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

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 cl...

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Autores principales: Winnicki, Wolfgang, Fichtenbaum, Andreas, Mitulovič, Goran, Herkner, Harald, Regele, Florina, Baier, Michael, Zelzer, Sieglinde, Wagner, Ludwig, Sengoelge, Guerkan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9687418/
https://www.ncbi.nlm.nih.gov/pubmed/36359401
http://dx.doi.org/10.3390/biomedicines10112882
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author Winnicki, Wolfgang
Fichtenbaum, Andreas
Mitulovič, Goran
Herkner, Harald
Regele, Florina
Baier, Michael
Zelzer, Sieglinde
Wagner, Ludwig
Sengoelge, Guerkan
author_facet Winnicki, Wolfgang
Fichtenbaum, Andreas
Mitulovič, Goran
Herkner, Harald
Regele, Florina
Baier, Michael
Zelzer, Sieglinde
Wagner, Ludwig
Sengoelge, Guerkan
author_sort Winnicki, Wolfgang
collection PubMed
description 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.
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spelling pubmed-96874182022-11-25 Individualization of Mycophenolic Acid Therapy through Pharmacogenetic, Pharmacokinetic and Pharmacodynamic Testing Winnicki, Wolfgang Fichtenbaum, Andreas Mitulovič, Goran Herkner, Harald Regele, Florina Baier, Michael Zelzer, Sieglinde Wagner, Ludwig Sengoelge, Guerkan Biomedicines Article 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. MDPI 2022-11-10 /pmc/articles/PMC9687418/ /pubmed/36359401 http://dx.doi.org/10.3390/biomedicines10112882 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Winnicki, Wolfgang
Fichtenbaum, Andreas
Mitulovič, Goran
Herkner, Harald
Regele, Florina
Baier, Michael
Zelzer, Sieglinde
Wagner, Ludwig
Sengoelge, Guerkan
Individualization of Mycophenolic Acid Therapy through Pharmacogenetic, Pharmacokinetic and Pharmacodynamic Testing
title Individualization of Mycophenolic Acid Therapy through Pharmacogenetic, Pharmacokinetic and Pharmacodynamic Testing
title_full Individualization of Mycophenolic Acid Therapy through Pharmacogenetic, Pharmacokinetic and Pharmacodynamic Testing
title_fullStr Individualization of Mycophenolic Acid Therapy through Pharmacogenetic, Pharmacokinetic and Pharmacodynamic Testing
title_full_unstemmed Individualization of Mycophenolic Acid Therapy through Pharmacogenetic, Pharmacokinetic and Pharmacodynamic Testing
title_short Individualization of Mycophenolic Acid Therapy through Pharmacogenetic, Pharmacokinetic and Pharmacodynamic Testing
title_sort individualization of mycophenolic acid therapy through pharmacogenetic, pharmacokinetic and pharmacodynamic testing
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9687418/
https://www.ncbi.nlm.nih.gov/pubmed/36359401
http://dx.doi.org/10.3390/biomedicines10112882
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