Table 1.
Summary of published population pharmacokinetic studies of mycophenolate mofetil in adult kidney transplant recipients co‐administered with tacrolimus
| 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 formulas | BSV% (BOV%) | Residual error | |
|---|---|---|---|---|---|---|---|---|---|---|
| Cremers et al. (2005) 34 | Netherlands (Single) | 31 (23/8) | IS+SSa (2748 tMPA, 2648 tMPAG) | (2–52 weeks) | HPLC | 2CMT (tMPA), 1CMT (tMPAG), Continuous EHC | CL/F (tMPA) | 11.9 | 30 (/) | 35%, tMPA 14%, tMPAG |
| VC/F (tMPA) | 10.3 | 74 (/) | ||||||||
| VP/F (tMPA) | 183 | 330 (/) | ||||||||
| Q/F (tMPA) | 11.2 | 51 (/) | ||||||||
| T1/2a | 0.567 | 57 (/) | ||||||||
| VC/F (tMPAG) | 8.91 | 20 (/) | ||||||||
| Ke (tMPAG) | 0.122 | 28 (/) | ||||||||
| KT (tMPAG) | 0.0410 | 78 (/) | ||||||||
| Staatz et al. (2005) 35 | Canada(Single) | > 55 | SSb (1376 tMPA) | 7 days (3–7) | HPLC | 2CMT (tMPA) | CL/F (tMPA) | 25.4 × [1–0.042 × (ALB‐26)] | 32 (35) | 41%, tMPA |
| VC/F (tMPA) | 65 | / | ||||||||
| VP/F (tMPA) | 496 | / | ||||||||
| Q/F (tMPA) | 30.7 | 78 (/) | ||||||||
| Ka | 0.64 | 109 (/) | ||||||||
| de Winter et al. (2009) 36 | Belgium & Netherlands (multiple) | 28 (18/10) | IS+SSc 45 profiles (489 tMPA, 489 fMPA, 488 tMPAG, 210 fMPAG) | 11 days (4–115) | HPLC, LC/MS/MS | 2CMT (fMPA), 1CMT (fMPAG), Intermittent EHC | CL/F (fMPA) | 747 | 97 (/) | 0.52, tMPA 0.993, fMPA 0.186, tMPAG 0.551, fMPAG log‐transformed additive model |
| VC/F (fMPA) | 189 | 116 (/) | ||||||||
| VP/F (fMPA) | 34 300 | / | ||||||||
| Q/F (fMPA) | 2010 | / | ||||||||
| Ka | 4 | / | ||||||||
| Tlag | 0.231 | 161 (/) | ||||||||
| CL/F (fMPAG) | 4.75 × (CLcr/45)1.36 | 106 (/) | ||||||||
| VC/F (fMPAG) | 8.56 | / | ||||||||
| BMAX | 35 100 × (ALB/33)1.39 | 48 (/) | ||||||||
| KB (fMPA) | 0.153 | / | ||||||||
| KUB (bMPA) | 169 | / | ||||||||
| KB (fMPAG) | 0.0133 | / | ||||||||
| KUB (bMPAG) | 93.1 | / | ||||||||
| KCG (fMPAG) | 0.0796 | 71 (/) | ||||||||
| KGB | 10.0 | / | ||||||||
| TGB | 7.90 | 141 (/) | ||||||||
| DGB | 1.00 | / | ||||||||
| de Winter et al. (2010) 37 | Austria, Belgium, Germany & Netherlands (multiple) | 17 | ISd (not available) | 6 days (3–8) | HPLC, LC/MS/MS | 2CMT (tMPA) | CL/F (tMPA) | 15.3 × (ALB/40)‐0.69 | 51 (/) | 0.61, tMPA log‐transformed additive model |
| VC/F (tMPA) | 79.4 | 103 (/) | ||||||||
| VP/F (tMPA) | 291 | / | ||||||||
| Q/F (tMPA) | 26.5 | / | ||||||||
| Ka | 4 | / | ||||||||
| Tlag | 0.293 | / | ||||||||
| Lamba et al. (2010) 38 | USA(multiple) | 9 (3/6) | SS Details of sampling were not available (406 tMPA) | (1 day −3.5 years) | LC/MS/MS | 2CMT (tMPA) | CL/F (tMPA) | 13.6 (if POT ≥ 30 days) or 17.0 (if POT < 30 days) | 26.7 (/) |
49.5%, tMPA 0.51 mg l−1, tMPA |
| VC/F (tMPA) | 61.8 | / | ||||||||
| VP/F (tMPA) | 518 | / | ||||||||
| Q/F (tMPA) | 22 | / | ||||||||
| Ka | 4.1 | / | ||||||||
| de Winter et al. (2011) 39 | Belgium & Netherlands (multiple) | 101 (73/28) | IS+SSc (7739 tMPA) | 23 days (3–168) | HPLC, LC/MS/MS | 2CMT (tMPA) | CL/F (tMPA) | 17 × (1 + 0.5 × e‐0.04×POT) | 31 (3.8) | 0.45, tMPA log‐transformed additive model |
| VC/F (tMPA) | 68 × (1 + 3.2 × e‐0.045×POT) | 71 (50) | ||||||||
| VP/F (tMPA) | 229 | / | ||||||||
| Q/F (tMPA) | 38 | / | ||||||||
| Ka | 3.9 | 125 (117) | ||||||||
| Tlag | 0.21 | 7.4 (/) | ||||||||
| F | 1 × (MMFdose/1000)−0.41 | 41 (24) | ||||||||
| de Winter et al. (2012) 40 | France (multiple) | 31 | IS+SSe 147 profiles (4718 tMPA) | (1 week–6 months) | LC/MS/MS | 2CMT (tMPA) | CL/F (tMPA) | 13 | 62 (36) | 37%, tMPA |
| VC/F (tMPA) | 34.9 (if POT ≥ 14 days) or 27.571 (if POT < 14 days) | 105 (/) | ||||||||
| VP/F (tMPA) | 4910 | / | ||||||||
| Q/F (tMPA) | 24.7 | / | ||||||||
| Ka | 1.9 | 36 (110) | ||||||||
| Tlag | 0.24 | / | ||||||||
| F | 1 | 79 (/) | ||||||||
| Colom et al. (2014) 41 | Belgium & Spain (multiple) | 10 | ISf (2038 tMPA, 2054 tMPAG, 1043 tAcMPAG) | 7 days–1 year | HPLC | 2CMT (tMPA), 2CMT (tMPAG), 1CMT (tAcMPAG), Continuous EHC | CL/F (tMPA) | 19.4 | 20.6 (/) |
0.39, tMPA 0.202, tMPAG 0.472, tAcMPAG log‐transformed additive model |
| VC/F (tMPA) | 24.8 | 113.6 (/) | ||||||||
| VP/F (tMPA) | 607 | / | ||||||||
| Q/F (tMPA) | 17.5 | / | ||||||||
| Ka | 1.22 | / | ||||||||
| Tlag | 0.206 | / | ||||||||
| fm | 0.85 | / | ||||||||
| CL/F (tMPAG) | 1.12 × (CLcr/59.51)0.977 | 46.0 (/) | ||||||||
| VC/F (tMPAG) | 2.60 | / | ||||||||
| VP/F (tMPAG) | 3.75 | / | ||||||||
| Q/F (tMPAG) | 21.2 | / | ||||||||
| KT (tMPAG) | 0.341751 | 85.6 (/) | ||||||||
| CL/F (tAcMPAG) | 38.5 × (CLcr/59.51)0.534 | 62.3 (/) | ||||||||
| VC/F (tAcMPAG) | 13.5 | / | ||||||||
| Velickovic‐Radovanovic et al. (2015) 42 | Serbia (single) | 61 | SS Details of sampling were not available (90 tMPA) | 51.14 months (1–204) | HPLC | 2CMT (tMPA) | CL/F (tMPA) | 0.741 + 0.00165 × 0.72 × MMFddose + 0.0804 × AGE | 24.7 (/) | 35.07%, tMPA |
| VC/F (tMPA) | 0.653 | 24.3 (/) | ||||||||
| VSS/F (tMPA) | 801 | 1241.1 (/) | ||||||||
| Q/F (tMPA) | 52.1 | 216.1 (/) | ||||||||
| Ka | 4.07 | 144.2 (/) | ||||||||
| Tlag | 0.21 | 34.64 (/) | ||||||||
| Yu et al. (2017) 43 | China (single) | 7 | IS+SSg (783 tMPA) | Not availableh | HPLC | 2CMT (tMPA) | CL/F (tMPA) | 0.0916 × BW + 0.0417 × SCr + 7.98 | 34.2 (13.7) |
15.8%, tMPA 0.15 mg l−1, tMPA |
| VC/F (tMPA) | 7.72 × UGT2B7 genotype+14.7 | 21.3 (13.7) | ||||||||
| KCP (tMPA) | 0.915 | 31.2 (/) | ||||||||
| KPC (tMPA) | 0.059 | 138 (/) | ||||||||
| Ka | 1.89 | 51.3 (/) | ||||||||
| Colom et al. (2018) 44 | Belgium & Spain (multiple) | 10 | ISf (2038 tMPA, 2046 fMPA) | 7 days–1 year | HPLC | 2CMT (fMPA), Intermittent EHC | CL/F (fMPA) | 410 | 26.81 (40.9) | 46.9%, tMPA 58.3%, fMPA |
| VC/F (fMPA) | 18.3 | 99.45 (137.6) | ||||||||
| VP/F (fMPA) | 29 100 | / | ||||||||
| Q/F (fMPA) | 749 | / | ||||||||
| Ka | 1.41 | / | ||||||||
| Tlag | 0.293 | / | ||||||||
| KB (fMPA) | 43.1 × (CLcr/59.51)0.394 | 24.10 (/) | ||||||||
| KCG (fMPA) | 0.224 | / | ||||||||
| KGB | 10 | / | ||||||||
| TGB | 2.0 | / | ||||||||
| DGB | 1.5 | / | ||||||||
ALB, albumin (g l−1); BMAX, maximum number of protein binding sites; bMPA, bound mycophenolic acid; bMPAG, bound 7‐O‐glucuronide mycophenolic acid; BOV, between‐occasion variability; BSV, between‐subject variability; BW, body weight (kg); CL/F, apparent clearance (l h−1); CLcr, creatinine clearance calculated by the Cockcroft‐Gault formula (ml min−1); CMT, compartment; co‐ad, co‐administration of mycophenolate mofetil and; DGB, duration of gallbladder emptying (h); EHC, enterohepatic circulation; F, bioavailability; fm, fraction of mycophenolic acid converted to 7‐O‐glucuronide mycophenolic acid; fMPA, free mycophenolic acid; fMPAG, free 7‐O‐glucuronide mycophenolic acid; HPLC, high performance liquid chromatography; IS, intensive sampling; Ka, absorption rate constant (h−1); KB, protein binding rate constant (h−1); KCG, transfer rate constant from the central compartment to gallbladder (h−1); KCP, transfer rate constant from the central compartment to peripheral compartment (h−1); Ke, elimination rate constant (h−1); KGB, gallbladder emptying rate constant (h−1); KPC, transfer rate constant from the peripheral compartment to central compartment (h−1); KT, transfer rate constant describing biliary excretion (h−1); KUB, protein unbinding rate constant (h−1); LC/MS/MS, liquid chromatography tandem‐mass spectrometry; MMF, mycophenolate mofetil; MMFdose, dose of mycophenolate mofetil (mg times−1); MMFddose, daily dose of mycophenolate mofetil (mg day−1); POT, postoperative time; Q/F, apparent inter‐compartmental clearance (l h−1); SCr, serum creatinine (μmol l−l); SD, standard deviation; SS, sparse sampling; T1/2a, absorption half‐life (h); TAC, tacrolimus; Tlag, absorption lag time (h); tAcMPAG, total acyl‐glucuronide mycophenolic acid; TGB, time of gallbladder emptying (h); tMPA, total mycophenolic acid; tMPAG, total 7‐O‐glucuronide mycophenolic acid; VC/F, apparent volume of distribution of central compartment (l); VP/F, apparent volume of distribution of peripheral compartment (l); VSS/F, apparent volume of distribution in steady‐state (l)
At weeks 2, 6, 12, 26, 39 and 52, intensive samples were taken around the morning dose at 0, 1, 2, 3, 4 and 6 h after drug administration. At weeks 4, 8, 10, 17 and 21, sparse samples were taken at 0, 2 and 3 h after drug administration
Sparse samples were collected at 0, 1, 2, 3 and 4 h post‐dose on days 3, 5 and 7 post‐operation
For patients co‐administered with tacrolimus, intensive samples were collected at 0, 0.5, 1, 2, 6 and 12 h post‐dose on day 6, and sparse samples were collected at 0, 0.5, 2 h post‐dose on days 21, 49 and 140 post‐operation
Intensive samples were collected at 0, 0.5, 1, 2, 6 and 12 h post‐dose for patients co‐administered with tacrolimus
Intensive samples were collected at 0, 0.33, 0.66, 1, 1.5, 2, 3, 4, 6 and 9 h post‐dose, and an extra sample was taken from hospitalized patients at 12 h post‐dose
Intensive samples were collected at 0, 20, 40, and 75 min and at 2, 3, 4, 6, 8, 10 and 12 h post‐dose on day 7 and months 1, 3, 6 and 12 post‐operation
Intensive samples were collected at 0, 0.5, 1, 1.5, 2, 4, 6, 8, 10 and 12 h after the morning dose. Sparse samples were collected at limited sampling times (0, 0.5, 2 h, or 0, 0.5, 2 and 8 h)
Postoperative time was not available in the article, and the duration of MMF therapy ranged between 2 and 209 days