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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| Format: | Article |
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MDPI AG
2022-11-01
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| Online Access: | https://www.mdpi.com/2227-9059/10/11/2882 |
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| author | Wolfgang Winnicki Andreas Fichtenbaum Goran Mitulovič Harald Herkner Florina Regele Michael Baier Sieglinde Zelzer Ludwig Wagner Guerkan Sengoelge |
| author_facet | Wolfgang Winnicki Andreas Fichtenbaum Goran Mitulovič Harald Herkner Florina Regele Michael Baier Sieglinde Zelzer Ludwig Wagner Guerkan Sengoelge |
| author_sort | Wolfgang Winnicki |
| collection | DOAJ |
| 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; <i>p</i> = 0.076). Furthermore, there was no association between MPA plasma levels and BPR (<i>p</i> = 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; <i>p</i> = 0.001), and relative to the baseline IMPDH activity before transplantation (<i>p</i> = 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. |
| first_indexed | 2024-03-09T19:14:50Z |
| format | Article |
| id | doaj.art-10ccdd199bc84f50821c50f819b5ee59 |
| institution | Directory Open Access Journal |
| issn | 2227-9059 |
| language | English |
| last_indexed | 2024-03-09T19:14:50Z |
| publishDate | 2022-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomedicines |
| spelling | doaj.art-10ccdd199bc84f50821c50f819b5ee592023-11-24T03:52:13ZengMDPI AGBiomedicines2227-90592022-11-011011288210.3390/biomedicines10112882Individualization of Mycophenolic Acid Therapy through Pharmacogenetic, Pharmacokinetic and Pharmacodynamic TestingWolfgang Winnicki0Andreas Fichtenbaum1Goran Mitulovič2Harald Herkner3Florina Regele4Michael Baier5Sieglinde Zelzer6Ludwig Wagner7Guerkan Sengoelge8Department of Medicine III, Division of Nephrology and Dialysis, Medical University of Vienna, 1090 Vienna, AustriaDepartment of Laboratory Medicine, Medical University of Vienna, 1090 Vienna, AustriaDepartment of Laboratory Medicine, Medical University of Vienna, 1090 Vienna, AustriaDepartment of Emergency Medicine, Medical University of Vienna, 1090 Vienna, AustriaDepartment of Medicine III, Division of Nephrology and Dialysis, Medical University of Vienna, 1090 Vienna, AustriaDepartment of Medicine III, Division of Nephrology and Dialysis, Medical University of Vienna, 1090 Vienna, AustriaClinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, 8036 Graz, AustriaDepartment of Medicine III, Division of Nephrology and Dialysis, Medical University of Vienna, 1090 Vienna, AustriaDepartment of Medicine III, Division of Nephrology and Dialysis, Medical University of Vienna, 1090 Vienna, AustriaMycophenolic 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; <i>p</i> = 0.076). Furthermore, there was no association between MPA plasma levels and BPR (<i>p</i> = 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; <i>p</i> = 0.001), and relative to the baseline IMPDH activity before transplantation (<i>p</i> = 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.https://www.mdpi.com/2227-9059/10/11/2882inosine monophosphate dehydrogenasemycophenolic acidkidney transplantationallograft rejectionpharmacogeneticspharmacokinetics |
| spellingShingle | Wolfgang Winnicki Andreas Fichtenbaum Goran Mitulovič Harald Herkner Florina Regele Michael Baier Sieglinde Zelzer Ludwig Wagner Guerkan Sengoelge Individualization of Mycophenolic Acid Therapy through Pharmacogenetic, Pharmacokinetic and Pharmacodynamic Testing Biomedicines inosine monophosphate dehydrogenase mycophenolic acid kidney transplantation allograft rejection pharmacogenetics pharmacokinetics |
| 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 | inosine monophosphate dehydrogenase mycophenolic acid kidney transplantation allograft rejection pharmacogenetics pharmacokinetics |
| url | https://www.mdpi.com/2227-9059/10/11/2882 |
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