Table 1.
A summary of published population pharmacokinetic studies of tacrolimus in adult renal transplant recipients.
| Study (publication year) | Country (Single/multiple sites) | Number of patients (Male/Female) | Sampling schedule (Number of samples) | Postoperative Time mean ± SD/median (range) | Bioassay | Structural model | PK parameters and formula | BSV% (IOV%) | Residual error | |
|---|---|---|---|---|---|---|---|---|---|---|
| Staatz et al. (2002) 16 | Australia (Multiple) | 70 (43/27) | C 0 (1060) | Therapy duration: 218 ± 249/128 (2–1475)days | LC–MS/MS | 1–CMT | CL/F V c/F K a | 23.6 + 76.7/AST + 31.9/POTΔ10704.48 (fixed) | 42 111/ | 3.7 ng ml−1 |
| Antignac et al. (2007) 17 | France (Single) | 83 (54/29) | C 0 (1589) | < 2 months after the initiation of TAC;38 ± 27/ 33 (1–158) days | MEIA | 1‐CMT | CLV c K a F | 1.81 × [1 + POT2.54/(POT2.54 + 3.812.54)]× (1.575, if concomitant prednisone >25 mg)98.44.5 (fixed)0.137 | 3179/32 | 18.6%0.96 ng ml−1 |
| Zhang et al. (2008) 18 | China (Single) | 41 (30/11) | C 0 (456) + C 2 (86) | 12.69 ± 20.89 months | MEIA | 1‐CMT | CL/F V c/F K a | 21.7× (0.582, if concomitant nicardipine)× (35.67/HCT)0.397 × (21.54/AST)0.244× 0.99 POT (in months )× (0.842, if concomitant diltiazem)2413.09 (fixed) | 41.649.7/ | 22.2%2.19 ng ml−1 |
| Press et al. (2009) 19 | Netherland (Single) | QD 16 (12/4) BID 15 (12/3) | IS (NA) + C 0/C 2/C 3 (NA) | IS: Week 2, 6, 12, 26 and 52; C 0/C 2/C 3: Week 4, 8, 10, 17, 21 and 39 | MEIA | 2‐CMT | CLV cQV p K a F | (3.7, if CYP3A5*3/*3) or (5.5, if CYP3A5*1/*3)(61, if QD) or (42, if BID)10(61, if QD) or (42, if BID)1.6 (fixed)0.23 × {1‐[DD/(25 + DD)]}× (0.85, if concomitant prednisolone >10 mg) | 19.528.3////(21.7) | 22.60% |
| Grover et al. (2011) 20 | USA (Single) | 24 (15/9) | IS (192): one PK profile per patient | 30 ± 23 months | CMIA | 2‐CMT | CL/F V c/FQ/F V p/F K a t lag | 10.1 ( 1 l h−1 increase with a 0.138 mg increase in DD)73.327.14621.380.573 | 43.536.950.4/46.013.3 | / |
| Woillard et al. (2011) * 21 | France (Multiple) | 32 (19/13) | IS (NA) + C12 (NA): totally 145 PK profiles | IS: Week 1 and 2, Month 1, 3, and 6;C 12: Week 1 and 2 | TFC–MS/MS | 2‐CMT | CL/F V c/FQ/F V p/F K tr | 21.2 × (HCT/35)‐1.14 × (2, if CYP3A5*1)140.94792715.11 | 28 (31)31 (75)546024 (33) | 11.3%0.71 ng ml−1 |
| Passey et al. (2011) 22 | USA and Canada (Multiple) | 681 (429/252) | C 0 (11823) | 3–180 days | 97.1% LC–MS | Steady‐state infusion model | CL/F | 38.4 × [(Age/50) ‐0.4] × (0.94, if concomitant CCB)× [(0.86, if POT 6‐10) or (0.71, if POT 11‐180)]× [(1.69, if CYP3A5*1/*3) or (2, if CYP3A5*1/*1)]× (0.70, if at a steroid sparing centre) | 40.1 | 3.19 ng ml−1 |
| Musuamba et al. (2012) 23 | Belgium (Single) | 65 (36/29) | IS (455): one PK profile per patient | Day 15 | MEIA | 2‐CMT | CL/F V c/FQ/F V p/F K a t lag | 16.3 + HCT/21 × 20.6 + (15.4, if CYP3A5*1)+ (7.6, if ABCB1 1236CC, 2677GG and 3435CC)86.458.211150.450.1 | 3255/4891 61 | 13%0.88 ng ml−1 |
| Gaïes et al. (2013) 24 | Tunisia (Single) | 20 (19/1) | IS (200): one PK profile per patient | NA | CMIA | 2‐CMT | CL/F V c/F Q/F V p/F K tr | 22.684.2 × (TBW/72)1.7750.4300 (fixed)3.77 | 41.837.69¶100/11.66 | 16%0.71 ng ml−1 |
| Ogasawara et al. (2013) 25 | USA (Single) | 102 (74/28) | IS (341) + C 0/C 2 (142) | 24 (2–123) months | LC‐ MS/MS | 2‐CMT | CL/F V c/F Q/F V p/F K a t lag | 20.7× (AGE/50)‐0.78 × (2.03, if CYP3A5*1)× (1.40, if MRP2 high‐activity group) §23470.713190.5440.183 × (2.6, if with diabetes mellitus) | 43.9157//// | 18% |
| Zuo et al. (2013) 26 | China (Single) | 161 (114/47) | C 0 (873) | 9 (0–95) days | EMIT | 1‐CMT | CL/F V c/F K a | 26.6 × (HCT/27.9)‐0.451× [(1.21, if CYP3A5*1 & CYP3A4*1)or (0.982, if CYP3A5*1 & CYP3A4*1G/*1G)or (0.77, if CYP3A5*3/*3 & CYP3A4*1)or (0.577, if CYP3A5*3/*3 & CYP3A4*1G/*1G)]10203.09 (fixed) | 24.258.5/ | 19.8%1.47 ng ml−1 |
| Han et al. (2013) 27 | Korea (Single) | 80 (51/29) | C 0 (2788) | 0–400 days | MEIA | 1‐CMT | CL/F V c/F K a | 22.9× POT‐0.00762× exp[(0.2225, if CYP3A5*1/*1)or (0.17, if CYP3A5*1/*3)or (0.0525, if CYP3A5*3/*3)]× exp[(0.297, if HCT ≤ 33) or (0.117, if HCT > 33)]716 × exp (0.355 × TBW/59.025)4.5 (fixed) | 49.848.7/ | 40% (fixed) |
| Han et al. (2014) 28 | Korea (Single) | 122 † (67/55) | IS (417)† + C 0 (1501)† | 2–20 days | LC– MS/MS | 1‐CMT | CL/F V c/F K a t lag | 21.9 × (1 + 0.0119 × (POT‐9.6))× (0.816, if CYP3A5*3/*3)2053.430.25 (fixed) | 42.664.6158.9/ | 1.94 ng ml−1 |
| Golubovic et al. (2014) 29 | Serbia (Single) | 105 (62/43) | C 0 (1999) | 60 ± 47.63 (0–206) days | CMIA | 1‐CMT | CL/F V c/F K a | 10.017 × (POT/47)‐0.0283 × (TBW/68)0.869 × (TP/63)0.161× [1–0.861 × (AST‐15)/1000]× [1–0.831 × (HCT/100–0.31)]0.68 l kg−1 (fixed)1.3 | 15.2// | 4.066 ng ml−1 |
| Størset et al. (2014) 30 | Norway and Australia (Multiple) | 242 (165/77) | IS (2068) + C 0 (1032) | 20 days (4 days ‐ 15 years); Predominantly ≤ 3 months | LC–MS/MS | 2‐CMT‡ | CLV cQV p F K a t la g | 16.1 × (FFM/60)3/4 × (1.3, if CYP3A5*1)125 × FFM/6023.8 × (FFM/60)3/4636 × FFM/601 × (2.68, if POT =1) × (0.82, if CYP3A5*1)× {1 – [0.67 × concomitant prednisolone dose (mg)]/ [35 + concomitant prednisolone dose (mg)]}1.010.41 | 40 **54 **63 **// (23)¶/ (120)/ | 14.90% |
| Andreu et al. (2015) 31 | Belgium and Spain (Multiple) | 16 (10/6) | IS (594) | Day 7, Month 1, 3, 6 and 12 | EMIT | 2‐CMT | CL/F V c/F Q/F V p/F K aMTTn K tr | 16.59.8935.56526.030.470.8333.61 | 39 (29)///3532// | 21% |
AST, aspartate transferase (U l−1); BID, twice daily; BSV, between‐subject variability; C n, concentration at n hours post‐dose; CCB, anti‐hypertensive drugs classified as calcium channel blocker; CL, clearance (l h−1); CL/F, apparent clearance (l h−1); CMIA, chemiluminescent microparticle immunoassay; CMT, compartment; CYP3A5*1, cytochrome P450 3A5 expresser (*1/*1 or *1/*3); DD, tacrolimus daily dose (mg); EMIT, enzyme multiplied immunoassay technique; exp, exponential; HCT, haematocrit (%); F, bioavailability; FFM, fat free mass (kg); IS, intensive sampling; IOV, inter‐occasion variability; K a, absorption rate constant (1 h−1); K tr, transfer rate constant (1 h−1); LC, liquid chromatography; MEIA, microparticle enzyme immunoassay; MRP2, multidrug resistance‐associated protein 2; MS, mass spectrum; MTT, mean transit time (h); n, number of transit compartments; NA, not available; POT, postoperative time (day); POTΔ, days of tacrolimus therapy; Q, inter‐compartmental clearance (l h−1); Q/F, apparent inter‐compartmental clearance (l h−1); QD, once daily; TBW, total body weight (kg); TFC, turbulent flow chromatography; t lag, lag time (h); TP, total protein (g l−1); V c, volume of distribution of central compartment (l); Vc/F, apparent volume of distribution of central compartment (l); V p, volume of distribution of peripheral compartment (l); V p/F, apparent volume of distribution of peripheral compartment (l).
Only information on immediate‐release formulation of tacrolimus is included.
The number included the data from both model development (102 patients, 1626 samples) and model evaluation (20 patients, 292 samples).
The covariate screening strategy of this study was theory‐based.
MRP2 high‐activity group (H2/H2 and H1/H2) indicates ABCC2 haplotypes H1 ‐24C, 1249G, and 3972C and H2 ‐24C, 1249 A, and 3972C.
TBW in the model by Gaies et al. 24 and POT in model by Størset et al. 30 had BSV of 41.8% and 57%, respectively.
Correlations are CL ~ V c 0.43; CL ~ Q 0.62.