Population Pharmacokinetics and Dose Optimization of Mycophenolic Acid in HCT Recipients Receiving Oral Mycophenolate Mofetil

Abstract

We sought to create a population pharmacokinetic model for total mycophenolic acid (MPA), to study the effects of different covariates on MPA pharmacokinetics, to create a limited sampling schedule (LSS) to characterize MPA exposure (i.e., area under the curve or AUC) with maximum a posteriori Bayesian estimation, and to simulate an optimized dosing scheme for allogeneic hematopoietic cell transplantation (HCT) recipients. 4,496 MPA concentration-time points from 408 HCT recipients were analyzed retrospectively using a nonlinear mixed effects modeling approach. MPA pharmacokinetics was characterized with a two-compartment model with first-order elimination and a time-lagged first-order absorption process. Concomitant cyclosporine and serum albumin were significant covariates. The median MPA clearance and volume of the central compartment were 24.2 L/hr and 36.4 L, respectively, for a 70 kg patient receiving tacrolimus with a serum albumin of 3.4 g/dL. Dosing simulations indicated that higher oral MMF doses are needed with concomitant cyclosporine, which increases MPA clearance by 33.8%. The optimal LSS was immediately before and at 0.25, 1.25, 2, and 4hr after oral MMF administration. MPA AUC in an individual HCT recipient can be accurately estimated using a five-sample LSS and maximum a posteriori Bayesian estimation.

Higher Dose of Mycophenolate Mofetil Reduces Acute Graft-versus-Host Disease in Reduced-Intensity Conditioning Double Umbilical Cord Blood Transplantation

“…Immunosuppressive therapy in our study consisted of MMF and CSA; therefore, the proposed MMF 3g/day dose examined in this study cannot be generalized to MMF when used in combination with tacrolimus because of underlying pharmacokinetic differences. 29 …”

Recipient Pretransplant Inosine Monophosphate Dehydrogenase Activity in Nonmyeloablative Hematopoietic Cell Transplantation

“…(29) There is considerable interindividual variability in MPA plasma exposure with weight-based dosing of either intravenous or oral MMF in HCT recipients. (10, 30) Pharmacodynamic data suggest a relationship between clinical outcomes and MPA plasma exposure (as reviewed in McDermott et al (31), and some HCT centers personalize MMF doses to a target MPA exposure. (32) We recently observed that low total MPA plasma exposure was associated with increased grades 3–4 acute GVHD and increased non-relapse mortality in nonmyeloabative HCT recipients with an unreIated donor graft.…”

“…MMF, at a dose of 15mg/kg, was given at two different dose frequencies, either three times a day (Q8h) to unrelated graft recipients or twice a day (Q12h) to related graft recipients. Adjusted ideal body weight(10) was used to determine MMF dosing, and all doses were rounded to the nearest 250mg. MMF doses were not adjusted based on recipient pretransplant IMPDH activity.…”

How I treat hepatitis C virus infection in patients with hematologic malignancies

“…54,[67][68][69][70] Ascitic fluid should be drained prior to administration of hydrophilic drugs such as fludarabine and methotrexate, 54 and if mycophenolate mofetil is used, it should be doseadjusted if the serum albumin level is low. 71 Supportive care should include ursodiol for prevention of cholestatic liver injury, antibiotics to prevent bacterial translocation during neutropenia, and attention to portal pressures and hepatorenal syndrome.…”