Pharmacodynamic assessment of mycophenolic acid in resting and activated target cell population during the first year after renal transplantation

Abstract

Aims:To explore the pharmacodynamics of mycophenolic acid (MPA) through inosine monophosphate dehydrogenase (IMPDH) capacity measurement and purine levels in peripheral blood mononuclear cells (PBMC) longitudinally during the first year after renal transplantation (TX).Methods: PBMC were isolated from renal recipients 0-4 days prior to and 6-9 days, 5-7 weeks and 1 year after TX (before and 1.5 hours after dose). IMPDH capacity and purine (guanine and adenine) levels were measured in stimulated and nonstimulated PBMC.Results: Twenty-nine patients completed the follow-up period, of whom 24 received MPA. In stimulated PBMC, the IMPDH capacity (pmol 10 −6 cells min −1 ) was median (interquartile range) 127 (95.8-147) before TX and thereafter 44.9 (19.2-93.2) predose and 12.1 (4.64-23.6) 1.5 hours postdose across study days after TX. The corresponding IMPDH capacity in nonstimulated PBMC was 5.71 (3.79-6.93), 3.35(2.31-5.62) and 2.71 (1.38-4.08), respectively. Predose IMPDH capacity in nonstimulated PBMC increased with time, reaching pre-TX values at 1 year. In stimulated PBMC, both purines were reduced before (median 39% reduction across days after TX) and after (69% reduction) dose compared to before TX. No alteration in the purine levels was observed in nonstimulated PBMC. Patients needing dose reductions during the first year had lower pre-dose IMPDH capacity in nonstimulated PBMC (1.87 vs 3.00 pmol 10 −6 cells min −1 , P = .049) at 6-9 days. Conclusion:The inhibitory effect of MPA was stronger in stimulated PBMC. Nonstimulated PBMC became less sensitive to MPA during the first year after TX. Early IMPDH capacity appeared to be predictive of dose reductions.The authors confirm that the Principal Investigator for this paper is Karsten Midtvedt MD PhD and that he had direct clinical responsibility for patients.

Personalized Therapy for Mycophenolate: Consensus Report by the International Association of Therapeutic Drug Monitoring and Clinical Toxicology

“…476,477 However, such an induction is not apparent in circulating mononuclear cells. In PBMCs from kidney and heart transplant recipients, the predose IMPDH activity may be restored 478 or partially restored 479 toward pretransplant activity during the first year on MPA therapy. The timing of sample collection has to be considered in relation to possible cut-off values because of the time-dependent alterations in the underlying IMPDH level.…”

“…273,478 However, a significant decrease 1.5 hours after the MMF dose has been demonstrated when the guanine pool was quantified in ex vivo-activated PBMCs. 478 The activated cells have a considerable need for guanine nucleotides that the salvage pathway cannot fulfill. Therefore, MPA may cause an immediate reduction of guanine nucleotides in immunoactivated lymphocytes.…”

“…Furthermore, measurements of IMPDH activity in PBMCs activated ex vivo did not improve the predictive properties of the biomarker. 478 Also, the longitudinal alteration of predose IMPDH activity in PBMCs has been associated with clinical outcomes. A steeper increasing trend over time for the enzyme activity was observed among long-term KTR experiencing acute rejections.…”

“…The guanine and adenine pool in PBMCs seem to be highly co-regulated in both resting and circulating ex vivo-activated cells also during clinical exposure to MPA. 478 The guanine pool in circulating mononuclear cells is rather stable within the MMF dose interval in liver (CD4 + cells) and kidney (PBMCs) transplant recipients. 273,478 However, a significant decrease 1.5 hours after the MMF dose has been demonstrated when the guanine pool was quantified in ex vivo-activated PBMCs.…”

“…478 The guanine pool in circulating mononuclear cells is rather stable within the MMF dose interval in liver (CD4 + cells) and kidney (PBMCs) transplant recipients. 273,478 However, a significant decrease 1.5 hours after the MMF dose has been demonstrated when the guanine pool was quantified in ex vivo-activated PBMCs. 478 The activated cells have a considerable need for guanine nucleotides that the salvage pathway cannot fulfill.…”