Pharmacodynamic Assessment of Mycophenolic Acidinduced Immunosuppression in Renal Transplant Recipients

Abstract

The combination of pharmacokinetic and pharmacodynamic monitoring of immunosuppressive drugs provides a novel method for the optimization of drug dosing. We chose to investigate this with the use of mycophenolic acid (MPA), an immunosuppressive drug that mediates its effect by the inhibition of inosine monophosphate dehydrogenase (IMPDH), a key enzyme in the de novo biosynthesis of purines. The relationship between MPA concentration in plasma, IMPDH activity in whole blood, and nucleotide concentration in lymphocytes was investigated in renal-transplant recipients, who were randomized to receive either mycophenolate mofetil (MMF) (n = 5) or azathioprine (AZA) (n = 7), in combination with cyclosporine and prednisone. Blood samples were collected throughout the dosing interval. Pharmacokinetic analysis revealed substantial variability among the patients in the absorption and clearance of MPA. An inverse relationship was found between the MPA concentration of IMPDH activity in whole blood. The peak concentration of MPA achieved at 1 hr after dosing resulted in approximately 40% inhibition of IMPDH activity. As the MPA concentration decreased throughout the dosing interval, there was a gradual restoration of IMPDH activity. The inhibition of IMPDH activity (P < 0.05) in MMF-treated patients as compared with the AZA-treated controls was maintained for approximately 8 hr after dosing. No statistically significant (P > 0.05) difference between the predose and the 12 hr postdose activity was observed. The concentrations of guanine nucleotides, GDP and GMP, were significantly lower than in the AZA-treated group at most of the time points after dosing; however, considerable variability was observed. The measurement of the pharmacodynamic response to immunosuppressive drugs may provide not only a mechanism to predict the most appropriate dosing regimen, but also a viable alternative to traditional therapeutic drug monitoring, by assessing the overall state of immunosuppression.

Pharmacodynamic Evaluation of the First Dose of Mycophenolate Mofetil Before Kidney Transplantation

“…In both populations, IMPDH activity inhibition persisted for 4 h, returning to baseline after 11 h and before the next dose (25)(26)(27). Langman et al also found that significant inhibition of IMPDH activity persisted for at least 8 h despite low MPA levels (28). More recently, Vethe et al demonstrated that in kidney allograft recipients, the maximal inhibition of IMPDH activity occurs 1 h after MMF intake (29).…”

Effect of mycophenolic acid on TNFα‐induced expression of cell adhesion molecules in human venous endothelial cells in vitro

“…The concentration-dependence of increased surface expression of adhesion molecules by MPA was similar for both VCAM-1 and E-selectin: an increase was detectable at 0.5 mM, the half-maximal e ective concentration of MPA, which increases the expression of the cell adhesion molecules VCAM-1 and E-selectin on TNFa-activated EC, was estimated to &1 mM, and a plateau was reached at 10 mM (Figure 4). ICAM-1 surface expression remained unchanged, but marked increases of VCAM-1 and E-selectin surface expression were observed at the clinically relevant concentrations of 0.5 ± 10 mM (Langman et al, 1996).…”

Pharmacokinetics and Pharmacodynamics of Mycophenolate in Patients After Renal Transplantation

“…(68). In addition, others report, that IMPDH-activity on peak concentration of MPA is approximately 40% and could be suppressed for 8 hours (69). In general, it is assumed, that IMPDH activity has a substantial interindividual, but low intraindividual variability (70).…”