Pharmacokinetics of mycophenolic acid after haplo-hematopoietic stem cell transplantation in Japanese recipients

Abstract

Purpose Mycophenolate mofetil (MMF), a mycophenolic acid (MPA) prodrug, is used to prevent graft-versus-host disease (GVHD) in hematopoietic stem cell transplantation (HSCT). Although previous studies have reported that enterohepatic circulation (EHC) of MPA, which is usually observed in MMF-treated patients, does not occur in HSCT patients, it is unclear what happens in haploidentical–HSCT (haplo-HSCT) patients, who are using post-transplant cyclophosphamide. This study was conducted to investigate MPA pharmacokinetics in haplo-HSCT patients. Methods Seventeen haplo-HSCT patients, who received MMF for GVHD prophylaxis, were enrolled in this study. We collected blood samples on days 14 and 28, and plasma MPA concentrations were measured by high-performance liquid chromatography; pharmacokinetic parameters such as area under the curve (AUC), mean residence time (MRT), and apparent oral clearance (CL/F) were measured with moment analysis. We also evaluated EHC as AUC6-12h/AUC0-12h. Results There was no significant difference in MPA pharmacokinetic parameters between days 14 and 28. There was also no difference between the pharmacokinetic parameter changes and diarrhea. Additionally, varying plasma MPA concentrations suggested that MPA EHC did not occur. Conclusion In this study, we revealed the pharmacokinetics of MMF in Japanese haplo-HSCT recipients. Additionally, our study demonstrated that MPA EHC might not occur in Japanese haplo-HSCT recipients.

Body Surface Area-Based Dosing of Mycophenolate Mofetil in Pediatric Hematopoietic Stem Cell Transplant Recipients: A Prospective Population Pharmacokinetic Study

“…In comparison to the pediatric drug label dosage of 600 mg/m 2 administered twice daily for pediatric solid organ transplantation, our study recommended a higher dosage for pediatric HSCT recipients [ 41 ]. Considering that HSCT patients exhibit lower MPA concentrations and AUC 0–12 levels compared to solid organ transplantation patients, our study suggests that a pediatric MMF dosage of 900 mg/m 2 administered orally twice daily is an adequate dose for pediatric HSCT patients [ 11 , 50 ]. Several factors, as mentioned earlier, can contribute to low AUC 0–12 levels in HSCT patients: including HSCT-mediated diarrhea, which can reduce MPA absorption and reabsorption by disrupting the intestinal flora caused by the conditioning regimen and antibiotics [ 50 ].…”

“…Considering that HSCT patients exhibit lower MPA concentrations and AUC 0–12 levels compared to solid organ transplantation patients, our study suggests that a pediatric MMF dosage of 900 mg/m 2 administered orally twice daily is an adequate dose for pediatric HSCT patients [ 11 , 50 ]. Several factors, as mentioned earlier, can contribute to low AUC 0–12 levels in HSCT patients: including HSCT-mediated diarrhea, which can reduce MPA absorption and reabsorption by disrupting the intestinal flora caused by the conditioning regimen and antibiotics [ 50 ]. When calculating the dosage based on the body weight and BSA of the study patients, the dosage regimen of 900 mg/m 2 was approximately 1.5–2-fold higher than the study regimen of 15 mg/kg, suggesting that the study dosage may be insufficient.…”