Pharmacokinetics-based optimal dose prediction of donor source-dependent response to mycophenolate mofetil in unrelated hematopoietic cell transplantation

• Published in: International journal of hematology Vol. 94; no. 2; pp. 193 - 202
• Main Authors: Wakahashi, Kanako, Yamamori, Motohiro, Minagawa, Kentaro, Ishii, Shinichi, Nishikawa, Shinichirou, Shimoyama, Manabu, Kawano, Hiroki, Kawano, Yuko, Kawamori, Yuriko, Sada, Akiko, Matsui, Toshimitsu, Katayama, Yoshio
• Format: Journal Article
• Language: English
• Published: Tokyo Springer Japan 01.08.2011; Springer; Springer Nature B.V
• Subjects: Adult; Aged; Antineoplastic Agents; Area Under Curve; Biological and medical sciences; Dose-Response Relationship, Drug; Drug Dosage Calculations; Drug monitoring; Female; Graft vs Host Disease - prevention & control; GVHD prophylaxis; Hematologic and hematopoietic diseases; Hematology; Hematopoietic Stem Cell Transplantation - adverse effects; Hematopoietic Stem Cell Transplantation - methods; Humans; Medical sciences; Medicine; Medicine & Public Health; Middle Aged; MMF; Mycophenolic Acid - administration & dosage; Mycophenolic Acid - analogs & derivatives; Mycophenolic Acid - pharmacokinetics; Oncology; Original Article; Pharmacokinetics; Retrospective Studies; Tissue Donors; Treatment Outcome; Unrelated donor; Young Adult; Drug monitoring; GVHD prophylaxis; Unrelated donor; MMF; Drug; Immunopathology; Graft versus host disease; Hematology; Enzyme; Stem cell; IMP dehydrogenase; Enzyme inhibitor; Hematopoietic cell; Homograft; Prevention; Surveillance; Graft; Oxidoreductases; Mycophenolate mofetil; Predictive factor; Pharmacokinetics; Dose
• ISSN: 0925-5710; 1865-3774; 1865-3774
• DOI: 10.1007/s12185-011-0888-6

Mycophenolate mofetil (MMF) has been widely used for prophylaxis against graft-versus-host disease (GVHD) following allogeneic hematopoietic stem cell transplantation (allo-SCT). However, no clear advantage over methotrexate has been reported, other than reduced incidence of mucositis. We speculated that the wide inter-individual variation of plasma mycophenolic acid (MPA) levels veiled the benefits of MMF. Data from 36 unrelated allogeneic bone marrow (allo-BMT) and cord blood transplantation (CBT) were analyzed retrospectively based on MPA area under the curve (AUC 0–24h ). In allo-BMT, high AUC 0–24h (>30 μg h/ml) resulted in no incidence of grade II–IV acute/extensive chronic GVHD and tended to show higher overall and disease-free survival, lower relapse rates, and non-relapse mortality. In CBT, AUC 0–24h less than 30 μg h/ml was sufficient for low incidence of acute/chronic GVHD and high survival. Strong correlation between AUC 0–24h and C 2h , plasma MPA concentration at 2 h after administration was observed. Single point assessment of C 2h was shown to provide a useful surrogate of AUC 0–24h to predict GVHD incidence. The results of this study suggest that individualized MMF dosing in a donor source-dependent fashion may be important for maximizing the benefit of MMF in allo-SCT.