Table 1.

MPA pharmacodynamic studies in adult alloHCT recipients receiving MMF as postgraft immunosuppression^a

Study	Study population	Immunosuppressant	MPA PK methods	MPA Pharmacodynamic results
Jenke et al., 200119	N=15 Ages 26–57 yr Regimens MA: N=15, varied Donors Related: N=9 URD: N=6 Graft sources Marrow: N=3 PBSC: N=12	MMF dose 12.5 to 17 mg/kg IV through day +21, then 1000 mg orally MMF frequency BID: N=15 Other IS CSA 2 mg/kg IV BID, TCI to whole blood C0 of 200–300 ng/mL by TDx immunoassay	Total or unbound Total MPA only Sampling days Trough: Daily through day +21 AUC: Days +1,+ 7, +14, +21 AUC sampling times IV: 1, 2, 2.5, 3, 3.5, 4, 5, 6, 8 and 12 h after morning dose Oral: Not collected Administration route for sampling IV Assay LC-fluorescent detection	Data analysis Analyzed both AUC and trough concentrations Engraftment Not evaluated Rejection Not evaluated Chimerism Not evaluated Acute GVHD Average MPA C0 between days +1 and +14 did not differ between patients experiencing grades 0–I acute GVHD and grades II–III acute GVHD Patients with grades II–III acute GVHD <200 ng/mL always had C0 Chronic GHVD Not evaluated NRM Not evaluated Relapse Not evaluated OS Not evaluated
Jacobson et al., 200511	N=87 Ages 19–69 yr Conditioning NMA: N=87, BU or CY + FLU/TBI Donors Related: N=33 URD: N=54 Graft sources Marrow: N=4 PBSC: N=33 UCB: N=50 (single or double unit not specified)	MMF dose 1000 mg oral or IV (if could not tolerate oral) MMF frequency BID: N=87 Other IS CSA 2.5 mg/kg IV BID, TCI to whole blood C0 of 200–400 ng/mL by HPLC	Total or unbound Total and unbound Sampling days Trough: with AUCs, then weekly until day +30 AUC: Once pre-transplant (between days −9 and −6), once after transplant (between days +3 and +7) AUC sampling times IV: 0, 2, 4, 6, 8, 12h after infusion Oral: 0, 1, 2, 4, 6, 8, 12h after dose Note: additional sample collected at 24h for pre-transplant AUC only Administration route for sampling IV or oral Assay HPLC-UV; assay accuracy 96–117.5%	Data analysis Pre- and post-transplant AUCs Engraftment All engraftment failures occurred in UCB Total MPA C0 increasing by 1 μg/mL increased likelihood of engraftment by 58% (p=0.05) Higher engraftment associated with total MPA C0 >1 μg/mL (p <0.01) Rejection Not evaluated Chimerism Not evaluated Acute GVHD Unbound MPA AUC0–6h< 150 ng×h/mL associated with higher cumulative incidence of grades II-IV acute GVHD vs. AUC0–6h> 150 ng×h/mL (68% vs. 40%, p=0.02) Unbound AUC0–12h <300 ng×h/mL associated with more frequent acute GVHD (58% vs. 35%, p=0.05) No association between GVHD and C0 (p≤0.62) No association between total or unbound C0 and grades II–IV or grades III–IV acute GVHD (p≥0.17) Chronic GHVD Not evaluated NRM Not evaluated Relapse Not evaluated OS Not evaluated
Frymoyer et al., 201226	N=132 Ages 19–69 yr Conditioning NMA: N=132, CY/FLU/TBI Donors Related: N=43 URD: N=89 Graft sources Marrow: N=8 PBSC: N=42 UCB: N=82	MMF dose 1000 mg BID or TID or 1500 mg BID MMF frequency BID: N=113 TID: N=19 Other IS CSA 2.5 mg/kg IV BID, TCI to C0 of 200–400 ng/mL	Total or unbound Unbound MPA only Sampling days Trough: With AUCs AUC: Variable, up to day +7; estimated unbound AUC0–24h AUC sampling times IV: 0, 2, 4, 6, 8, 12h after infusion Oral: 0, 1, 2, 4, 6, 8, 12h after dose Note: 12h samples not collected in TID patients Administration route for sampling IV or PO	Data analysis PopPK model created with unbound MPA concentrations Two-compartment model with first-order absorption and linear elimination MPA exposure defined by composite of that accounted for average daily AUC0–24h differences in exposure between oral and IV and time patient spent with each dosing route Engraftment No relationship was found between unbound MPA and engraftment Rejection Not evaluated Chimerism Not evaluated Acute GVHD Risk of grades II–IV acute GVHD decreased 16% for every 200 ng×h/mL increase in AUC0–24h (p=0.026) Unbound MPA concentrations were not predictive of grades III–IV acute GVHD Chronic GHVD Not evaluated NRM Not evaluated Relapse Not evaluated OS Not evaluated Other Not evaluated
Giaccone et al., 200510	N=85 Ages 18–70 yr Regimens NMA: N=85, FLU/TBI Donors URD: N=85 Graft sources Marrow: N=6 PBSC: N=79	MMF dose 15 mg/kg PO MMF frequency BID: N=38 TID: N=47 Other IS CSA 6.25 mg PO BID, TCI to C0 of 500 ng/mL	Total or unbound Both total and unbound Sampling days Trough: Days +7 and +21 AUC: Days +7 and +21; estimated total and unbound AUC0–8h or AUC0–12h AUC sampling times IV: Not collected Oral: 0, 1, 2, 4, 6, 8, 10h after morning dose Note: 10h sample not collected in TID patients Administration route for sampling Oral	Data analysis All AUC results divided by dosing interval to provide concentration at steady state (Css) Engraftment Engraftment and rejection worse with marrow compared to PBSC7, so recipients of marrow graft excluded from PD analysis Rejection 6 patients with total MPA Css <2.5 μg/mL had graft rejection (p=0.34) Chimerism 16 patients with a total MPA Css <3 μg/mL had low (< 50%) donor T-cell chimerism (p=0.03) Acute GVHD No association with total or unbound MPA Css Chronic GHVD Not evaluated NRM Not evaluated Relapse No association with total or unbound MPA Css OS Not evaluated Other Elevated unbound MPA Css associated with CMV reactivation (p=0.03)
McDermott et al., 201377	N=308 Ages 9.2–74.5 yr Regimens NMA: N=308, TBI alone or FLU/TBI Donors Related: N=132 URD: N=176 Graft sources Not specified	MMF dose 15mg/kg PO MMF frequency BID: N=167 TID: N=141 Other IS CSA: N=251 TAC: N=57	Total or unbound Both total and unbound Sampling days Trough: Days +7 and +21 AUC: Days +7 and +21; estimated AUC0–8h or AUC0–12h AUC sampling times IV: Not collected Oral: 0, 1, 2, 4, 6, 8, 10h after morning dose Note: 10h sample not collected in TID patients Administration route for sampling Oral Assay LC-MS	Data analysis All AUC results divided by dosing interval to provide concentration at steady state (Css) Engraftment Engraftment and rejection worse with marrow compared to PBSC7, so recipients of marrow graft excluded from PD analysis Rejection Occurred in 9 patients, 8 of whom had a total MPA Css <3 μg/mL (p=0.36) Chimerism Donor T-cell chimerism on day 28 had no association with total or unbound MPA Css Acute GVHD For recipients with an unrelated donor, risk of grades III–IV acute GVHD was higher with a total MPA Css <2.96 μg/mL Chronic GVHD Not evaluated NRM No association with total or unbound MPA Css Relapse No association with total or unbound MPA Css OS Not evaluated Other In patients receiving a related donor graft, total MPA Css, unbound MPA Css, and total MPA C0 were not associated with clinical outcomes
Harnicar et al., 201572	N=174 Ages 1–71 yr Regimens MA: N=136, varied NMA: N=38, varied Donors URD: N=174 Graft sources Double UCB: N=174	MMF dose 1000 mg IV in adults, 15–20 mg/kg/dose for children ≤12 years MMF frequency BID: N=81 TID: N=93 Other IS CSA: Number not provided; CSA TCI to C0 of 200–400 ng/mL TAC: Number not provided; TAC TCI to C0 of 5–12 ng/mL	Total or unbound Total MPA only Sampling days Trough: Days +1, +8, +15, +22, +29, and +36 (N=85) AUC: Not collected AUC sampling times AUCs not collected Administration route for sampling IV Assay LC-MS	Data analysis Subset analysis in 85 patients looking at weekly total MPA C0 through week 6 after alloHCT Engraftment No difference in the cumulative incidence of day +100 neutrophil engraftment in myeloablated patients with mean week 1 to 2 MPA C0 of <2 and ≥2 μg/mL (p=0.422) No differences in platelet engraftment in myeloablated patients Rejection Not evaluated Chimerism Not evaluated Acute GVHD Cumulative incidence of grades II–IV acute GHVD by day +100 was higher in low-dose group than high-dose group (24% vs 8%, p=0.008) No difference in the cumulative incidence of day +100 grades II–IV acute GVHD in MPA C0 groups of <0.5 (N=19) and ≥0.5 (N=64) μg/mL (p=0.611) Difference in cumulative incidence of day +100 grades III–IV acute GVHD in MPA in MPA C0 groups of <0.5 (26%) and ≥0.5 μg/mL (9%, p=0.063) Chronic GVHD Not evaluated NRM Not evaluated Relapse Not evaluated OS Not evaluated Other No difference in duration of TPN in myeloablated patients with mean week 1 to 2 MPA C0 of <2 or ≥2 μg/mL
Arai et al., 201578	N=24 Ages 19–65 yr Regimens MA: N=8, varied RIC: N=16, varied Donors URD: N=24 Graft sources Single UCB: N=24	MMF dose 10 mg/kg PO MMF frequency TID: N=24 Other IS CSA: N=1, CSA TCI not specified TAC: N=23, TAC TCI not specified	Total or unbound Total MPA only Sampling days Trough: Days +7 and +21 AUC: Days +7 and +21, estimated AUC0–24h by multiplying AUC0–8h × 3) AUC sampling times IV: Not collected Oral: 0, 1, 2, 4, 8h after morning dose Administration route for sampling Oral Assay EMIT	Data analysis MPA concentration quantified with EMIT At week one and week three, patients were divided into two groups based on MPA AUC The lower-concentration group defined as was below the patients whose MPA AUC 0–24h lower quartile (40μg×h/mL) in week 1 and week 3; remaining patients formed the higher-concentration group Engraftment No difference in cumulative incidence of pre-engraftment syndrome between lower-concentration and higher-concentration groups in the first week after alloHCT (14.3% vs 5.9%, p=0.53) Rejection Not evaluated Chimerism Not evaluated Acute GVHD Cumulative incidence of grades II–IV acute GVHD by day +100 was significantly higher patients in lower-concentration group in the third week than patients in higher-concentration group in the third week (75% vs 31.2%, p=0.02) Difference between incidence of grades II–IV acute GVHD by day +100 in lower-and higher-concentration groups remained after adjusting for various confounders Relative risk was 8.05 (95% CI: 1.09–59.7, p=0.04) Chronic GVHD Not evaluated NRM Not evaluated Relapse No difference in relapse rates between lower-concentration and higher-concentration groups (16.7% vs 22.8%, respectively; p=0.76) OS Not evaluated Other Authors found that a certain level of MPA is necessary to effectively prevent acute GVHD after UCB alloHCT Suggested minimal requirement of an AUC0–24h of 40μg×h/mL in the third week after alloHCT

^aExcludes studies where MMF was used as treatment of GVHD,^206–209 where only PK results were reported,^{7,13,20,23,28,115,210}, or where MMF doses were personalized to total MPA PK, specifically an AUC_0–12h of 35–60 μg/mL/h¹³, C₀ < 3.5 μg/mL,¹² or C₀ of 1 – 3.5 μg/mL.²²

Abbreviations: alloHCT: allogeneic hematopoietic cell transplantation; AUC: area under the concentration-time curve; BU: busulfan; C₀: trough concentration; CI: confidence interval; CMV: cytomegalovirus; CSA: cyclosporine; C_ss: Concentration at steady state; CY: cyclophosphamide; EMIT: enzyme multiplied immunoassay technique; FLU: fludarabine monophosphate; GVHD: graft-versus-host disease; HPLC: high pressure liquid chromatography; IV: intravenous(ly); LC-MS: HPLC with mass spectrometry detection; MA: myeloablative; MMF: mycophenolate mofetil; MPA: mycophenolic acid; NMA: nonmyeloablative; NRM: non-relapse mortality; PBSC: peripheral blood stem cell; PD: pharmacodynamic; PK: pharmacokinetic; PO: oral(ly); RIC: reduced intensity conditioning; TBI: total body irradiation; UCB: umbilical cord blood; URD: unrelated donor