Pharmacokinetic and Pharmacodynamic Markers of Mycophenolic Acid Associated with Effective Prophylaxis for Acute Graft-Versus-Host Disease and Neutrophil Engraftment in Cord Blood Transplant Patients

Kazuaki Yoshimura; Ikuko Yano; Takashi Yamamoto; Tadakazu Kondo; Misaki Kawanishi; Yui Isomoto; Atsushi Yonezawa; Akifumi Takaori-Kondo; Kazuo Matsubara

doi:10.1016/j.bbmt.2018.01.040

Pharmacokinetic and Pharmacodynamic Markers of Mycophenolic Acid Associated with Effective Prophylaxis for Acute Graft-Versus-Host Disease and Neutrophil Engraftment in Cord Blood Transplant Patients

Biol Blood Marrow Transplant. 2018 Jul;24(7):1441-1448. doi: 10.1016/j.bbmt.2018.01.040. Epub 2018 Feb 7.

Authors

Kazuaki Yoshimura¹, Ikuko Yano², Takashi Yamamoto³, Tadakazu Kondo⁴, Misaki Kawanishi¹, Yui Isomoto³, Atsushi Yonezawa¹, Akifumi Takaori-Kondo⁴, Kazuo Matsubara³

Affiliations

¹ Department of Clinical Pharmacy and Education, Graduate School of Pharmaceutical Science, Kyoto University, Kyoto, Japan; Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Kyoto, Japan.
² Department of Clinical Pharmacy and Education, Graduate School of Pharmaceutical Science, Kyoto University, Kyoto, Japan; Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Kyoto, Japan; Department of Pharmacy, Kobe University Hospital, Kobe, Japan. Electronic address: iyano@med.kobe-u.ac.jp.
³ Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Kyoto, Japan.
⁴ Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

PMID: 29427741
DOI: 10.1016/j.bbmt.2018.01.040

Abstract

Mycophenolate mofetil (MMF) is a prodrug of mycophenolic acid (MPA) and is frequently used to prevent acute graft-versus-host disease (aGVHD) in patients receiving hematopoietic stem cell transplantation (HSCT). However, optimal doses of MMF and target MPA concentrations in HSCT patients have not been defined. In this study, relationships between pharmacokinetic or pharmacodynamic markers of MPA and successful aGVHD prevention and neutrophil engraftment were evaluated to inform individualized MPA treatments in HSCT patients. We recruited 35 patients undergoing cord blood transplantation (CBT) who were treated with MMF. Area under the concentration-time curves from 0 to 24 hours (AUC_0-24) for free MPA and MPA acyl glucuronide (AcMPAG) at 1 week after the start of MMF treatments were significantly higher in patients with gastrointestinal (GI) aGVHD at stage ≥I than those at stage 0. Patients with faster neutrophil engraftment had higher free MPA AUC_0-24 at 1 week after the start of MMF treatments compared with those with slower neutrophil engraftment. Inosine-5'-monophosphate dehydrogenase activity in peripheral blood mononuclear cells and single nucleotide polymorphisms in genes that were previously associated with MPA pharmacokinetics and pharmacodynamics were not an independent predictor for the clinical outcomes. Receiver-operating characteristic model analyses showed that cutoff values of AUC_0-24 for successful GI aGVHD prevention were .689 and 15.6 µg⋅hour⋅mL^-1 for free MPA and AcMPAG, respectively. In addition, the cut-off value of free MPA AUC_0-24 for neutrophil engraftment by day 25 was .405 µg⋅hour⋅mL^-1. In conclusion, free MPA AUC_0-24 may be a better predictor of the prevention of GI aGVHD and neutrophil engraftment compared with that of total MPA in patients receiving CBT. Hence, monitoring of the free MPA AUC_0-24 between .405 and .689 µg⋅hour⋅mL^-1 could be considered informative of individualized MPA treatments in CBT patients.

Keywords: Cord blood transplantation; Mycophenolic acid; Pharmacodynamics; Pharmacokinetics.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cord Blood Stem Cell Transplantation / methods*
Female
Graft vs Host Disease / drug therapy*
Humans
Male
Middle Aged
Mycophenolic Acid / pharmacokinetics*
Mycophenolic Acid / pharmacology*
Neutrophils / metabolism*

Substances

Mycophenolic Acid