Table X. Tacrolimus pharmacokinetic parameters in cohort studies.
Results are expressed as mean±SD (range), unless otherwise specified
| Ref | Number of patients | Post-transplant period | Tacrolimus dose | Co-administered immunosuppressant | Assay | F, transfer k | Vd/F (unless otherwise specified) | CL/F (unless otherwise specified) | T1/2 (h) |
|---|---|---|---|---|---|---|---|---|---|
| HEART TRANSPLANTATION | |||||||||
|
| |||||||||
| [102] | 14 adults 55.5 years (23–61) |
< 6 months | First D = 0.03–0.40 mg/kg (median: 0.052 mg/kg) | ATG AZA Prednisone |
MEIA – IMx | PK parameters after the first dose of tacrolimus | |||
|
ka, kel: h−1 Lag-time: h |
Vd/F: L/kg | CL/F: L.h−1/kg | |||||||
| Non-compartmental PK analysis using Pharm-NCA computer program | |||||||||
| -- | 2.4±0.79 | 0.21±0.08 | 8.7±3.5 kel = .091±0.040 |
||||||
| One-compartment open model with first-order elimination using P-Pharm computer program | |||||||||
| ka = 1.26±0.61 | 2.0±0.4 (1.3–3.9) | 0.23±0.08 (0.098–0.328) | 6.5±2.4 | ||||||
| Lag-time = 0.22±0.13 | CV = 33% | CV = 36.3% | kel = 0.116±0.034 | ||||||
|
| |||||||||
| [100] | 11 adults OHT |
First D up to 0.15 mg/kg BID D adjusted on C0 < 15 μg/L |
N/R | Non-compartmental PK analysis using TOPFIT v2.0 software | |||||
| Profile 1 (day 1) | D = 0.053±0.031 mg/kg (0.026–0.143) | ELISA | -- | -- | -- | 7.1±4.3 (2.4–15.9) | |||
| NG tube | CV = 59% | CV = 60% – n = 7 | |||||||
| HPLC-MS/MS | 4.0±1.0 (2.8–5.3) CV = 24% – n = 5 |
||||||||
| Profile 2 (last day) | D = 0.076±0.069 mg/kg (0.013–0.250) | ELISA | -- | -- | -- | 14.1±6.3 (7.1–19.5) | |||
| Hard capsules | CV = 91% | CV = 32% – n = 10 | |||||||
| HPLC-MS/MS | -- | -- | -- | 10.7±5.3 (1.8–18.5) CV = 50% – n = 10 |
|||||
|
| |||||||||
| [103] | Immediate post-transplantation period | N/R | HPLC-MS/MS | Non-compartmental PK analysis using PC Modfit v/6 software CL: L/h |
|||||
| 10 adults 57±9 years |
IV, continuous infusion D = 0.01 to 0.02 mg/kg/day |
Induction: N/R | -- | -- | CL = 2.4 | -- | |||
| 25 adults 47±10 years |
Oral | Induction: ATG/OKT3 | After the first dose: | ||||||
| n: N/R | D = 0.075 mg/kg/day | -- | -- | -- | 10.9±7.0 | ||||
| D = 0.15 mg/kg/day | -- | -- | -- | 9.8±5.2 | |||||
|
| |||||||||
| [115] | 19 adults 46 years (28–48) OHT |
D = 0.06 mg/kg/day (0.04–0.08) D adjusted on C0 = 5-20μg/L |
ATG AZA Prednisone |
MEIA –IMx | 2-compartment open model – PK analysis using P-Pharm popPK software | ||||
|
ka: h−1 Lag-time: h |
V1/F: L/kg | CL/F: L.h−1/kg | |||||||
| PK1 (day 10) | ka = 1.1±0.5 (0.3–1.6) | V1/F = 1.7±0.6 (0.7–3.5) | 0.19±0.08 (0.09–0.38) | -- | |||||
| CV = 42% | CV = 36% | CV = 42% | |||||||
| Lag-time = 0.22±0.09 (0.1–0.45) CV = 41% | |||||||||
| PK2 (month 2) | ka = 1.0±0.5 (0.1–1.8) | V1/F = 1.1±0.4 (0.3–1.8) – p < 0.01 | 0.23±0.15 (0.04–0.62) | -- | |||||
| CV = 48% | CV = 34% | CV = 65% | |||||||
| Lag-time = 0.44±0.05 (0.29–0.50) – p ≤ 0.05 CV = 11% | |||||||||
|
| |||||||||
| [111] | 8 adults 45–60 years |
4 to 16 months (mean: 10.6) | D = 0.02–0.1 mg/kg/day D adjusted on C0 = 5–12 μg/L |
MMF Prednisone |
MEIA II – IMx | Non-compartmental PK analysis using PK Calc software | |||
| -- | -- | -- | Mean = 13.8 (95% CI = 7.0–20.7) | ||||||
|
| |||||||||
| [109] | 22 adults 55±8 years (36–64) OHT |
First year | D = 0.3 mg/kg/day D adjusted on C0 = 10–20μg/L Steady-state |
MMF or AZA Steroids |
MEIA –IMx | Non-compartmental PK analysis using MOMENT software (n = 25 PK profiles) CL/F: L/h |
|||
| -- | -- | 11.6±5.5 (3.8–23.5) | -- | ||||||
|
| |||||||||
| [105] | 23 adults 38 years (18–56) |
D = 0.10 mg/kgd D adjusted on C0 = 10–20 μg/L |
N/R | MEIA –IMx | Non-compartmental PK analysis | ||||
| First dose | -- | -- | -- | 11.1±6.3 | |||||
| Day 3 | -- | -- | -- | 10.6±5.8 | |||||
| Day 7 | -- | -- | -- | 9.8±5.5 | |||||
|
| |||||||||
| LUNG TRANSPLANTATION | |||||||||
|
| |||||||||
| [114] | 16 adults (5 CF) 45.5±3.4 years |
98±19 wks | D = 3.6±2.5 mg BID (0.25–7.0) D adjusted on C0 = 5–15 μg/L |
N/R | HPLC-MS/MS | Non-compartmental PK analysis (n = 22 profiles) | |||
| -- | -- | -- | 7.9±2.3 (4.0–12.0) | ||||||
|
| |||||||||
| HEART-LUNG TRANSPLANTATION | |||||||||
|
| |||||||||
| [112] | 22 adults | MEIA –IMx | One-compartment model with first-order elimination convoluted with a double gamma absorption phase – PK analysis using Ciclo®2.3 software |
||||||
|
MAT, SDAT: h AIV: L−1 |
V1/F: L | CL/F: L/h; λ: h−1 | |||||||
| 11 CF 30 years (21–43) |
3–116 months | D = 0.23 mg/kg/day (0.09–0.47) | MAT1 = 1.10±0.68 | V1/F = 2,011±1,740 | 68.22±29.80 | λ = 0.64±0.33 | |||
| SDAT1 = 0.27±0.15 | |||||||||
| MAT2 = 5.14±2.11 | |||||||||
| SDAT2 = 1.96±0.68 | |||||||||
| AIV = 4.03±1.67 | |||||||||
| r = 0.58±0.22 | |||||||||
| 11 non-CF 51 years (31–56) p < 0.01 |
9–86 months | D = 0.1 mg/kg/day (0.06–0.19) | AZA (n = 6) | MAT1 = 0.92±0.43 (ns) | V1/F = 444±326 (p < 0.01) | 36.49±18.98 (p < 0.05) | λ = 0.80±0.31 (p < 0.01) | ||
| SDAT1 = 0.30±0.10 (ns) | |||||||||
| MAT2 = 5.47±2.30 (ns) | |||||||||
| SDAT2 = 1.89±0.71 (ns) | |||||||||
| AIV = 9.36±4.98 (p < 0.01) | |||||||||
| r = 0.62±0.12 (ns) | |||||||||
ATG: Antithymocyte globulin – AZA: Azathioprine – CF: Cystic fibrosis – D: Dose – NG: Nasogastric – N/R: not reported – OHT: orthotopic heart transplantation – r: fraction of the dose absorbed by the faster phase.