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

Wolfgang Winnicki; Andreas Fichtenbaum; Goran Mitulovič; Harald Herkner; Florina Regele; Michael Baier; Sieglinde Zelzer; Ludwig Wagner; Guerkan Sengoelge

doi:10.3390/biomedicines10112882

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

Biomedicines. 2022 Nov 10;10(11):2882. doi: 10.3390/biomedicines10112882.

Authors

Wolfgang Winnicki¹, Andreas Fichtenbaum², Goran Mitulovič², Harald Herkner³, Florina Regele¹, Michael Baier¹, Sieglinde Zelzer⁴, Ludwig Wagner¹, Guerkan Sengoelge¹

Affiliations

¹ Department of Medicine III, Division of Nephrology and Dialysis, Medical University of Vienna, 1090 Vienna, Austria.
² Department of Laboratory Medicine, Medical University of Vienna, 1090 Vienna, Austria.
³ Department of Emergency Medicine, Medical University of Vienna, 1090 Vienna, Austria.
⁴ Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, 8036 Graz, Austria.

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.

Keywords: allograft rejection; inosine monophosphate dehydrogenase; kidney transplantation; mycophenolic acid; pharmacodynamics; pharmacogenetics; pharmacokinetics.

Grants and funding

This research did not receive any specific grant from funding agencies in the public or not-for-profit sectors. The authors W.W. and G.S. acknowledge having received financial support from a nonrestricted grant from Novartis during the conduct of the study.