Relationship of mycophenolic acid exposure to clinical outcome after hematopoietic cell transplantation

Abstract

Mycophenolate mofetil is used increasingly to provide immunosuppression after nonmyeloablative allogeneic hematopoietic cell transplantation. There is wide variability in the pharmacokinetics of mycophenolic acid (MPA), the active metabolite, and low concentrations are associated with rejection after organ transplantation. We hypothesized that low MPA was associated with poorer engraftment and a higher incidence of acute graft versus host disease. We evaluated the pharmacokinetics in 87 adult subjects undergoing nonmyeloablative-related and nonmyeloablative-unrelated hematopoietic cell transplantation who were receiving 1 g mycophenolate mofetil orally or intravenously every 12 hours plus cyclosporine (INN, ciclosporin). Subjects with an unbound MPA area under the curve (AUC) from 0 to 6 hours of less than 150 ng . h/mL had a higher cumulative incidence of grade II-IV acute graft versus host disease than subjects with a greater AUC (68% versus 40%, P = .02). An unbound AUC from 0 to 12 hours of less than 300 ng . h/mL was also associated with more frequent acute graft versus host disease (58% versus 35%, P = .05). There was no association between graft versus host disease and trough concentrations (P < or = .62). A higher cumulative incidence of engraftment was associated with total MPA trough concentrations greater than 1 microg/mL (P < .01). All engraftment failures occurred in the cord blood recipients. About one half of subjects were below the unbound AUC target after oral dosing with nearly a 5-fold variability in AUC. Intravenous dosing achieved unbound targets better than oral dosing. The current practice of dosing with 1 g twice daily provides inadequate plasma concentrations in many patients, and doses of at least 3 g/d are likely necessary. Therapeutic monitoring of MPA concentrations with dose adjustment into the therapeutic target appears to be necessary for the most effective use of mycophenolate mofetil.

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

“…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. 27 Only recently, our results concerning shortened half-life and decreased MPA exposure in recipients of HSCTs have been confirmed by other investigators. 28 Tacrolimus combined with MMF has already been explored as GVHD prophylaxis in two trials after nonmyeloablative conditioning and in children receiving standard intensity regimens.…”

Pharmacokinetics of oral mycophenolate mofetil in combination with CsA in dogs after nonmyeloablative allogeneic hematopoietic stem cell transplantation

“…The impairment of enterohepatic recirculation after myeloablative and nonmyeloablative HSCT was observed in clinical studies as well. 6,7,[14][15][16] On the one hand this may occur due to the gastrointestinal toxicity of the preceding conditioning regimen. On the other hand the CsA-MPA drug interaction may account for this phenomenon.…”

“…They observed large interindividual variabilities in MPA AUC ranging from 5-to 10-fold. 6,29 Giaccone et al 8 found variabilities of MPA AUC in the range of seven-to eightfold despite using an adjusted ideal body weight dosage. Nevertheless, in our study a body weight adjusted dosing was performed as well, resulting in a 2.5-fold interindividual variability in the 20 mg/kg MMF treatment group and even smaller variabilities in the 10 and 30 mg/kg groups.…”

“…19,20 In consequence, similar MMF doses as used in SOT achieved lower AUC values in the range of 10-30 mg/ml h and C min levels o1 mg/ml. [5][6][7][14][15][16] In accordance with these clinical data we found in our study total MPA AUC 0À12 h and median blood trough levels below the recommended target ranges and shortened Table 2 Correlation coefficients (r) between MPA AUC 0-12 h and each MPA concentration Table 3 Pharmacokinetic parameters of total MPA after oral application of 20 mg/kg MMF in combination with 15 mg/kg CSA twice daily at different days after hematopoietic stem cell transplantation Pharmacokinetics of MMF following transplantation S Lange et al median half-life as well. Body weight-adjusted apparent oral clearance of MMF following HSCT seems to be comparable between dogs and humans.…”

“…5 In addition, perturbations of enterohepatic recycling following HSCT were observed. 6 This resulted in MPA concentrations below the therapeutic range recommended for SOT. 7 Furthermore, correlations of MPA plasma concentrations at steady state and AUC with degree of T-cell chimerism 8 and incidence of graft rejection 6,8 have been suggested.…”