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

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.

Ganodermanontriol Suppresses the Progression of Lung Adenocarcinoma by Activating CES2 to Enhance the Metabolism of Mycophenolate Mofetil

“…In lung cancer cells, the expression of CES2 was increased by GDNT with/without MMF but was not significantly affected in the presence of MMF alone. MPA can target IMPDH which has been confirmed to be highly expressed in many tumors [44,45]. In this study, the results of Western blot revealed that both IMPDH1 and IMPDH2 expressions were down-regulated by MMF in the cells, which was further strengthened by GDNT.…”

Quantitation of Mycophenolic Acid and Mycophenolic Acid Glucuronide in Serum or Plasma by LC‐MS/MS

“…Underdosing can result in organ rejection, and overdosing can result in bone marrow suppression and an increased risk of infections. Therefore, therapeutic drug monitoring for MPA and its major metabolite MPAG is needed (Seyfinejad & Jouyban, 2021; Winnicki et al., 2022).…”

“…All calibrators are stable for 6 months when stored below -5°C. (Ferreira et al, 2020;Winnicki et al, 2022). Due to its superior anti-rejection profile, MPA has primarily replaced azathioprine in organ transplantation (Ferreira et al, 2020;van Gelder et al, 2006).…”

“…At high doses and increased MPA levels, bone marrow suppression and anemia can occur, which may result in a higher risk of infections. This could be a significant problem in patients with renal failure, as MPA and its metabolites can accumulate to significantly high levels (Butch, 2007;Meier-Kriesche et al, 2000;Winnicki et al, 2022).…”