title: A Pilot Study of Continuous Infusion of Mycophenolate Mofetil for Prophylaxis of Graft-versus-Host-Disease in Pediatric Patients.
abstract: Mycophenolate mofetil (MMF), an ester prodrug of mycophenolic acid (MPA), is used increasingly for graft-versus-host disease (GVHD) prophylaxis. Empiric fixed-dose-escalation strategies in pediatric hematopoietic cell transplantation (HCT) recipients have failed to achieve target MPA exposure. We evaluated the safety and feasibility of a pharmacokinetics-based dosing approach using a novel continuous infusion (CI) method of administration of MMF in pediatric HCT recipients. All patients received a myeloablative conditioning with cyclosporine A and MMF for GVHD prophylaxis. MMF was initiated on day 0 at a dose of 15 mg/kg every 8 hours. Based on steady-state pharmacokinetics, MMF was converted to CI to target a total MPA AUC(0-24) of 40 to 80 μg·hour/mL. The MMF dose was adjusted to maintain a total MPA steady-state concentration (Css) of 1.7 to 3.3 μg/mL. During the CI schedule, MPA AUC(0-24) was maintained at a mean of 40.1 μg·hour/mL (range, 20.6 to 63.8), and 17 of 19 patients (89%) achieved MPA Css within target of 1.7 to 3.3 μg/mL. Eighteen of 19 patients (95%) achieved neutrophil engraftment at a median of 13 days (range, 8 to 41) post-transplant and platelet engraftment at 39 days (range, 17 to 298) days post-transplant. Six of 18 assessable patients (33%) developed stages II to IV acute GVHD and 2 of 15 (13%) developed chronic GVHD. The MMF dose was reduced in 9 patients due to gastrointestinal symptoms (n = 6), low blood counts (n = 4), and viral infection (n = 3). Five patients with acute lymphoblastic leukemia relapsed, of whom 4 have died. Fifteen of 19 patients are alive with a median follow-up of 2.4 years (range, .4 to 4.9), with 3-year event-free and overall survival rates of 68% and 79%, respectively. In this pilot study of pharmacokinetically directed MMF dosing, we observed no toxic deaths, excellent engraftment, and low rates of grades III to IV acute and chronic GVHD. We found significantly lower half-life and higher drug clearance in pediatric HCT recipients compared with stable pediatric renal transplant patients or adult transplant patients. This regimen deserves further validation in a larger cohort of pediatric patients undergoing myeloablative transplantation.
authors.affiliation: Division of Blood and Marrow Transplantation and Cellular Therapies, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; Department of Pediatrics, School of Medicine, University of Pittsburgh, Pennsylvania.
authors.forename: Randy M
authors.initials: RM
authors.lastname: Windreich
authors.affiliation: Division of Blood and Marrow Transplantation and Cellular Therapies, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; Department of Pediatrics, School of Medicine, University of Pittsburgh, Pennsylvania. Electronic address: rakeshkgyl@gmail.com.
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Goyal
authors.affiliation: Department of Pharmaceutical Science, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Rujuta
authors.initials: R
authors.lastname: Joshi
authors.affiliation: Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Tanya S
authors.initials: TS
authors.lastname: Kenkre
authors.affiliation: Department of Pharmacy, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
authors.forename: Denise
authors.initials: D
authors.lastname: Howrie
authors.affiliation: Department of Pharmaceutical Science, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; Thomas Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Raman
authors.initials: R
authors.lastname: Venkataramanan
mesh_terms: D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D002648:Child; D002675:Child, Preschool; D016572:Cyclosporine / Q000627:therapeutic use; D006086:Graft vs Host Disease / Q000276:immunology / Q000401:mortality / Q000473:pathology / Q000517:prevention & control*; D006207:Half-Life; D019337:Hematologic Neoplasms / Q000276:immunology / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007223:Infant; D007262:Infusions, Intravenous; D009173:Mycophenolic Acid / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019653:Myeloablative Agonists / Q000627:therapeutic use; D010865:Pilot Projects; D011446:Prospective Studies; D016019:Survival Analysis; D019172:Transplantation Conditioning
chemical_list: D007166:Immunosuppressive Agents; D019653:Myeloablative Agonists; D016572:Cyclosporine; D009173:Mycophenolic Acid
keywords: GVHD prophylaxis; MMF; Pediatric; Pharmacokinetics