Individualization of Mycophenolic Acid Therapy through Pharmacogenetic, Pharmacokinetic and Pharmacodynamic Testing

Author:

Winnicki WolfgangORCID,Fichtenbaum Andreas,Mitulovič GoranORCID,Herkner HaraldORCID,Regele Florina,Baier Michael,Zelzer Sieglinde,Wagner Ludwig,Sengoelge Guerkan

Abstract

Mycophenolic acid (MPA) is a widely used immunosuppressive agent and exerts its effect by inhibiting inosine 5′-monophosphate dehydrogenase (IMPDH), the main regulating enzyme of purine metabolism. However, significant unexplained differences in the efficacy and tolerability of MPA therapy pose a clinical challenge. Therefore, broad pharmacogenetic, pharmacokinetic, and pharmacodynamic approaches are needed to individualize MPA therapy. In this prospective cohort study including 277 renal transplant recipients, IMPDH2 rs11706052 SNP status was assessed by genetic sequencing, and plasma MPA trough levels were determined by HPLC and IMPDH enzyme activity in peripheral blood mononuclear cells (PBMCs) by liquid chromatography–mass spectrometry. Among the 277 patients, 84 were identified with episodes of biopsy-proven rejection (BPR). No association was found between rs11706052 SNP status and graft rejection (OR 1.808, and 95% CI, 0.939 to 3.479; p = 0.076). Furthermore, there was no association between MPA plasma levels and BPR (p = 0.69). However, the patients with graft rejection had a significantly higher predose IMPDH activity in PBMCs compared to the controls without rejection at the time of biopsy (110.1 ± 50.2 vs. 95.2 ± 45.4 pmol/h; p = 0.001), and relative to the baseline IMPDH activity before transplantation (p = 0.042). Our results suggest that individualization of MPA therapy, particularly through pharmacodynamic monitoring of IMPDH activity in PBMCs, has the potential to improve the clinical outcomes of transplant patients.

Funder

Novartis

Publisher

MDPI AG

Subject

General Biochemistry, Genetics and Molecular Biology,Medicine (miscellaneous)

Reference65 articles.

1. A novel variant L263F in human inosine 5’-monophosphate dehydrogenase 2 is associated with diminished enzyme activity;Wang;Pharm. Genom.,2007

2. Mycophenolate mofetil treatment in conditions different from organ transplantation;Quiroz;Transpl. Proc.,2002

3. Tacrolimus and Mycophenolate Mofetil as Second-Line Therapies for Pediatric Patients with Autoimmune Hepatitis;Efe;Dig. Dis. Sci.,2018

4. Mycophenolate mofetil as a successful therapy for idiopathic granulomatous mastitis;Di Xia;Derm. Online J.,2017

5. An inosine 5′-monophosphate dehydrogenase 2 single-nucleotide polymorphism impairs the effect of mycophenolic acid;Winnicki;Pharm. J.,2010

Cited by 3 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3