Pharmacokinetics of Mycophenolic Acid Administered 3 Times Daily after Hematopoietic Stem Cell Transplantation with Reduced-Intensity Regimen

Abstract

Mycophenolate mofetil (MMF) is an immunosuppressive drug used as a prophylactic agent to prevent acute graft-versus-host disease (aGVHD) after hematopoietic stem cell transplantation (HSCT). After reduced-intensity conditioning (RIC) regimen, administration of MMF orally 3 times a day (tid) seems to be more beneficial than twice a day (bid). However, information regarding the pharmacokinetic (PK) parameters of mycophenolic acid (MPA), the active metabolite of MMF, administered in this regimen are very limited. We performed a prospective study in 15 patients for whom 3 sets of sampling were performed: at the beginning of the treatment, after 1 week, and after 1 month. Two consecutive 8-hour sets of sampling were performed at day 0 (D0) and D7. Plasma concentrations of MPA were quantified and areas under the curve for 8hours (AUC(0-8)), and maximal and through concentrations were calculated. The results show that AUC(0-8) increases between the beginning of treatment and the end of the first week, but remains stable thereafter. Moreover, a trend to lower AUC(0-8) was observed for the patients who experienced GVHD > or =2 compared to those patients who did not. The other PK parameters are not associated with pharmacodynamic events. A limited sampling strategy with Bayesian estimators is currently under investigation to confirm these data and the role of D7 AUC(0-8) as a potential target of therapeutic drug monitoring (TDM).

Pharmacokinetics, Pharmacodynamics, and Pharmacogenomics of Immunosuppressants in Allogeneic Hematopoietic Cell Transplantation: Part II

“…71–73 The notable exception to this guideline is nonmyeloablative alloHCT recipients of a related donor graft, who should receive 15 mg/kg orally every 12 h. 74 Currently, some alloHCT centers personalize MMF via TCI using either trough concentrations , 12,22 AUC, 13 or Bayesian estimates of AUC. 75 The conflicting results on the benefit of MPA TCI in renal transplant recipients 48,76 and heterogeneous results of MPA pharmacodynamics in alloHCT (Table 1) may have diminished enthusiasm for such an approach in alloHCT patients.…”

“…10–12,14,19,22,77 There was variability in how these studies reported plasma exposure – using either AUC, C ss, or trough concentration – and in whether total or unbound MPA concentrations were evaluated. Many of these studies, however, are limited in sample size and include heterogeneous patient populations that vary in both donor source and type.…”

“…To summarize, TCI of MPA is conducted at some alloHCT centers using either trough concentrations , 12,22 AUC, 13 or Bayesian estimates of AUC. 75 Tacrolimus is the preferred CNI to be administered with MPA, because of the findings of Li et al that concomitant cyclosporine was associated with a 34% increase in total MPA clearance compared to concomitant tacrolimus.…”

Optimal Storage Temperature and Matrix Before Analyzing Mycophenolic Acid

“…2 Evidence to support monitoring of MPA after transplantation 3 has accumulated in liver, 4,5 renal 6-8 and hematopoietic stem cell recipients, 9 and MPA is predominantly metabolized by glucuronidation to form an inactive metabolite, MPA glucuronide (MPAG), in addition to a number of minor metabolites including the acyl glucuronide (AcMPAG). MPAG is known to be unstable in plasma from a study using spiked samples, 10 and a recent publication 11 has shown marked instability of AcMPAG in spiked plasma and whole blood.…”

Delayed neutrophil engraftment in cord blood transplantation with intensive administration of mycophenolate mofetil for GVHD prophylaxis

“…1 Three-times daily administration of MMF after allo-SCT has been demonstrated to maintain higher plasma levels of the active metabolite, mycophenolic acid (MPA), and possibly result in better clinical outcomes. [2][3][4] We retrospectively analyzed the effect of MMF dosing on neutrophil engraftment in single-unit cord blood transplantation (s-CBT) and unrelated BMT.…”