The pharmacokinetics and pharmacodynamics of MMF have been extensively studied in solid organ transplantation; however, relatively limited data are available in HCT. In organ transplant the relationship between mycophenolate pharmacokinetics and development of acute allograft rejection has been reported in numerous studies and although controversial, most support an association between higher MPA exposure and protection from acute rejection.33, 39–42
More recent data in kidney transplant showed that prophylactic calcineurin inhibitors could be safely minimized or corticosteroids withdrawn if total MPA trough concentrations were maintained >1.2 or 1.6 mcg/ml, or if AUC0–12
was ≥ 40 mcg hr/mL.27, 43
To achieve these targets, oral MMF doses of 2.5–3 gm/day were typically required.27
Higher starting doses of MMF in kidney transplant are now under investigation.33
The optimal dose of MMF in HCT remains debated. Most centers have adopted the common prophylactic dose for kidney transplant of 1 gm twice daily. However, plasma concentrations are typically lower in HCT recipients relative to organ transplantation at this dose, especially when combined with cyclosporine.18, 22, 23, 28, 34, 44–51
We have previously studied mycophenolate pharmacokinetics early post transplant after nonmyeloablative conditioning and found that low total MPA trough concentrations are associated with poorer engraftment and low unbound MPA AUCs are associated with higher rates of acute GVHD.23
Similarly, Giaccone et al showed that low total MPA exposure was associated with lower donor T-cell chimerism after nonmyeloablative HCT.28
Doses of 3 gm/day are typically required to achieve the target concentrations defined in these studies when combined with cyclosporine.37
MMF use for the treatment of acute GVHD is growing and data from BMT CTN trial 0302 suggests that MMF plus corticosteroids may have significant activity against GVHD.16
In the treatment setting, MPA pharmacokinetic disposition, exposure-response relationship and optimal dosing are unclear. Two previous studies evaluated the use of MMF for the treatment of acute and chronic GVHD and measured MPA concentrations.34, 52
There was a suggestion in both studies that individuals with higher MPA exposure had better GVHD response; however; both studies were small. In the current pharmacokinetic analysis conducted with BMT CTN 0302, we found that subjects with total MPA trough concentrations >0.5 mcg/mL or unbound troughs >0.015 mcg/mL were more likely to achieve a CR+PR at day 28 and 56 than those below these thresholds. In week 1 of MMF treatment, 55–69% of subjects and in week 2, 37–50% of subjects had MPA exposure below these therapeutically favorable thresholds. These data suggest that MMF doses >2 gm/day may be required in a substantial number of patients.
Higher doses of MMF (3 gm/day) are increasingly common in the prophylactic setting. Significantly higher donor T-cell chimerism was observed in a group of patients receiving prophylactic MMF 3 gm/day compared to 2 gm/day.53
Although there was a slightly higher rate of infection in the 3 gm/day group, no difference in overall or progression free survival was observed. Studies in kidney transplant and HCT have shown a higher incidence of leukopenia or CMV reactivation when the MPA exposure is high.28, 30, 31, 54
In our analysis, only a small number of patients achieved exposure levels potentially associated with these events. Although higher MMF doses might result in more patients’ MPA exposure in the range associated with higher risk of infectious complications, no data in the context of GVHD treatment supports this as yet. This risk may be mitigated by better GVHD control and more rapid discontinuation of immunosuppression. In the current study, no increase in infections followed higher MPA exposure.
Several factors that affect MMF pharmacokinetics warrant discussion. First, the potential effect of intestinal and liver GVHD on MPA disposition is of concern. MPA is metabolized in the intestine and liver, common sites of GVHD involvement. A previous pilot study in 14 patients treated with MMF for acute GVHD found that total MPA concentrations were lower in individuals with intestinal GVHD relative to those with skin or liver involvement.34
This was further supported in our analysis where patients with lower GI or liver GVHD had trough concentrations lower than those with skin only involvement. Larger studies with pharmacokinetic analyses will be required to determine if the site of GVHD involvement affects dosing recommendations. Second, steroids are potent inducers of glucuronidation of many substrates in vitro and may affect MPA metabolism which is highly dependent on glucuronidation to form its metabolites including the major metabolite, MPAG.55
MPAG is known to displace MPA from protein binding sites thereby increasing unbound MPA. It is possible that steroids induce glucuronidation thereby enhancing MPAG formation and lowering MPA concentrations. The effect of corticosteroids on MPA metabolism has been studied in organ transplantation with conflicting conclusions.56, 57
In our analysis, MPAG to MPA exposure ratio was high, 45–66, while ratios of around 30 have been found in other HCT studies.23, 58
This suggests that MPAG formation may be enhanced or MPAG excretion reduced. MPAG readily accumulates in renal dysfunction; however, the mean serum creatinine in our subjects was 0.9 mg/dL; therefore it is unlikely that MPAG accumulated as a result of poor renal clearance alone. Therefore, high dose corticosteroids may affect the formation of MPAG and MPA concentrations; however, this requires confirmation in formal drug interaction studies.
Interestingly, total MPA trough concentrations were higher in subjects receiving oral MMF compared to IV. We have observed this finding in our other MMF pharmacokinetic studies and suspect it may be secondary to enterohepatic recirculation of MPAG or delayed absorption of the oral solid formulations. MPA metabolites, in particular MPAG, are available in the gut and subject to deglucuronidation back to MPA which is then reabsorbed into the systemic circulation. Although CSA is known to block enterohepatic recirculation of MPA, recirculation may still occur to some extent, albeit limited, resulting in slightly higher MPA trough concentrations after oral administration.
In conclusion, MPA total trough concentrations >0.5 mcg/mL or unbound concentrations >0.015 mcg/mL may be associated with better acute GVHD response at day 28 and 56 post treatment. There was no association between MPA pharmacokinetics and infections or survival. MMF 1 gm every 12 hours achieves these threshold concentrations in approximately 50% of patients and higher doses are required in many patients to achieve these therapeutically effective targets. These data should be confirmed in future independent trials.