Pharmacodynamics of mycophenolate mofetil after nonmyeloablative conditioning and unrelated donor hematopoietic cell transplantation

Abstract

The immunosuppressive drug mycophenolate mofetil (MMF) is used after nonmyeloablative hematopoietic cell transplantation (HCT); however, limited pharmacodynamic data are available. We evaluated plasma concentrations of mycophenolic acid (MPA), the active metabolite of MMF, and outcomes in 85 patients with hematologic malignancies conditioned with fludarabine and 2 Gy total body irradiation followed by HLAmatched unrelated-donor HCT and postgrafting cyclosporine and MMF. The first 38 patients received MMF 15 mg/kg twice daily; the next 47 patients received MMF 3 times daily. MPA pharmacokinetics were determined on days 7 and 21. Comparing the twice-daily and 3-times-daily MMF groups, the mean total MPA concentration steady state (Css) was 1.9 and 3.1 g/mL; the unbound Css was 18 and 36 ng/mL, respectively (P < .001). Sixteen patients with a total MPA Css less than 3 g/mL had low (< 50%) donor T-cell chimerism (P ‫؍‬ .03), and 6 patients with MPA Css less than 2.5 g/mL had graft rejection. An elevated unbound Css was associated with cytomegalovirus reactivation (P ‫؍‬ .03). There were no significant associations between MPA pharmacokinetics and acute graft-versus-host disease (GVHD) or relapse. We conclude that increased MPA Css's predicted higher degrees of donor T-cell chimerism after unrelated donor nonmyeloablative HCT and suggest that targeting MPA Css's greater than 2.5 g/mL could prevent graft rejection.

MTX or mycophenolate mofetil with CsA as GVHD prophylaxis after reduced-intensity conditioning PBSCT from HLA-identical siblings

“…28 Furthermore, pharmacokinetic assays of mycophenolic acid have shown a higher therapeutic area under the curve at a dosage of 3 g daily in unrelated donor allo-RIC. 29,30 An interesting observation in our study was that patients who received CsA/MTX had an earlier median onset of cGVHD (146 days) than those in the CsA/MMF group (186 days). This may reflect a longer immunosuppression exposure in the CsA/MMF group.…”

Targeting mycophenolate mofetil for graft-versus-host disease prophylaxis after allogeneic blood stem cell transplantation

“…In a study on the pharmacokinetics of MMF within the context of nonmyeloablative conditioning, application of MMF every 8 h was associated with a significantly higher MPA exposition and trough blood levels, which led to a decreased incidence of mixed T-cell chimerism and graft failure. 26 Unfortunately, the more profound state of immunosuppression led to an increased rate of CMV infections. A negative correlation between the rates of graft failure and GVHD and 6 h unbound MPA AUC has been described in a retrospective study providing further arguments for therapeutic drug monitoring.…”

Lentiviral vector conferring resistance to mycophenolate mofetil and sensitivity to ganciclovir for in vivo T-cell selection

“…Cells transduced with the IMPDH IY vectors showed robust proliferation with MMF concentrations ranging from 0.1 to 5 mM, which are drug concentrations that are routinely achieved in clinical use of MMF. 22 The transgeneencoded cell surface expression of DCD34 permitted efficient immunomagnetic selection of transduced cells. With the cytoplasmic domain deleted, DCD34 is a potentially ideal clinical marker for transduced cells, given that CD34 immunoselection protocols are well established and readily available, facilitating future applications of this vector in preclinical and clinical models.…”