (19) | 0.019 (19) | 0.020 (0.013 to 0.031) |
| TCL: θΔ of CL | 0.98 (16) | 0.50 (36) | 0.55 (0.26 to 1.00) |
| TCL: θrate of CL (day−1) | 0.046 (22) | 0.040 (35) | 0.038 (0.003 to 0.085) |
| CsA: θΔ of Vc | 1.11 (28) | 1.13 (27) | 1.25 (0.58 to 2.15) |
| θrate of Vc (day−1) | 0.050 (19) | 0.045 (22) | 0.047 (0.026 to 0.072) |
| TCL: θΔ of Vc | 4.5 (22) | 3.2 (27) | 3.2 (1.8 to 5.4) |
| Relationship of MMF dose Frel | |||
| CsA: θdose of F | −0.15 (30) | −0.15 (−0.24 to −0.06) | |
| TCL: θdose of F | −0.41 (25) | −0.41 (−0.62 to −0.19) | |
| Interpatient variability | |||
| TLAG (%) | 7.3 (189) | 7.4 (207) | 17 (4 to 155) |
| ka (%) | 124 (18) | 125 (18) | 140 (102 to 199) |
| Vc (%) | 71 (29) | 71 (29) | 70 (41 to 108) |
| CL (%) | 31 (24) | 31 (24) | 34 (23 to 49) |
| Frel (%) | 43 (17) | 41 (17) | 44 (34 to 59) |
| Interoccasion variability | |||
| ka (%) | 117 (10) | 117 (10) | 120 (106 to 134) |
| Vc (%) | 50 (20) | 50 (21) | 48 (19 to 70) |
| CL (%) | 3.3 (452) | 3.8 (297) | 5.3 (0.1 to 12) |
| Frel (%) | 25 (12) | 24 (12) | 24 (20 to 26) |
Values of estimated parameters with coefficient of variation (CV). IPV, interpatient variability; IOV, interoccasion variability; OFV, minimum value of objective function; TLAG, lag time; ka, absorption rate constant; Vc, volume of distribution of the central compartment; CL, clearance; Vp, volume of distribution of the peripheral compartment; Q, intercompartmental clearance; CsA, cyclosporine; TCL, tacrolimus; Frel, relative bioavailability; θCsA, fractional change in patients cotreated with CsA; θΔ, relative change in time posttransplantation; θrate, first-order rate constant describing the relative change of a parameter posttransplantation; θdose, exponent determining the shape of the relationship between a parameter and the MMF dose. For example, MPA clearance in cyclosporine-cotreated patients: CL = θpop × θCsACsA = 17.0 × 1.13 = 19.2 L/h; MPA clearance at 30 days posttransplantation in tacrolimus-cotreated patients: CL = θpop(1 + θΔ × e−θrate×time) = 17.0 × (1 + 0.50 × e−0.040×30) = 19.6 L/h; relative bioavailability of 1.5 g of MMF in patients cotreated with tacrolimus: Frel = θpop × (dose/1000)θdose = 1 × (1500/1000)−0.41 = 0.85.