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

• Published in: Biology of blood and marrow transplantation 2010-03, Vol.16 (3), p.333-343
• Main Authors: Bhatia, Monica, Militano, Olga, Jin, Zhezhen, Figurski, Michal, Shaw, Leslie, Moore, Virginia, Morris, Erin, Tallamy, Bradford, van deVen, Carmella, Ayello, Janet, Baxter-Lowe, LeeAnn, Satwani, Prakash, George, Diane, Bradley, M. Brigid, Garvin, James, Cairo, Mitchell S
• Format: Article
• Language: English
• Subjects: Adolescent; Aging - physiology; AlloSCT; Area Under Curve; Child; Child, Preschool; Drug Therapy, Combination; Female; Graft vs Host Disease - diagnosis; Graft vs Host Disease - prevention & control; Hematology, Oncology and Palliative Medicine; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents - administration & dosage; Immunosuppressive Agents - adverse effects; Immunosuppressive Agents - pharmacokinetics; Immunosuppressive Agents - therapeutic use; Infant; Kaplan-Meier Estimate; Male; MMF; Mycophenolic Acid - administration & dosage; Mycophenolic Acid - adverse effects; Mycophenolic Acid - analogs & derivatives; Mycophenolic Acid - pharmacokinetics; Mycophenolic Acid - therapeutic use; Pediatric; Pharmacokinetics; Tacrolimus - administration & dosage; Tacrolimus - therapeutic use; Tissue Donors; Transplantation Conditioning - methods; Transplantation, Homologous; Treatment Outcome
• ISSN: 1083-8791; 1523-6536
• DOI: 10.1016/j.bbmt.2009.10.007

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. Although 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 (i.v.) and oral (p.o.) administration (900 mg/m2 every 6 hours) in conjunction with tacrolimus, after myeloablative (MA) and nonmyeloablative (NMA) conditioning and AlloSCT in 3 distinct age groups of pediatric AlloSCT recipients (0-6 years, 6-12 years, and 12-16 years). Mycophenolic acid (MPA) in plasma samples was measured either by high-performance liquid chromatography (HPLC) or liquid chromatography/mass spectrometry (LC/MS/MS) as we have previously described. Plasma samples were obtained at baseline and at 0.5, 1, 2, 3, 4, and 6 hours after i.v. dosing on days +1, +7, +14, and at 2 time points between day +45 and +100 after p.o. administration post AlloSCT. MPA PK analysis included AUC (0-6 hours), Cmax , Tmax , Css , Vss , C trough ( C0 ), CL , and T½. Thirty-eight patients, with a median age of 8 years (0.33-16 years), 20/18 M:F ratio, 21/17 malignant/nonmalignant disease, 17/21 MA: NMA conditioning, 16 of 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 (cGVHD) was 54% and 34%, respectively. There was significant intra- and interpatient MMF PK variability. There was a significant increase in i.v. MPA area under the curve (AUC)0-6hour and Cmax ( P < .0003) and a significant decrease in CLss ( P < .002) and Vss ( P < .001) on day +14 versus day +7. Children