Abstract: SA-PO632
Identification of Patients with High Probability of Not or Poorly Responding to Mycophenolic Acid Prodrugs
Session Information
- Pharmacology
October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)
- 1700 Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)
Authors
- Winnicki, Wolfgang, Medical University of Vienna , Vienna, Austria
- Sengoelge, Gurkan, Medical University of Vienna , Vienna, Austria
Background
The antiproliferative agent mycophenolic acid (MPA) exerts its immunosuppressive effect by a selective inhibition of inosine 5’-monophosphate dehydrogenase (IMPDH), the rate-limiting enzyme of purine metabolism. The isoenzyme IMPDH2 predominates in activated lymphocytes, and its inhibition by MPA is part of standard immunosuppressive therapy in transplant medicine. Previously, factors which might explain differences in MPA efficacy and tolerability among patients have been studied: polymorphism rs11706052 in the IMPDH2 gene has been identified to reduce the antiproliferative effect of MPA on lymphocytes; data on therapeutic drug monitoring using MPA trough levels and IMPDH activity were not conclusive. Yet, whether a combination of pharmacogenomic, pharmacokinetic and pharmacodynamic factors explain the differences in response to MPA therapy and drug tolerance remains to be elucidated.
Methods
This was designed as a prospective study of kidney transplant patients with and without biopsy-proven rejection (BPR). Both groups were tested for the presence of SNP rs11706052. In addition, MPA trough levels in plasma were measured by high performance liquid chromatography and IMPDH enzyme activity in peripheral blood mononuclear cells was tested by liquid chromatography–mass spectrometry. Correlations between BPR and the presence of rs11706052, MPA trough levels, IMPDH activity as well as the IMPDH/MPA ratio (assuming that a higher IMPDH activity requires higher MPA trough levels for an adequate immunosuppressive effect) were examined.
Results
Preliminary results from 50 kidney transplant recipients with biopsy-proven rejection and 100 controls without rejection suggest 1.) IMPDH activity was significantly higher in patients with BPR compared to patients with a stable graft function over 12 months with no immunological complications, 2.) no correlation between IMPDH activity and MPA levels, BPR and the IMPDH/MPA ratio, 3.) no influence of rs11706052.
Conclusion
This is the clinical extension of our previous in vitro study, which has shown that the polymorphism rs11706052 reduces the immunosuppressive effect of MPA. This prospective study investigates the susceptibility to reject kidney allografts using a combined pharmacogenomic, pharmacokinetic and pharmacodynamic approach.