Bhatia M, Militano O, Jin Z, Figurski M, Shaw L, Moore V, Morris E, Tallamy B, van Deven C, Ayello J, Baxter-Lowe L, Satwani P, George D, Bradley MB, Garvin J, Cairo MS
An Age Dependent Pharmacokinetic Study of Intravenous and Oral Mycophenolate Mofetil in Combination with Tacrolimus for GVHD Prophylaxis in Pediatric Allogeneic Stem Cell Transplantation Recipients. [JOURNAL ARTICLE]
Biol Blood Marrow Transplant 2009 Oct 13.
Acute graft-versus-host disease (aGVHD) still remains a major limiting factor following allogeneic stem cell transplantation (AlloSCT) in pediatric recipients. Mycophenolate mofetil (MMF), an uncompetitive selective inhibitor of inosine monophosphate dehydrogenase, is a new immunosuppressant agent without major mucosal, hepatic or renal toxicity compared to other prophylactic aGVHD immunosuppressant drugs. While there has been an extensive pharmacokinetic (PK) experience with MMF administration following solid organ transplantation in children, there is a paucity of PK data following its use in pediatric AlloSCT recipients. We investigated the safety and PK of MMF as GVHD prophylaxis following intravenous (IV) and oral (PO) administration (900mg/m(2)/q6h) in conjunction with tacrolimus, after myeloablative (MA) and nonmyeloablative (NMA) conditioning and AlloSCT in three distinct age groups of pediatric AlloSCT recipients (0-6 yrs, 6-12 yrs, 12-16 yrs). Mycophenolic acid (MPA) in plasma samples was measured either by HPLC or LC/MS/MS as we have previously described. Plasma samples were obtained at baseline and at 0.5, 1, 2, 3, 4 and 6 hrs after IV dosing on days +1, +7, +14 and at two timepoints between day +45 and +100 after PO administration post AlloSCT. MPA PK analysis included AUC (0-6 hrs), C(max), T(max), C(ss), V(ss), C trough (C(0)), CL and T(1/2). Thirty-eight patients, median age 8 (0.33-16) yrs, 20/18M:F ratio, 21/17 malignant/nonmalignant disease, 17/21 myeloblative (MA):non-myeloablative (NMA) conditioning, 16/22 related/unrelated allografts. Median time to myeloid and platelet engraftment was 18 and 31 days, respectively. Mean donor chimerism on day +60 and +100 was 83 and 90%, respectively. Probability of developing aGVHD grade II-IV and extensive chronic GVHD was 54 and 34%, respectively. There was significant intra- and interpatient MMF PK variability. There was a significant increase in IV MPA AUC(0-6hr) and C(max) (p<0.0003) and a significant decrease in CL(ss) (p<0.002) and V(ss) (p<0.001) on day +14 vs day +7. Children less than 12 yrs of age had a significant increase in IV MPA Tmax (p=0.01), Vss (p=0.028) and CL(ss) (p<0.001) compared to the older age group. There was a trend in IV MPA CL(ss) following MA vs NMA conditioning (p<0.054). IV and PO MMF administration (900mg/m(2)/q6h) in combination with tacrolimus was well tolerated in pediatric AlloSCT recipients. There was a significant increase in MPA exposure on Day +14 vs day +7 suggesting improved enterohepatic recirculation at day +14 post AlloSCT. Children less than 12 yrs of age appear to have a significantly different MPA PK profile compared to older children and adolescents and may require more frequent dosing.
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