Table I.

Description of published population pharmacokinetic (PK) modelling studies of mycophenolate mofetil (MMF) enterohepatic recirculation

Study	Dose	Time post-transplant	No. of patients	Sample times	No. of samples	Concomitant medication	Adequate for EHCa	Description of concentration-time profile; evidence second peak	When second peak seen; absorption or post-absorption phaseb	Comments
Funaki (1999)[67]	0.1–2.5 g MMFc		140 adults	0.5, 1, 2, 3, 4, 6, 8, 12 hours post-dose	270 MPA	Maalox®	Yes	Yes	Absorption phase	Meta-analysisd study compared PK between different races
Shum et al. (2003)[83]	1g MMFe	Day 2, 5, 28	22 adults	Pre-dose, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12 hours post-dose	557 MPA	Ciclosporin	Yes	Yes	Absorption and post-absorption phase	Evidence of lag time during absorption, complex absorption process and EHC
Le Guellec et al. (2004)[84]	0.5–2g MMFe	Stable (>6 months)	60 adults	Pre-dose, 0.33, 0.66, 1, 1.5, 2, 3, 4, 6, 9 hours post-dose	300 MPA	Ciclosporin	Yes	Yes	Post-absorption phase	Dose administered under fasting conditions and meals given 0.5 and 4 hours after dose; Bayesian model for estimation individual MPA
Staatz et al. (2005)[85]	1g MMFe	Day 3, 5, 7	117 adults	Pre-dose, 1, 2, 3, 4 hours post-dose	1376 MPA	Ciclosporin, tacrolimus	No	Yes	Absorption phase	Evidence of lag time during absorption, complex absorption process and EHC
Van Hest et al. (2005)[86]	0.45–1.7 g MMFe	Day 3, 7, 11, 21, 28, 56, 84, 112, 140	140 adults	Pre-dose, 0.33, 0.66, 1.25, 2, 6, 8, 12 hours post-dose	6523 MPA	Ciclosporin, corticosteroids	Yes	No	No	PK data obtained from an RCCT
Payen et al. (2005)[68]	600mg/m2 MMFe	10–1538 days	41 children (2–21 years)	Pre-dose, 1, 2, 4, 6, 8, 10, 12 hours post-dose	449 MPA	Ciclosporin, tacrolimus, corticosteroids	No	No	No	Profiles taken median 183 (12–3754) days post-transplant, 40 (10–1538) days post-start of MMF
Premaud et al. (2005)[87]	0.5–2g MMFe	Day 3, 7, 30 stable (>3 months)	45 adults	Pre-dose, 0.33, 0.66, 1, 1.5, 2, 3, 4, 6, 9, 12 hours post-dose		Ciclosporin, corticosteroids	Yes	Yes	Absorption and post-absorption phase	Dose administered under fasting conditions and meals given 0.5 and 4 hours after dose
Cremers et al. (2005)[42]	0.5–1g MMFe	≤1 year: week 2, 4, 6, 8, 10, 17, 21, 29, 39, 52	64 adults	Pre-dose, 1, 2, 3, 4, 6 hours post-dose	2748 MPA, 2648 MPAG	Ciclosporin, tacrolimus	No	No	No	Modelled MPA and MPAG plasma concentrations simultaneously
Van Hest et al. (2007)[88]	0.25–2.2 g MMFe	Day 1, 3, 4, 5, 7, 18, 21, month 1, 2, 3, 4, 5, 6, 7, 12	468 adults	Pre-dose, 0.33, 0.5, 0.67, 1, 1.25, 2, 3, 4, 6, 8, 12 hours post-dose	1894 MPA	Ciclosporin, sirolimus, corticosteroids	Yes	No	No	Data pooled from 6 clinical studies in post-renal transplant subjects
Jiao et al. (2008)[26]	0.5g MMFe		42 adults	Pre-dose, 0.17, 0.25, 0.33, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48 hours post-dose	590 MPA, 589 MPAG		Yes	Yes	Post-absorption phase	Healthy adult Chinese subjects enrolled in 2 open-label, randomized crossover design studies with a washout of 12 days; dose administered under fasting conditions and meals 4, 9.5/10, 24.25 hours after dose; modelled MPA and MPAG plasma concentrations simultaneously
de Winter et al. (2008)[89]	0.25–2.2 g MMFe 0.72g EC-MPSe	Stable (4–257 months)	259 adults	Pre-dose, 0.25, 0.33, 0.5, 0.66, 0.75, 1, 1.25, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 hours post-dosef	3764 MPA (208EC-MPS, 184 MMF profiles)	Ciclosporin, tacrolimus, everolimus, corticosteroids	Yes	Yes	Absorption and post-absorption phase	Pooled data from 7 clinical trials and 2 unpublished studies
Zahr et al. (2008)[90]	0.5–1.5 g MMFe		20 adults	Predose, 0.33, 0.66, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose	220 MPA	Corticosteroids	Yes	Yes	Absorption and post-absorption phase	Patients with SLE on a stable MMF regimen for at least 10 weeks, and standard meals given 1, 5 and 10 hours after dose; EHC could not be described well in model
Yau et al. (2009)[69]	0.5–1g MMFe	>1 month	14 adults	Pre-dose, 0.5, 1, 1.5, 2, 6, 12 hours post-dose	98 MPA and MPAG	Ciclosporin, corticosteroids	Yes	Yes	Post-absorption phase	Open-label study in Asian patients; modelled MPA and MPAG plasma concentrations simultaneously
Sam et al. (2009)[70]	0.36–0.72 g EC-MPSe	>1 month	18 adults	Predose, 0.25, 0.5, 0.75, 1.5, 2, 3, 4, 5, 7, 9, 10, 12 hours post-dose	232 MPA, MPAG and AcMPAG	Ciclosporin, tacrolimus	Yes	Yes	Post-absorption phase	Stable patients with diabetes mellitus post-renal transplant; modelled MPA, MPAG and AcMPAG plasma concentrations simultaneously
de Winter et al. (2009)[71]	1g MMFe		38 adults	Predose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 12, 14, 24 hours post-dose	492 MPA	Ciclosporin, corticosteroids	Yes	Yes	Post-absorption phase	Patients with autoimmune disease on a stable MMF regimen for at least 10 weeks
Musuamba et al. (2009)[91]	1g MMFe	7, 9, 15 months	40 adults	Predose, 0.33, 0.66, 1.25, 2, 4, 6, 8, 12 hours post-dose	1035 MPA and MPAG	Ciclosporin, sirolimus, corticosteroids	Yes	Yes	Post-absorption phase	Modelled MPA and MPAG plasma concentrations simultaneously
de Winter et al. (2009)[92]	1g MMFe	Day 3, 6, 7, 11, 21, 28, 49, 56, 84, 112, 140	75 adults	Predose, 0.33, 0.5, 0.66, 1, 1.25, 2, 6, 7, 12 hours post-dose (48 ciclosporin, 45 tacrolimus profiles)	489 total and unbound MPA, 488 total MPAG, 210 unbound MPAG	Ciclosporin, tacrolimus, corticosteroids	Yes	Yes	Post-absorption phase	Data from 2 studies in de novo renal transplant patients; relationship between total MPA, unbound MPA, total MPAG and unbound MPAG

^aSampling determined to NOT be adequate for detecting EHC or second peak if no sampling time between 0 and 1 hours post-dosing.

^bAbsorption phase – second peak observed during first 3 hours post-dosing or post-absorption phase – second peak observed between 6 and 12 hours post-dosing.

^cOnce- or twice-daily dosing.

^dStudy also included subjects with rheumatoid arthritis treated with MMF.

^eTwice-daily dosing.

^fNot all sample times were available for EC-MPS analysis.

AcMPAG=MPA acyl-glucuronide; EC-MPS=enteric-coated mycophenolate sodium; EHC=enterohepatic circulation; MPA=mycophenolic acid; MPAG=7-O-MPA-β-glucuronide; NONMEM=nonlinear mixed-effects modelling; RCCT= randomized controlled clinical trial; SLE = systemic lupus erythematosus.