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. Author manuscript; available in PMC: 2013 Jun 11.
Published in final edited form as: Clin Pharmacokinet. 2009;48(7):419–462. doi: 10.2165/11317230-000000000-00000

Table XI. Mycophenolate exposure indices in cohort studies.

Results are expressed as mean±SD unless otherwise specified

Ref Number of patients Post-transplant period MMF dose Co-administered immunosuppressant Analytical method, molecule Measured AUC (h.mg/L) C0 (mg/L) Cmax (mg/L) tmax (h) Others
HEART TRANSPLANTATION
[122] 9 patients
55±11 years (33–71)		 First 10 days
Day 3		 Cyclosporine (same dose throughout the period)
Prednisolone		 HPLC-UV Non-compartmental PK analysis; AUC Trap; data are presented as median (range)
IV, D = 1.5 g BID
Infusion over 3 hours (day 0 – day 5)		 AUC0-6
MMF 7.5 (4.2–37.2) -- 4.7 (2.2–18.4) 2.0 (1.0–3.0) --
AUC0-12
MPA 34.2 (22.3–52.1) 0.65 (0.24–1.35) 10.2 (7.6–16.7) 2.0 (1.0–3.0)
MPAG 1,030 (537–2,049) 69 (34–153) 110 (65–187) 3.0 (2.5–3.5)
AcMPAG 8.5 (5.6–11.9) 0.36 (0.09–0.69) 1.31 (0.99–1.68) 1.3 (1.0–1.7)
Day 5 AUC0-6
MMF 6.5 (5.0–26.3) -- 3.7 (2.3–10.3) 2.0 (1.0–2.0) --
AUC0-12
MPA 33.8 (23.7–43.1) 0.96 (0.26–1.11) 9.8 (6.1–11.2) 2.0 (2.0–3.0)
MPAG 881 (456–1,584) 63 (34–135) 109 (51–166) 3.2 (3.0–4.0)
AcMPAG 5.4 (1.8–9.3) 0.25 (<0.05–0.59) 0.86 (0.38–1.22) 3.0 (3.0–4.0)
Day 6 Oral, D = 1.5 g BID (day 5 – day 10) AUC0-12
MPA 29.7 (22.3–37.6) 0.56 (0.24–1.12) 6.0 (4.4–10.5) 2.0 (0.33–6.0) --
MPAG 959 (471–1,216) 56 (26–82) 96 (51–111) 4.0 (0.67–8.0)
AcMPAG 5.1 (3.2–5.9) 0.14 (<0.05–0.4) 0.77 (0.48–1.30) 2.0 (0.67–6.0)
Day 10 AUC0-12
MPA 33.8 (26.6–40.3) 0.95 (0.48–1.39) 9.0 (3.6–10.8) 1.25 (0.67–1.25) --
MPAG 1,032 (573–1,498) 79 (28–122) 108 (59–179) 2.5 (1.25–4.0)
AcMPAG 6.4 (4.5–10.7) 0.32 (0.19–0.85) 0.90 (0.44–1.36) 2.0 (1.25–4.0)
[121] 9 patients
Mean: 59 years		 Weeks 1, 2, 4, 8, 12 D = 1 g or 1.5 g BID Cyclosporine
Prednisone		 HPLC-UV Non-compartmental PK analysis (n = 44 full MPA profiles); AUC0-12 Trap
45.9±15.4 (13.4–91.7) -- 10.4±6.6 1.25 --
r2 C2-AUC0-12 = 0.610; r2 C12-AUC0-12 = 0.003
Recommended sparse sampling algorithms:

  • AUC0-12 = 5.568 + 0.902*C1.25 + 2.022*C2 + 4.594*C6; r2 = 0.926

  • AUC0-12 = 3.800 + 1.015*C1.25 + 1.819*C2 + 1.566*C4 + 3.479*C6; r2 = 0.948

[137] 14 patients
57±13 years		 54±42 months D = 35±7 mg/kg/day Cyclosporine N/R Method for PK analysis: N/R
MPA AUC0-12 = 63±11 -- -- 1–2 Cav = 5.2±1.0
r2 AUC0-12

  • C0 = 0.48

  • C1, C2 = 0.08–0.09

  • C3, C4, C6, C8, C12 = 0.23 to 0.60

[132] 38 patients
OHT
53±10 years		 310±278 days Steady-state

D = 1.1±0.4 g BID (13.6±4.9 mg/kg BID)		 No induction
Cyclosporine
Prednisone		 HPLC-UV MPA AUC0-12 calculated from a 2-hour abbreviated AUC developed in renal transplant patients[216]
AUC0-12
MPA 44.5±16.1 1.2±0.6 -- -- f = 1.9±0.4%
Free MPA 0.83±0.30
r2 MPA C0-AUC0-12 = 0.40 (p = 0.01)
r2 MPA C0-MPA free fraction : ns
[134] 62 patients
Mean: 59 years		 Stable, > 1 year Steady-state EMIT Non-compartmental PK analysis; AUC0-12 estimated from C0, C30, C120 using a sparse sampling algorithm developed in renal transplant patients[120]
AUC/D: (h.mg/L)/g MMF C0/D: (mg/L)/g MMF Cmax/D: (mg/L)/g MMF
n = 47
57±9 years		 3.6±4.0 years D = 2.9±0.8 g/day
D ≥ 3 g/d, n = 32		 Cyclopsorine
Corticosteroids (45% patients)		 AUC0-12 C0/D = 1.41±0.95 Cmax/D = 18.9 Med.: 40 min --
MPA 41.9±14.1 (19.7–81.8) Mean: 75 min
< 40 in 50% pts with dose ≥ 3 g/day
AUC0-12/D = 31.9±16.1 (13.4–82.3)
r2 AUC0-12

  • C0 = 0.36, p < 0.01

  • C40, C75, C120 = 0.62–0.64, p < 0.01
n = 15
64±10 years		 8.5±3.6 years (p < 0.01) D = 1.9±0.7 g/day
p < 0.001
D = 1–3 g/day, n = 15		 Sirolimus
Corticosteroids (13% patients; p < 0.01)		 AUC0-12 C0/D = 5.10±3.41 Cmax/D = 21.8 (ns) Med.: 40 min --
MPA 51.1±15.8 (34.4–87.6); p < 0.03 p < 0.001 Mean: 75 min
< 40 in 27% pts with dose = 1–3 g/day
AUC0-12/D = 61.0±27.4 (23.7–131.5); p < 0.001
r2 AUC0-12

  • C0, C75, C120 = 0.56–0.61, p < 0.01

  • C40 = 0.82, p < 0.01
56 years 3.4 years Mean D
Before the switch: 2.9±1.0 g/day		 Switch group (cyclosporine to sirolimus), n = 9
AUC0-12 C0/D = 4.85±4.39 (0.44–5.20) -- -- --
MPA 49.9±12.4 (34.3–56.9)
AUC0-12/D = 37.5±19.9 (20.6–73.6)
After the switch: 2.0±0.7 g/day (p < 0.01) 37.5±20.0 (34.6–70.1) (p < 0.001) C0/D = 2.00±1.68 (0.33–14.6) -- -- --
p < 0.001
AUC0-12/D = 58.3±32.5 (27.7–131.5); p < 0.001
[136] 26 patients
15±10 years (1 month –33 years)		 50% < 1 year
50% > 1 year		 Steady-state

D = 37.9±12.5 mg/kg = 1.207±0.302 g/m2 		Cyclosporine or tacrolimus
Corticosteroids		 HPLC Non-compartmental PK analysis; 120 samples
MPA -- 2.2±2.0
C0 ≥ 1 mg/L in50% of patients		 -- -- --
MPAG -- 48±4 -- -- --
16 children 1.1±0.3 g/m2/day Cyclosporine, n = 8
40 samples		 MPA -- 1.6±1.5 -- -- --
MPAG -- 49±38 -- -- --
MPAG/MPA -- 25.2±21.7 -- -- --
D: N/R Tacrolimus, n = 8
42 samples		 MPA -- 3.0±2.2 (vs children on CsA, p = 0.04) -- -- --
MPAG -- 36±17 (vs children on CsA, p = 0.04) -- -- --
10 adults 1.3±0.4 g/m2/day (vs. children on cyclosporine, ns) Cyclosporine, n = 10
37 samples		 MPA -- 2.3 ±2.2 (vs children on CsA, ns) -- -- --
MPAG -- 98±47 (vs children on CsA, p < 0.0001) -- -- --
MPAG/MPA -- 37.7±40.2 (vs children on CsA, p = 0.016) -- -- --
[143] 7 patients
21–63 years		 6–23 days Steady-state

D = 1 or 1.5 g BID		 Cyclosporine
Corticosteroids		 HPLC-UV Non-compartmental PK analysis
-- -- -- -- fMPA = 3.6±3.9%
fMPA – total MPA
r2 = 0.20
fMPAG = 26±8%
fMPAG – total MPAG
r2 = 0.87
fMPA – fMPAG :
r2 = 0.83
[135] 23 adults

n = 14
57±13 years		 Stable, > 1 year Steady-state

34.6±6.0 mg/kg/day

Group 1
Cyclosporine		 EMIT Non-compartmental analysis – AUC0-12 Trap
62.8±11.5 2.9±1.3 -- 1-2 --
r2 AUC0-12

  • C30, C1, C2 = 0.06–0.09

  • C0, C3, C4, C8, C12 = 0.23–0.69

  • C6 = 0.60

n = 9
54±12 years		 24.3±11.6 mg/kg/day Group 2
Tacrolimus		 55±24 2.4±1.2 -- 30 min–1 h --
r2 AUC0-12

  • C30 = 0.04

  • C0, C1, C2, C3, C12 = 0.38–0.72

  • C4, C6, C8 = 0.85–0.93

[167] 28 patients
54 years (19–67)		 Stable, > 1 year
2.5±3 years		 1.5 g/day (0.5–4.0)
D adjusted on C0 = 1.5–4 mg/L		 Tacrolimus HPLC-UV Non-compartmental PK analysis –AUC0-12 Trap
42.0±18.3 (12.2–79.8) 2.0±1.2 -- -- C12h = 2.0±1.7
r2 AUC0-12

  • C0, C3 = 0.14–0.17

  • C2, C10, C12 = 0.25–0.39

  • C0.5, C1, C6, C8 = 0.48–0.57

Recommended sparse sampling algorithms:

  • AUC0-12 = 1.11*C0.5 + 1.16*C1 + 3.72*C2; r2 = 0.84

  • AUC0-12 = 3.37*C0 + 0.97*C0.5 + 1.20*C1 + 2.70*C2; r2 = 0.87

HEART TRANSPLANT RECIPIENTS + LUNG TRANSPLANT RECPIENTS
[124] 9 patients(5 HTx, 4 LTx) Steady-state
2–3 g/day		 ATG in HTx patients
Cyclosporine (n = 7) or tacrolimus (n = 2)
Prednisone		 HPLC-UV

Total and unbound
MPA		 Non-compartmental PK analysis using WinNonlin in the 7 patients on cyclosporine (4 HTx, 3 LTx)
AUC0-τ, τ = N/R
53±11 years Period 1
15±13 days (n = 10)		 2.4±0.5 g/day AUC = 30.1±18.2 3.79±4.04 Cmax = 9.34±4.24 4.0±4.2 Cmin = 0.33±0.58
DN-AUC = 26.0±15.0 DN-Cmax = 8.00±4.15 f = 6.1±2.8 %
fAUC = 2.22±2.32
Period 2
56±33 days (n = 46) 2.4±0.5 g/day AUC = 19.8±11.0 2.21±2.63 Cmax = 8.30±4.19 0.7±0.4 Cmin = 0.28±0.50
DN-AUC = 18.2±12.0 DN-Cmax = 7.20±3.81 f = 4.3±2.4 %
fAUC = 1.01±0.81
Period 3
125±73 days (n = 114) 2.2±0.4 g/day AUC = 36.8±29.7 2.20±2.29 Cmax = 10.32±7.86 1.7±1.3 Cmin = 1.21±1.78
DN-AUC = 32.5±23.7 DN-Cmax = 9.49±7.78 f = 4.4±3.0 %
fAUC = 1.50±2.16
[130] 50 patients
56.5 years (20.7–77.6)		 Steady-state HPLC-UV Non-compartmental PK analysis using WinNonlin
27 LTx (6 CF)
49.9 years (20.7–70.5)		 2.1 years (0.2–14.0) 1.5 g BID (0.50–1.50)

0.034 g/kg/day (0.013–0.054)		 Prednisone (n = 27)
Cyclosporine (n = 11)
DN-AUC0-12 DN-Cmax MPA DN-Cmin
MPA 18.6 (3.4–35.1) -- 5.66 (0.64–15.53) 1.0 (0.3–6.0) 0.44 (ND-1.05)
MPAG 387 (152–909) -- -- --
AcMPAG 8.7 (ND-147) -- -- -- fMPA: N/R
MPA DN-AUC0-6
MPAG 14.3 (2.5–28.2)
AcMPAG 226 (69–495)
5.8 (ND-76)
MPA DN-AUC6-12
MPAG 6.5 (0.9–16.8)
AcMPAG 162 (61–427)
3.0 (ND-70)
MPA AUC6-12/AUC0-12 ratio
0.27 (0.12–0.55)
fAUC: N/R
MPAG/MPA = 28.5 (9.8–55.2)
AcMPAG/MPA = 0.4 (ND-12.3)
Tacrolimus (n = 16) DN-AUC0-12 DN-Cmax MPA DN-Cmin
MPA 41.4 (8.3–115.31) (p = 0.022) -- 8.24 (1.81–37.11) 1.1 (0.3–10.0) 1.13 (0.17–3.64) (p = 0.002)
MPAG 471 (72–928) -- -- --
AcMPAG 12.7 (0.7–160) -- -- -- fMPA = 1.9% (0.7–3.8)
DN-AUC0-6
MPA 25.4 (5.5–96.1) (p = 0.046)
MPAG 257 (43–603)
AcMPAG 4.6 (0.5–101)
DN-AUC6-12
MPA 14.8 (2.8–26.4) (p = 0.007)
MPAG 166 (29–389)
AcMPAG 7.40 (ND-59)
AUC6-12/AUC0-12 ratio
MPA 0.33 (0.17–0.56)
fAUC = 1.73 (0.51–2.43)
MPAG/MPA = 12.6 (2.4–25.8) (p = 0.002)
AcMPAGMPA = 0.3 (0.05–2.4)
21 HTx(and heart + kidney) 4.0 years (0.4–19.7) 0.75 g BID (0.25–1.50) (p < 0.05, lung vs heart) Prednisone (n = 1)
Cyclosporine (n = 14)
DN-AUC0-12 DN-Cmax MPA DN-Cmin
MPA 50.9 (16.9–218.7) -- 16.8 (3.6–47.3) 1.5 (0.3–12.0) 1.45 (0.34–3.02)
59.8 years (23.3–77.6) (p < 0.05) 0.019 g/kg/day (0.008–0.038) (p < 10−4, lung vs heart) MPAG 219 (50–1869) -- -- --
AcMPAG 17.9 (2.2–178) -- -- -- fMPA = 2.2% (0.2-15)
DN-AUC0-6
MPA 34.9 (10.7–134.0)
MPAG 408 (35–1142)
AcMPAG 7.7 (1.2–101)
DN-AUC6-12
MPA 18.9 (5.3–102.2)
MPAG 287 (14–726)
AcMPAG 6.6 (0.8–77)
AUC6-12/AUC0-12 ratio
MPA 0.33 (0.16–0.49)
fAUC =1.38 (0.05–12.26)
MPAG/MPA = 11.9 (0.9–28.6)
AcMPAG/MPA = 0.2 (0.07–2.03)
Tacrolimus (n = 9) DN-AUC0-12 DN-Cmax MPA DN-Cmin
MPA 106.8 (40.9–180.5) -- 21.8 (9.9–44.5) 1.0 (0.4–10.0) 3.28 (1.29–8.40) (p = 0.009)
MPAG 717 (113–1723) -- -- --
AcMPAG 20.1 (2.6–109) -- -- -- fMPA: 3.5% (0.5–14)
DN-AUC0-6
MPA 58.1 (23.9–90.1)
MPAG 419 (40–940)
AcMPAG 13.4 (1.7–80.3)
DN-AUC6-12
MPA 29.2 (9.9–89.8)
MPAG 298 (60–829)
AcMPAG 9.4 (0.9–62.6)
AUC6-12/AUC0-12 ratio
MPA 0.42 (0.23–0.61)
fAUC = 3.54 (0.85–18.89)
MPAG/MPA = 8.7 (2.3–13.4)
AcMPAG/MPA = 0.3 (0.06–0.87)
LUNG TRANSPLANTATION
[119] 7 patients
50±10 years		 4.4±3.9 years (0.3–11.5) Steady-state, 1–3 g/day
2.4±0.9 g/day (35.5±14.1 mg/kg/day)		 Cyclosporine
Prednisone		 HPLC-UV

Total Unbound		 Non-compartmental analysis using WinNonlin
AUC0-τ, τ = N/R
AUC = 45.8±18.4 -- Cmax = 17.37±7.69 1.2±0.4 Cmin = 3.12±1.41
DN-AUC = 23.6±15.8 DN-Cmax = 9.30±9.66 f = 2.9±0.6%
fAUC = 1.29±0.50
[138] 19 adults (4 CF)
48±15 years		 Stable
4.2±3.7 years		 Steady-state
2.5±0.5 g/day		 Prednisone

Cyclosporine (n = 9) or tacrolimus (n = 10)		 HPLC-UV Non-compartmental analysis using WinNonlin
29.4±17.9 -- -- -- --
r2 C0-AUC0-12 = 0.714; r2 C2-AUC0-12 = 0.663; r2 C8-AUC0-12 = 0.884 ; otherwise, r2 = 0.176–0.732
Recommended sparse sampling algorithms:

  • log(AUC0-12) = 1.140 + 0.241*log(C0) + 0.406*log(C2); r2 = 0.828, ME = −5.8%, RMSE = 6.0%

  • log(AUC0-12) = 1.09 + 0.202*log(C0) + 0.411*log(C1.5); r2 = 0.791, ME = −5.7%, RMSE = 7.0%

D: Dose – DN: Normalized to a 1000 mg MMF dose – f: Free fraction – HTx: Heart transplantation – LTx: Lung transplantation – N/R: not reported – OHT: Orthotopic heart transplantation.